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Enzyme

Enzymes are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. Almost all metabolic processes in the cell need enzyme catalysis in order to occur at rates fast enough to sustain life. Metabolic pathways depend upon enzymes to catalyze individual steps. The study of enzymes is called enzymology and the field of pseudoenzyme analysis recognizes that during evolution, some enzymes have lost the ability to carry out biological catalysis, which is often reflected in their amino acid sequences and unusual 'pseudocatalytic' properties.

Enzymes are known to catalyze more than 5,000 biochemical reaction types.

Other biocatalysts are catalytic RNA molecules, also called ribozymes. They are sometimes described as a type of enzyme rather than being like an enzyme, but even in the decades since ribozymes' discovery in 1980-1982, the word enzyme alone often means the protein type specifically (as is used in this article).

An enzyme's specificity comes from its unique three-dimensional structure.

Like all catalysts, enzymes increase the reaction rate by lowering its activation energy. Some enzymes can make their conversion of substrate to product occur many millions of times faster. An extreme example is orotidine 5'-phosphate decarboxylase, which allows a reaction that would otherwise take millions of years to occur in milliseconds. Chemically, enzymes are like any catalyst and are not consumed in chemical reactions, nor do they alter the equilibrium of a reaction. Enzymes differ from most other catalysts by being much more specific. Enzyme activity can be affected by other molecules: inhibitors are molecules that decrease enzyme activity, and activators are molecules that increase activity. Many therapeutic drugs and poisons are enzyme inhibitors. An enzyme's activity decreases markedly outside its optimal temperature and pH, and many enzymes are (permanently) denatured when exposed to excessive heat, losing their structure and catalytic properties.

Some enzymes are used commercially, for example, in the synthesis of antibiotics. Some household products use enzymes to speed up chemical reactions: enzymes in biological washing powders break down protein, starch or fat stains on clothes, and enzymes in meat tenderizer break down proteins into smaller molecules, making the meat easier to chew.

Etymology and history

By the late 17th and early 18th centuries, the digestion of meat by stomach secretions and the conversion of starch to sugars by plant extracts and saliva were known but the mechanisms by which these occurred had not been identified.

French chemist Anselme Payen was the first to discover an enzyme, diastase, in 1833. A few decades later, when studying the fermentation of sugar to alcohol by yeast, Louis Pasteur concluded that this fermentation was caused by a vital force contained within the yeast cells called "ferments", which were thought to function only within living organisms. He wrote that "alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells."

In 1877, German physiologist Wilhelm Kühne (1837–1900) first used the term enzyme, which comes, to describe this process. The word enzyme was used later to refer to nonliving substances such as pepsin, and the word ferment was used to refer to chemical activity produced by living organisms.

Eduard Buchner submitted his first paper on the study of yeast extracts in 1897. In a series of experiments at the University of Berlin, he found that sugar was fermented by yeast extracts even when there were no living yeast cells in the mixture. He named the enzyme that brought about the fermentation of sucrose "zymase". In 1907, he received the Nobel Prize in Chemistry for "his discovery of cell-free fermentation". Following Buchner's example, enzymes are usually named according to the reaction they carry out: the suffix -ase is combined with the name of the substrate (e.g., lactase is the enzyme that cleaves lactose) or to the type of reaction (e.g., DNA polymerase forms DNA polymers).

The biochemical identity of enzymes was still unknown in the early 1900s. Many scientists observed that enzymatic activity was associated with proteins, but others (such as Nobel laureate Richard Willstätter) argued that proteins were merely carriers for the true enzymes and that proteins per se were incapable of catalysis. In 1926, James B. Sumner showed that the enzyme urease was a pure protein and crystallized it; he did likewise for the enzyme catalase in 1937. The conclusion that pure proteins can be enzymes was definitively demonstrated by John Howard Northrop and Wendell Meredith Stanley, who worked on the digestive enzymes pepsin (1930), trypsin and chymotrypsin. These three scientists were awarded the 1946 Nobel Prize in Chemistry.

The discovery that enzymes could be crystallized eventually allowed their structures to be solved by x-ray crystallography. This was first done for lysozyme, an enzyme found in tears, saliva and egg whites that digests the coating of some bacteria; the structure was solved by a group led by David Chilton Phillips and published in 1965. This high-resolution structure of lysozyme marked the beginning of the field of structural biology and the effort to understand how enzymes work at an atomic level of detail.

Classification and nomenclature
Enzymes can be classified by two main criteria: either amino acid sequence similarity (and thus evolutionary relationship) or enzymatic activity.

Enzyme activity. An enzyme's name is often derived from its substrate or the chemical reaction it catalyzes, with the word ending in -ase. Examples are lactase, alcohol dehydrogenase and DNA polymerase. Different enzymes that catalyze the same chemical reaction are called isozymes.

The International Union of Biochemistry and Molecular Biology have developed a nomenclature for enzymes, the EC numbers (for "Enzyme Commission"). Each enzyme is described by "EC" followed by a sequence of four numbers which represent the hierarchy of enzymatic activity (from very general to very specific). That is, the first number broadly classifies the enzyme based on its mechanism while the other digits add more and more specificity.

The top-level classification is:
 * EC 1, Oxidoreductases: catalyze oxidation/reduction reactions
 * EC 2, Transferases: transfer a functional group (e.g. a methyl or phosphate group)
 * EC 3, Hydrolases: catalyze the hydrolysis of various bonds
 * EC 4, Lyases: cleave various bonds by means other than hydrolysis and oxidation
 * EC 5, Isomerases: catalyze isomerization changes within a single molecule
 * EC 6, Ligases: join two molecules with covalent bonds.
 * EC 7, Translocases: catalyze the movement of ions or molecules across membranes, or their separation within membranes.

These sections are subdivided by other features such as the substrate, products, and chemical mechanism. An enzyme is fully specified by four numerical designations. For example, hexokinase (EC 2.7.1.1) is a transferase (EC 2) that adds a phosphate group (EC 2.7) to a hexose sugar, a molecule containing an alcohol group (EC 2.7.1).

Sequence similarity. EC categories do not reflect sequence similarity. For instance, two ligases of the same EC number that catalyze exactly the same reaction can have completely different sequences. Independent of their function, enzymes, like any other proteins, have been classified by their sequence similarity into numerous families. These families have been documented in dozens of different protein and protein family databases such as Pfam.

Non-homologous isofunctional enzymes. Unrelated enzymes that have the same enzymatic activity have been called non-homologous isofunctional enzymes. Horizontal gene transfer may spread these genes to unrelated species, especially bacteria where they can replace endogenous genes of the same function, leading to hon-homologous gene displacement.

Structure

Enzymes are generally globular proteins, acting alone or in larger complexes. The sequence of the amino acids specifies the structure which in turn determines the catalytic activity of the enzyme. Although structure determines function, a novel enzymatic activity cannot yet be predicted from structure alone. Enzyme structures unfold (denature) when heated or exposed to chemical denaturants and this disruption to the structure typically causes a loss of activity. Enzyme denaturation is normally linked to temperatures above a species' normal level; as a result, enzymes from bacteria living in volcanic environments such as hot springs are prized by industrial users for their ability to function at high temperatures, allowing enzyme-catalysed reactions to be operated at a very high rate.

Enzymes are usually much larger than their substrates. Sizes range from just 62 amino acid residues, for the monomer of 4-oxalocrotonate tautomerase, to over 2,500 residues in the animal fatty acid synthase. Only a small portion of their structure (around 2–4 amino acids) is directly involved in catalysis: the catalytic site. This catalytic site is located next to one or more binding sites where residues orient the substrates. The catalytic site and binding site together compose the enzyme's active site. The remaining majority of the enzyme structure serves to maintain the precise orientation and dynamics of the active site.

In some enzymes, no amino acids are directly involved in catalysis; instead, the enzyme contains sites to bind and orient catalytic cofactors. Enzyme structures may also contain allosteric sites where the binding of a small molecule causes a conformational change that increases or decreases activity.

A small number of RNA-based biological catalysts called ribozymes exist, which again can act alone or in complex with proteins. The most common of these is the ribosome which is a complex of protein and catalytic RNA components.

Substrate binding
Enzymes must bind their substrates before they can catalyse any chemical reaction. Enzymes are usually very specific as to what substrates they bind and then the chemical reaction catalysed. Specificity is achieved by binding pockets with complementary shape, charge and hydrophilic/hydrophobic characteristics to the substrates. Enzymes can therefore distinguish between very similar substrate molecules to be chemoselective, regioselective and stereospecific.

Some of the enzymes showing the highest specificity and accuracy are involved in the copying and expression of the genome. Some of these enzymes have "proof-reading" mechanisms. Here, an enzyme such as DNA polymerase catalyzes a reaction in a first step and then checks that the product is correct in a second step. This two-step process results in average error rates of less than 1 error in 100 million reactions in high-fidelity mammalian polymerases. Similar proofreading mechanisms are also found in RNA polymerase, aminoacyl tRNA synthetases and ribosomes.

Conversely, some enzymes display enzyme promiscuity, having broad specificity and acting on a range of different physiologically relevant substrates. Many enzymes possess small side activities which arose fortuitously (i.e. neutrally), which may be the starting point for the evolutionary selection of a new function.

"Lock and key" model
To explain the observed specificity of enzymes, in 1894 Emil Fischer proposed that both the enzyme and the substrate possess specific complementary geometric shapes that fit exactly into one another. This is often referred to as "the lock and key" model. This early model explains enzyme specificity, but fails to explain the stabilization of the transition state that enzymes achieve.

Induced fit model
In 1958, Daniel Koshland suggested a modification to the lock and key model: since enzymes are rather flexible structures, the active site is continuously reshaped by interactions with the substrate as the substrate interacts with the enzyme. As a result, the substrate does not simply bind to a rigid active site; the amino acid side-chains that make up the active site are molded into the precise positions that enable the enzyme to perform its catalytic function. In some cases, such as glycosidases, the substrate molecule also changes shape slightly as it enters the active site. The active site continues to change until the substrate is completely bound, at which point the final shape and charge distribution is determined. Induced fit may enhance the fidelity of molecular recognition in the presence of competition and noise via the conformational proofreading mechanism.

Catalysis
Enzymes can accelerate reactions in several ways, all of which lower the activation energy (ΔG‡, Gibbs free energy) Enzymes may use several of these mechanisms simultaneously. For example, proteases such as trypsin perform covalent catalysis using a catalytic triad, stabilize charge build-up on the transition states using an oxyanion hole, complete hydrolysis using an oriented water substrate.
 * 1) By stabilizing the transition state:
 * 2) * Creating an environment with a charge distribution complementary to that of the transition state to lower its energy
 * 3) By providing an alternative reaction pathway:
 * 4) * Temporarily reacting with the substrate, forming a covalent intermediate to provide a lower energy transition state
 * 5) By destabilizing the substrate ground state:
 * 6) * Distorting bound substrate(s) into their transition state form to reduce the energy required to reach the transition state
 * 7) * By orienting the substrates into a productive arrangement to reduce the reaction entropy change (the contribution of this mechanism to catalysis is relatively small)

Dynamics
Enzymes are not rigid, static structures; instead they have complex internal dynamic motions – that is, movements of parts of the enzyme's structure such as individual amino acid residues, groups of residues forming a protein loop or unit of secondary structure, or even an entire protein domain. These motions give rise to a conformational ensemble of slightly different structures that interconvert with one another at equilibrium. Different states within this ensemble may be associated with different aspects of an enzyme's function. For example, different conformations of the enzyme dihydrofolate reductase are associated with the substrate binding, catalysis, cofactor release, and product release steps of the catalytic cycle, consistent with catalytic resonance theory.

Substrate presentation
Substrate presentation is a process where the enzyme is sequestered away from its substrate. Enzymes can be sequestered to the plasma membrane away from a substrate in the nucleus or cytosol. Or within the membrane, an enzyme can be sequestered into lipid rafts away from its substrate in the disordered region. When the enzyme is released it mixes with its substrate. Alternatively, the enzyme can be sequestered near its substrate to activate the enzyme. For example, the enzyme can be soluble and upon activation bind to a lipid in the plasma membrane and then act upon molecules in the plasma membrane.

Allosteric modulation
Allosteric sites are pockets on the enzyme, distinct from the active site, that bind to molecules in the cellular environment. These molecules then cause a change in the conformation or dynamics of the enzyme that is transduced to the active site and thus affects the reaction rate of the enzyme. In this way, allosteric interactions can either inhibit or activate enzymes. Allosteric interactions with metabolites upstream or downstream in an enzyme's metabolic pathway cause feedback regulation, altering the activity of the enzyme according to the flux through the rest of the pathway.

Cofactors

Some enzymes do not need additional components to show full activity. Others require non-protein molecules called cofactors to be bound for activity. Cofactors can be either inorganic (e.g., metal ions and iron–sulfur clusters) or organic compounds (e.g., flavin and heme). These cofactors serve many purposes; for instance, metal ions can help in stabilizing nucleophilic species within the active site. Organic cofactors can be either coenzymes, which are released from the enzyme's active site during the reaction, or prosthetic groups, which are tightly bound to an enzyme. Organic prosthetic groups can be covalently bound (e.g., biotin in enzymes such as pyruvate carboxylase).

An example of an enzyme that contains a cofactor is carbonic anhydrase, which uses a zinc cofactor bound as part of its active site. These tightly bound ions or molecules are usually found in the active site and are involved in catalysis. For example, flavin and heme cofactors are often involved in redox reactions.

Enzymes that require a cofactor but do not have one bound are called apoenzymes or apoproteins. An enzyme together with the cofactor(s) required for activity is called a holoenzyme (or haloenzyme). The term holoenzyme can also be applied to enzymes that contain multiple protein subunits, such as the DNA polymerases; here the holoenzyme is the complete complex containing all the subunits needed for activity.

Coenzymes
Coenzymes are small organic molecules that can be loosely or tightly bound to an enzyme. Coenzymes transport chemical groups from one enzyme to another. Examples include NADH, NADPH and adenosine triphosphate (ATP). Some coenzymes, such as flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), thiamine pyrophosphate (TPP), and tetrahydrofolate (THF), are derived from vitamins. These coenzymes cannot be synthesized by the body de novo and closely related compounds (vitamins) must be acquired from the diet. The chemical groups carried include: Since coenzymes are chemically changed as a consequence of enzyme action, it is useful to consider coenzymes to be a special class of substrates, or second substrates, which are common to many different enzymes. For example, about 1000 enzymes are known to use the coenzyme NADH.
 * the hydride ion (H−), carried by NAD or NADP+
 * the phosphate group, carried by adenosine triphosphate
 * the acetyl group, carried by coenzyme A
 * formyl, methenyl or methyl groups, carried by folic acid and
 * the methyl group, carried by S-adenosylmethionine

Coenzymes are usually continuously regenerated and their concentrations maintained at a steady level inside the cell. For example, NADPH is regenerated through the pentose phosphate pathway and S-adenosylmethionine by methionine adenosyltransferase. This continuous regeneration means that small amounts of coenzymes can be used very intensively. For example, the human body turns over its own weight in ATP each day.

Thermodynamics

As with all catalysts, enzymes do not alter the position of the chemical equilibrium of the reaction. In the presence of an enzyme, the reaction runs in the same direction as it would without the enzyme, just more quickly. For example, carbonic anhydrase catalyzes its reaction in either direction depending on the concentration of its reactants:

The rate of a reaction is dependent on the activation energy needed to form the transition state which then decays into products. Enzymes increase reaction rates by lowering the energy of the transition state. First, binding forms a low energy enzyme-substrate complex (ES). Second, the enzyme stabilises the transition state such that it requires less energy to achieve compared to the uncatalyzed reaction (ES‡). Finally the enzyme-product complex (EP) dissociates to release the products.

Enzymes can couple two or more reactions, so that a thermodynamically favorable reaction can be used to "drive" a thermodynamically unfavourable one so that the combined energy of the products is lower than the substrates. For example, the hydrolysis of ATP is often used to drive other chemical reactions.

Kinetics
Enzyme kinetics is the investigation of how enzymes bind substrates and turn them into products. The rate data used in kinetic analyses are commonly obtained from enzyme assays. In 1913 Leonor Michaelis and Maud Leonora Menten proposed a quantitative theory of enzyme kinetics, which is referred to as Michaelis–Menten kinetics. The major contribution of Michaelis and Menten was to think of enzyme reactions in two stages. In the first, the substrate binds reversibly to the enzyme, forming the enzyme-substrate complex. This is sometimes called the Michaelis–Menten complex in their honor. The enzyme then catalyzes the chemical step in the reaction and releases the product. This work was further developed by G. E. Briggs and J. B. S. Haldane, who derived kinetic equations that are still widely used today.

Enzyme rates depend on solution conditions and substrate concentration. To find the maximum speed of an enzymatic reaction, the substrate concentration is increased until a constant rate of product formation is seen. This is shown in the saturation curve on the right. Saturation happens because, as substrate concentration increases, more and more of the free enzyme is converted into the substrate-bound ES complex. At the maximum reaction rate (Vmax) of the enzyme, all the enzyme active sites are bound to substrate, and the amount of ES complex is the same as the total amount of enzyme.

Vmax is only one of several important kinetic parameters. The amount of substrate needed to achieve a given rate of reaction is also important. This is given by the Michaelis–Menten constant (Km), which is the substrate concentration required for an enzyme to reach one-half its maximum reaction rate; generally, each enzyme has a characteristic KM for a given substrate. Another useful constant is kcat, also called the turnover number, which is the number of substrate molecules handled by one active site per second.

The efficiency of an enzyme can be expressed in terms of kcat/Km. This is also called the specificity constant and incorporates the rate constants for all steps in the reaction up to and including the first irreversible step. Because the specificity constant reflects both affinity and catalytic ability, it is useful for comparing different enzymes against each other, or the same enzyme with different substrates. The theoretical maximum for the specificity constant is called the diffusion limit and is about 108 to 109 (M−1 s−1). At this point every collision of the enzyme with its substrate will result in catalysis, and the rate of product formation is not limited by the reaction rate but by the diffusion rate. Enzymes with this property are called catalytically perfect or kinetically perfect. Example of such enzymes are triose-phosphate isomerase, carbonic anhydrase, acetylcholinesterase, catalase, fumarase, β-lactamase, and superoxide dismutase. The turnover of such enzymes can reach several million reactions per second. But most enzymes are far from perfect: the average values of $$k_{\rm cat}/K_{\rm m}$$ and $$k_{\rm cat}$$ are about $$ 10^5 {\rm s}^{-1}{\rm M}^{-1}$$ and $$10 {\rm s}^{-1}$$, respectively.

Michaelis–Menten kinetics relies on the law of mass action, which is derived from the assumptions of free diffusion and thermodynamically driven random collision. Many biochemical or cellular processes deviate significantly from these conditions, because of macromolecular crowding and constrained molecular movement. More recent, complex extensions of the model attempt to correct for these effects.

Inhibition
Enzyme reaction rates can be decreased by various types of enzyme inhibitors.

Competitive
A competitive inhibitor and substrate cannot bind to the enzyme at the same time. Often competitive inhibitors strongly resemble the real substrate of the enzyme. For example, the drug methotrexate is a competitive inhibitor of the enzyme dihydrofolate reductase, which catalyzes the reduction of dihydrofolate to tetrahydrofolate. The similarity between the structures of dihydrofolate and this drug are shown in the accompanying figure. This type of inhibition can be overcome with high substrate concentration. In some cases, the inhibitor can bind to a site other than the binding-site of the usual substrate and exert an allosteric effect to change the shape of the usual binding-site.

Non-competitive
A non-competitive inhibitor binds to a site other than where the substrate binds. The substrate still binds with its usual affinity and hence Km remains the same. However the inhibitor reduces the catalytic efficiency of the enzyme so that Vmax is reduced. In contrast to competitive inhibition, non-competitive inhibition cannot be overcome with high substrate concentration.

Uncompetitive
An uncompetitive inhibitor cannot bind to the free enzyme, only to the enzyme-substrate complex; hence, these types of inhibitors are most effective at high substrate concentration. In the presence of the inhibitor, the enzyme-substrate complex is inactive. This type of inhibition is rare.

Mixed
A mixed inhibitor binds to an allosteric site and the binding of the substrate and the inhibitor affect each other. The enzyme's function is reduced but not eliminated when bound to the inhibitor. This type of inhibitor does not follow the Michaelis–Menten equation.

Irreversible
An irreversible inhibitor permanently inactivates the enzyme, usually by forming a covalent bond to the protein. Penicillin and aspirin are common drugs that act in this manner.

Functions of inhibitors
In many organisms, inhibitors may act as part of a feedback mechanism. If an enzyme produces too much of one substance in the organism, that substance may act as an inhibitor for the enzyme at the beginning of the pathway that produces it, causing production of the substance to slow down or stop when there is sufficient amount. This is a form of negative feedback. Major metabolic pathways such as the citric acid cycle make use of this mechanism.

Since inhibitors modulate the function of enzymes they are often used as drugs. Many such drugs are reversible competitive inhibitors that resemble the enzyme's native substrate, similar to methotrexate above; other well-known examples include statins used to treat high cholesterol, and protease inhibitors used to treat retroviral infections such as HIV. A common example of an irreversible inhibitor that is used as a drug is aspirin, which inhibits the COX-1 and COX-2 enzymes that produce the inflammation messenger prostaglandin. Other enzyme inhibitors are poisons. For example, the poison cyanide is an irreversible enzyme inhibitor that combines with the copper and iron in the active site of the enzyme cytochrome c oxidase and blocks cellular respiration.

Factors affecting enzyme activity
As enzymes are made up of proteins, their actions are sensitive to change in many physio chemical factors such as pH, temperature, substrate concentration, etc.

The following table shows pH optima for various enzymes.

Biological function
Enzymes serve a wide variety of functions inside living organisms. They are indispensable for signal transduction and cell regulation, often via kinases and phosphatases. They also generate movement, with myosin hydrolyzing adenosine triphosphate (ATP) to generate muscle contraction, and also transport cargo around the cell as part of the cytoskeleton. Other ATPases in the cell membrane are ion pumps involved in active transport. Enzymes are also involved in more exotic functions, such as luciferase generating light in fireflies. Viruses can also contain enzymes for infecting cells, such as the HIV integrase and reverse transcriptase, or for viral release from cells, like the influenza virus neuraminidase.

An important function of enzymes is in the digestive systems of animals. Enzymes such as amylases and proteases break down large molecules (starch or proteins, respectively) into smaller ones, so they can be absorbed by the intestines. Starch molecules, for example, are too large to be absorbed from the intestine, but enzymes hydrolyze the starch chains into smaller molecules such as maltose and eventually glucose, which can then be absorbed. Different enzymes digest different food substances. In ruminants, which have herbivorous diets, microorganisms in the gut produce another enzyme, cellulase, to break down the cellulose cell walls of plant fiber.

Metabolism

Several enzymes can work together in a specific order, creating metabolic pathways. In a metabolic pathway, one enzyme takes the product of another enzyme as a substrate. After the catalytic reaction, the product is then passed on to another enzyme. Sometimes more than one enzyme can catalyze the same reaction in parallel; this can allow more complex regulation: with, for example, a low constant activity provided by one enzyme but an inducible high activity from a second enzyme.

Enzymes determine what steps occur in these pathways. Without enzymes, metabolism would neither progress through the same steps and could not be regulated to serve the needs of the cell. Most central metabolic pathways are regulated at a few key steps, typically through enzymes whose activity involves the hydrolysis of ATP. Because this reaction releases so much energy, other reactions that are thermodynamically unfavorable can be coupled to ATP hydrolysis, driving the overall series of linked metabolic reactions.

Control of activity
There are five main ways that enzyme activity is controlled in the cell.

Regulation
Enzymes can be either activated or inhibited by other molecules. For example, the end product(s) of a metabolic pathway are often inhibitors for one of the first enzymes of the pathway (usually the first irreversible step, called committed step), thus regulating the amount of end product made by the pathways. Such a regulatory mechanism is called a negative feedback mechanism, because the amount of the end product produced is regulated by its own concentration. Negative feedback mechanism can effectively adjust the rate of synthesis of intermediate metabolites according to the demands of the cells. This helps with effective allocations of materials and energy economy, and it prevents the excess manufacture of end products. Like other homeostatic devices, the control of enzymatic action helps to maintain a stable internal environment in living organisms.

Post-translational modification
Examples of post-translational modification include phosphorylation, myristoylation and glycosylation. For example, in the response to insulin, the phosphorylation of multiple enzymes, including glycogen synthase, helps control the synthesis or degradation of glycogen and allows the cell to respond to changes in blood sugar. Another example of post-translational modification is the cleavage of the polypeptide chain. Chymotrypsin, a digestive protease, is produced in inactive form as chymotrypsinogen in the pancreas and transported in this form to the stomach where it is activated. This stops the enzyme from digesting the pancreas or other tissues before it enters the gut. This type of inactive precursor to an enzyme is known as a zymogen or proenzyme.

Quantity
Enzyme production (transcription and translation of enzyme genes) can be enhanced or diminished by a cell in response to changes in the cell's environment. This form of gene regulation is called enzyme induction. For example, bacteria may become resistant to antibiotics such as penicillin because enzymes called beta-lactamases are induced that hydrolyse the crucial beta-lactam ring within the penicillin molecule. Another example comes from enzymes in the liver called cytochrome P450 oxidases, which are important in drug metabolism. Induction or inhibition of these enzymes can cause drug interactions. Enzyme levels can also be regulated by changing the rate of enzyme degradation. The opposite of enzyme induction is enzyme repression.

Subcellular distribution
Enzymes can be compartmentalized, with different metabolic pathways occurring in different cellular compartments. For example, fatty acids are synthesized by one set of enzymes in the cytosol, endoplasmic reticulum and Golgi and used by a different set of enzymes as a source of energy in the mitochondrion, through β-oxidation. In addition, trafficking of the enzyme to different compartments may change the degree of protonation (e.g., the neutral cytoplasm and the acidic lysosome) or oxidative state (e.g., oxidizing periplasm or reducing cytoplasm) which in turn affects enzyme activity. In contrast to partitioning into membrane bound organelles, enzyme subcellular localisation may also be altered through polymerisation of enzymes into macromolecular cytoplasmic filaments.

Organ specialization
In multicellular eukaryotes, cells in different organs and tissues have different patterns of gene expression and therefore have different sets of enzymes (known as isozymes) available for metabolic reactions. This provides a mechanism for regulating the overall metabolism of the organism. For example, hexokinase, the first enzyme in the glycolysis pathway, has a specialized form called glucokinase expressed in the liver and pancreas that has a lower affinity for glucose yet is more sensitive to glucose concentration. This enzyme is involved in sensing blood sugar and regulating insulin production.

Involvement in disease

Since the tight control of enzyme activity is essential for homeostasis, any malfunction (mutation, overproduction, underproduction or deletion) of a single critical enzyme can lead to a genetic disease. The malfunction of just one type of enzyme out of the thousands of types present in the human body can be fatal. An example of a fatal genetic disease due to enzyme insufficiency is Tay–Sachs disease, in which patients lack the enzyme hexosaminidase.

One example of enzyme deficiency is the most common type of phenylketonuria. Many different single amino acid mutations in the enzyme phenylalanine hydroxylase, which catalyzes the first step in the degradation of phenylalanine, result in build-up of phenylalanine and related products. Some mutations are in the active site, directly disrupting binding and catalysis, but many are far from the active site and reduce activity by destabilising the protein structure, or affecting correct oligomerisation. This can lead to intellectual disability if the disease is untreated. Another example is pseudocholinesterase deficiency, in which the body's ability to break down choline ester drugs is impaired. Oral administration of enzymes can be used to treat some functional enzyme deficiencies, such as pancreatic insufficiency and lactose intolerance.

Another way enzyme malfunctions can cause disease comes from germline mutations in genes coding for DNA repair enzymes. Defects in these enzymes cause cancer because cells are less able to repair mutations in their genomes. This causes a slow accumulation of mutations and results in the development of cancers. An example of such a hereditary cancer syndrome is xeroderma pigmentosum, which causes the development of skin cancers in response to even minimal exposure to ultraviolet light.

Evolution
Similar to any other protein, enzymes change over time through mutations and sequence divergence. Given their central role in metabolism, enzyme evolution plays a critical role in adaptation. A key question is therefore whether and how enzymes can change their enzymatic activities alongside. It is generally accepted that many new enzyme activities have evolved through gene duplication and mutation of the duplicate copies although evolution can also happen without duplication. One example of an enzyme that has changed its activity is the ancestor of methionyl aminopeptidase (MAP) and creatine amidinohydrolase (creatinase) which are clearly homologous but catalyze very different reactions (MAP removes the amino-terminal methionine in new proteins while creatinase hydrolyses creatine to sarcosine and urea). In addition, MAP is metal-ion dependent while creatinase is not, hence this property was also lost over time. Small changes of enzymatic activity are extremely common among enzymes. In particular, substrate binding specificity (see above) can easily and quickly change with single amino acid changes in their substrate binding pockets. This is frequently seen in the main enzyme classes such as kinases.

Artificial (in vitro) evolution is now commonly used to modify enzyme activity or specificity for industrial applications (see below).

Industrial applications
Enzymes are used in the chemical industry and other industrial applications when extremely specific catalysts are required. Enzymes in general are limited in the number of reactions they have evolved to catalyze and also by their lack of stability in organic solvents and at high temperatures. As a consequence, protein engineering is an active area of research and involves attempts to create new enzymes with novel properties, either through rational design or in vitro evolution. These efforts have begun to be successful, and a few enzymes have now been designed "from scratch" to catalyze reactions that do not occur in nature.

Enzyme databases

 * BRENDA
 * ExPASy
 * IntEnz
 * KEGG
 * MetaCyc

title: Enzyme


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Ethics

Ethics is the philosophical study of moral phenomena. Also called moral philosophy, it investigates normative questions about what people ought to do or which behavior is morally right. The main branches of ethics include normative ethics, applied ethics, and metaethics.

Normative ethics aims to find general principles that govern how people should act. According to consequentialists, an act is right if it leads to the best consequences. Deontologists say morality consists in fulfilling duties, like telling the truth and keeping promises. Virtue ethics sees the manifestation of virtues, like courage and compassion, as the fundamental principle of morality. Applied ethics examines concrete ethical problems in real-life situations, such as abortion, treatment of animals, and business practices. Metaethics examines the underlying assumptions and concepts of ethics. It asks whether there are objective moral facts, how moral knowledge is possible, and how moral judgments motivate people.

Ethics is closely connected to value theory, which studies the nature and types of value, like the contrast between intrinsic and instrumental value. Moral psychology is a related empirical field and investigates psychological processes involved in morality, such as reasoning and the formation of character. Descriptive ethics describes the dominant moral codes and beliefs in different societies and considers their historical dimension.

The history of ethics started in the ancient period with the development of ethical principles and theories in ancient Egypt, India, China, and Greece. This period saw the emergence of ethical teachings associated with Hinduism, Buddhism, Confucianism, Daoism, and contributions of philosophers like Socrates and Aristotle. During the medieval period, ethical thought was strongly influenced by religious teachings. In the modern period, this focus shifted to a more secular approach concerned with moral experience, reasons for acting, and the consequences of actions. An influential development in the 20th century was the emergence of metaethics.

Definition

Ethics, also called moral philosophy, is the study of moral phenomena. It is one of the main branches of philosophy and investigates the nature of morality and the principles that govern the moral evaluation of conduct, character traits, and institutions. It examines what obligations people have, what behavior is right and wrong, and how to lead a good life. Some of its key questions are "How should one live?" and "What gives meaning to life?". In contemporary philosophy, ethics is usually divided into normative ethics, applied ethics, and metaethics.

Morality is about what people ought to do rather than what they actually do, what they want to do, or what social conventions require. As a rational and systematic field of inquiry, ethics studies practical reasons why people should act one way rather than another. Most ethical theories seek universal principles that express a general standpoint of what is objectively right and wrong. In a slightly different sense, the term "ethics" can also refer to individual ethical theories in the form of a rational system of moral principles, such as Aristotelian ethics, and to a moral code that certain societies, social groups, or professions follow, as in Protestant work ethic and medical ethics.

The English word ethics has its roots in the Ancient Greek word êthos (ἦθος), meaning "character, personal disposition". This word gave rise to the Ancient Greek word ēthikós (ἠθικός), which was translated into Latin as ethica and entered the English language in the 15th century through the Old French term éthique. The term morality originates in the Latin word moralis, meaning manners and character. It was introduced into the English language through the Old French term moralité.

The terms "ethics" and "morality" are usually used interchangeably but some philosophers distinguish between the two. According to one view, morality focuses on what moral obligations people have while ethics is broader and includes ideas about what is good and how to lead a meaningful life. Another difference is that codes of conduct in specific areas, such as business and environment, are usually termed "ethics" rather than morality, as in business ethics and environmental ethics.

Normative ethics
Normative ethics is the philosophical study of ethical conduct and investigates the fundamental principles of morality. It aims to discover and justify general answers to questions like "How should one live?" and "How should people act?", usually in the form of universal or domain-independent principles that determine whether an act is right or wrong. For example, given the particular impression that it is wrong to set a child on fire for fun, normative ethics aims to find more general principles that explain why this is the case, like the principle that one should not cause extreme suffering to the innocent, which may itself be explained in terms of a more general principle. Many theories of normative ethics also aim to guide behavior by helping people make moral decisions.

Theories in normative ethics state how people should act or what kind of behavior is correct. They do not aim to describe how people normally act, what moral beliefs ordinary people have, how these beliefs change over time, or what ethical codes are upheld in certain social groups. These topics belong to descriptive ethics and are studied in fields like anthropology, sociology, and history rather than normative ethics.

Some systems of normative ethics arrive at a single principle covering all possible cases. Others encompass a small set of basic rules that address all or at least the most important moral considerations. One difficulty for systems with several basic principles is that these principles may conflict with each other in some cases and lead to ethical dilemmas.

Distinct theories in normative ethics suggest different principles as the foundation of morality. The three most influential schools of thought are consequentialism, deontology, and virtue ethics. These schools are usually presented as exclusive alternatives, but depending on how they are defined, they can overlap and do not necessarily exclude one another. In some cases, they differ in which acts they see as right or wrong. In other cases, they recommend the same course of action but provide different justifications for why it is right.

Consequentialism
Consequentialism, also called teleological ethics, says that morality depends on consequences. According to the most common view, an act is right if it brings the best future. This means that there is no alternative course of action that has better consequences. A key aspect of consequentialist theories is that they provide a characterization of what is good and then define what is right in terms of what is good. For example, classical utilitarianism says that pleasure is good and that the action leading to the most overall pleasure is right.

Consequentialists usually understand the consequences of an action in a very wide sense that includes the totality of its effects. This is based on the idea that actions make a difference in the world by bringing about a causal chain of events that would not have existed otherwise. A core intuition behind consequentialism is that what matters is not the past but the future and that it should be shaped to achieve the best possible outcome.

The act itself is usually not seen as part of the consequences. This means that if an act has intrinsic value or disvalue, it is not included as a relevant factor. Some consequentialists try to avoid this complication by including the act itself as part of the consequences. A related approach is to characterize consequentialism not in terms of consequences but in terms of outcome, with the outcome being defined as the act together with its consequences.

Most forms of consequentialism are agent-neutral. This means that the value of consequences is assessed from a neutral perspective, that is, acts should have consequences that are good in general and not just good for the agent. It is controversial whether agent-relative moral theories, like ethical egoism, should be considered as types of consequentialism.

Types
There are many different types of consequentialism. They differ based on what type of entity they evaluate, what consequences they take into consideration, and how they determine the value of consequences. Most theories assess the moral value of acts. However, consequentialism can also be used to evaluate motives, character traits, rules, and policies.

Many types assess the value of consequences based on whether they promote happiness or suffering. But there are also alternative evaluative principles, such as desire satisfaction, autonomy, freedom, knowledge, friendship, beauty, and self-perfection. Some forms of consequentialism hold that there is only a single source of value. The most prominent among them is utilitarianism, which states that the moral value of acts only depends on the pleasure they cause. An alternative approach says that there are many different sources of value, which all contribute to one overall value. Traditionally, consequentialists were only concerned with the total of value or the aggregate good. In the 20th century, alternative views were developed that additionally consider the distribution of value. One of them states that an equal distribution of goods is better than an unequal distribution even if the aggregate good is the same.

There are disagreements about what consequences should be assessed. An important distinction is between act and rule consequentialism. According to act consequentialism, the consequences of an act determine its moral value. This means that there is a direct relation between the consequences of an act and its moral value. Rule consequentialism, by contrast, holds that an act is right if it follows a certain set of rules. Rule consequentialism determines the best rules by considering their outcomes at a community level. People should follow the rules that lead to the best consequences when everyone in the community follows them. This implies that the relation between an act and its consequences is indirect. For example, if not lying is one of the best rules, then according to rule consequentialism, a person should not lie even in specific cases where lying would lead to better consequences.

Another disagreement is between actual and expected consequentialism. According to the traditional view, only the actual consequences of an act affect its moral value. One difficulty of this view is that many consequences cannot be known in advance. This means that in some cases, even well-planned and intentioned acts are morally wrong if they inadvertently lead to negative outcomes. An alternative perspective states that what matters are not the actual consequences but the expected consequences. This view takes into account that when deciding what to do, people have to rely on their limited knowledge of the total consequences of their actions. According to this view, a course of action has positive moral value despite leading to an overall negative outcome if it had the highest expected value, for example, because the negative outcome could not be anticipated or was unlikely.

A further difference is between maximizing and satisficing consequentialism. According to maximizing consequentialism, only the best possible act is morally permitted. This means that acts with positive consequences are wrong if there are alternatives with even better consequences. One criticism of maximizing consequentialism is that it demands too much by requiring that people do significantly more than they are socially expected to. For example, if the best action for someone with a good salary would be to donate 70% of their income to charity, it would be morally wrong for them to only donate 65%. Satisficing consequentialism, by contrast, only requires that an act is "good enough" even if it is not the best possible alternative. According to this view, it is possible to do more than one is morally required to do.

Mohism in ancient Chinese philosophy is one of the earliest forms of consequentialism. It argues that political action should promote justice as a means to increase the welfare of the people.

Utilitarianism
The most well-known form of consequentialism is utilitarianism. In its classical form, it is an act consequentialism that sees happiness as the only source of intrinsic value. This means that an act is morally right if it produces "the greatest good for the greatest number" by increasing happiness and reducing suffering. Utilitarians do not deny that other things also have value, like health, friendship, and knowledge. However, they deny that these things have intrinsic value. Instead, they say that they have extrinsic value because they affect happiness and suffering. In this regard, they are desirable as a means but, unlike happiness, not as an end. The view that pleasure is the only thing with intrinsic value is called ethical or evaluative hedonism.

Classical utilitarianism was initially formulated by Jeremy Bentham at the end of the 18th century and further developed by John Stuart Mill. Bentham introduced the hedonic calculus to assess the value of consequences. Two key aspects of the hedonic calculus are the intensity and the duration of pleasure. According to this view, a pleasurable experience has a high value if it has a high intensity and lasts for a long time. A common criticism of Bentham's utilitarianism argued that its focus on the intensity of pleasure promotes an immoral lifestyle centered around indulgence in sensory gratification. Mill responded to this criticism by distinguishing between higher and lower pleasures. He stated that higher pleasures, like the intellectual satisfaction of reading a book, are more valuable than lower pleasures, like the sensory enjoyment of food and drink, even if their intensity and duration are the same. Since its original formulation, many variations of utilitarianism have developed, including the difference between act and rule utilitarianism and between maximizing and satisficing utilitarianism.

Deontology
Deontology assesses the moral rightness of actions based on a set of norms or principles. These norms describe the requirements that all actions need to follow. They may include principles like telling the truth, keeping promises, and not intentionally harming others. Unlike consequentialists, deontologists hold that the validity of general moral principles does not depend on their consequences. They state that these principles should be followed in every case since they express how actions are inherently right or wrong. According to moral philosopher David Ross, it is wrong to break a promise even if no harm comes from it. Deontologists are interested in which actions are right and often allow that there is a gap between what is right and what is good. Many focus on prohibitions and describe which acts are forbidden under any circumstances.

Agent-centered and patient-centered
Agent-centered deontological theories focus on the person who acts and the duties they have. Agent-centered theories often focus on the motives and intentions behind people's actions, highlighting the importance of acting for the right reasons. They tend to be agent-relative, meaning that the reasons for which people should act depend on personal circumstances. For example, a parent has a special obligation to their child, while a stranger does not have this kind of obligation toward a child they do not know. Patient-centered theories, by contrast, focus on the people affected by actions and the rights they have. An example is the requirement to treat other people as ends and not merely as a means to an end. This requirement can be used to argue, for example, that it is wrong to kill a person against their will even if this act would save the life of several others. Patient-centered deontological theories are usually agent-neutral, meaning that they apply equally to everyone in a situation, regardless of their specific role or position.

Kantianism

Immanuel Kant is one of the most well-known deontologists. He states that moral action should not follow fixed goals that people desire, such as being happy. Instead, he argues that there are universal principles that apply to everyone independent of their desires. He uses the term categorical imperative for these principles, saying that they have their source in the structure of practical reason and are true for all rational agents. According to Kant, to act morally is to act in agreement with reason as expressed by these principles while violating them is both immoral and irrational.

Kant provided several formulations of the categorical imperative. One formulation says that a person should only follow maxims that can be universalized. This means that the person would want everyone to follow the same maxim as a universal laws applicable to everyone. Another formulation states that one should treat other people always as ends in themselves and never as mere means to an end. This formulation focuses on respecting and valuing other people for their own sake rather than using them in the pursuit of personal goals.

In either case, Kant says that what matters is to have a good will. A person has a good will if they respect the moral law and form their intentions and motives in agreement with it. Kant states that actions motivated in such a way are unconditionally good, meaning that they are good even in cases where they result in undesirable consequences.

Others
Divine command theory says that God is the source of morality. It states that moral laws are divine commands and that to act morally is to obey and follow God's will. While all divine command theorists agree that morality depends on God, there are disagreements about the precise content of the divine commands, and theorists belonging to different religions tend to propose different moral laws. For example, Christian and Jewish divine command theorists may argue that the Ten Commandments express God's will while Muslims may reserve this role for the teachings of the Quran.

Contractualists reject the reference to God as the source of morality and argue instead that morality is based on an explicit or implicit social contract between humans. They state that actual or hypothetical consent to this contract is the source of moral norms and duties. To determine which duties people have, contractualists often rely on a thought experiment about what rational people under ideal circumstances would agree on. For example, if they would agree that people should not lie then there is a moral obligation to refrain from lying. Because it relies on consent, contractualism is often understood as a patient-centered form of deontology.

Discourse ethics also focuses on social agreement on moral norms but says that this agreement is based on communicative rationality. It aims to arrive at moral norms for pluralistic modern societies that encompass a diversity of viewpoints. A universal moral norm is seen as valid if all rational discourse participants do or would approve. This way, morality is not imposed by a single moral authority but arises from the moral discourse within society. This discourse should aim to establish an ideal speech situation to ensure fairness and inclusivity. In particular, this means that discourse participants are free to voice their different opinions without coercion but are at the same time required to justify them using rational argumentation.

Virtue ethics
The main concern of virtue ethics is how virtues are expressed in actions. As such, it is neither directly interested in the consequences of actions nor in universal moral duties. Virtues are positive character traits like honesty, courage, kindness, and compassion. They are usually understood as dispositions to feel, decide, and act in a certain manner by being wholeheartedly committed to this manner. Virtues contrast with vices, which are their harmful counterparts.

Virtue theorists usually say that the mere possession of virtues by itself is not sufficient. Instead, people should manifest virtues in their actions. An important factor is the practical wisdom, also called phronesis, of knowing when, how, and which virtue to express. For example, a lack of practical wisdom may lead courageous people to perform morally wrong actions by taking unnecessary risks that should better be avoided.

Different types of virtue ethics differ on how they understand virtues and their role in practical life. Eudaimonism is the classical view and draws a close relation between virtuous behavior and happiness. It states that people flourish by living a virtuous life. Eudaimonist theories often hold that virtues are positive potentials residing in human nature and that actualizing these potentials results in leading a good and happy life. Agent-based theories, by contrast, see happiness only as a side effect and focus instead on the admirable traits and motivational characteristics expressed while acting. This is often combined with the idea that one can learn from exceptional individuals what those characteristics are. Feminist ethics of care are another form of virtue ethics. They emphasize the importance of interpersonal relationships and say that benevolence by caring for the well-being of others is one of the key virtues.

Influential schools of virtue ethics in ancient philosophy were Aristotelianism and Stoicism. According to Aristotle, each virtue is a golden mean between two types of vices: excess and deficiency. For example, courage is a virtue that lies between the deficient state of cowardice and the excessive state of recklessness. Aristotle held that virtuous action leads to happiness and makes people flourish in life. The Stoics believed that, through virtue alone, people can achieve happiness characterized by a peaceful state of mind free from emotional disturbances. They advocated rationality and self-mastery to achieve this state. In the 20th century, virtue ethics experienced a resurgence thanks to philosophers such as Elizabeth Anscombe, Philippa Foot, Alasdair MacIntyre, and Martha Nussbaum.

Other traditions
There are many other schools of normative ethics in addition to the three main traditions. Pragmatist ethics focuses on the role of practice and holds that one of the key tasks of ethics is to solve practical problems in concrete situations. It has certain similarities to utilitarianism and its focus on consequences but concentrates more on how morality is embedded in and relative to social and cultural contexts. Pragmatists tend to give more importance to habits than to conscious deliberation and understand morality as a habit that should be shaped in the right way.

Postmodern ethics agrees with pragmatist ethics about the cultural relativity of morality. It rejects the idea that there are objective moral principles that apply universally to all cultures and traditions. It asserts that there is no one coherent ethical code since morality itself is irrational and humans are morally ambivalent beings. Postmodern ethics instead focuses on how moral demands arise in specific situations as one encounters other people.

Ethical egoism is the view that people should act in their self-interest or that an action is morally right if the person acts for their own benefit. It differs from psychological egoism, which states that people actually follow their self-interest without claiming that they should do so. Ethical egoists may act in agreement with commonly accepted moral expectations and benefit other people, for example, by keeping promises, helping friends, and cooperating with others. However, they do so only as a means to promote their self-interest. Ethical egoism is often criticized as an immoral and contradictory position.

Normative ethics has a central place in most religions. Key aspects of Jewish ethics are to follow the 613 commandments of God according to the Mitzvah duty found in the Torah and to take responsibility for societal welfare. Christian ethics puts less emphasis on following precise laws and teaches instead the practice of selfless love, such as the Great Commandment to "love your neighbor as yourself". The Five Pillars of Islam constitute a basic framework of Muslim ethics and focus on the practice of faith, prayer, charity, fasting during Ramadan, and pilgrimage to Mecca. Buddhists emphasize the importance of compassion and loving-kindness towards all sentient entities. A similar outlook is found in Jainism, which has non-violence as its principal virtue. Duty is a central aspect of Hindu ethics and is about fulfilling social obligations, which may vary depending on a person's social class and stage of life. Confucianism places great emphasis on harmony in society and sees benevolence as a key virtue. Taoism extends the importance of living in harmony to the whole world and teaches that people should practice effortless action by following the natural flow of the universe. Indigenous belief systems, like Native American philosophy and the African Ubuntu philosophy, often emphasize the interconnectedness of all living beings and the environment while stressing the importance of living in harmony with nature.

Metaethics
Metaethics is the branch of ethics that examines the nature, foundations, and scope of moral judgments, concepts, and values. It is not interested in what actions are right but in what it means for an action to be right and whether moral judgments are objective and can be true at all. It further examines the meaning of morality and moral terms. Metaethics is a metatheory that operates on a higher level of abstraction than normative ethics by investigating its underlying assumptions. Metaethical theories typically do not directly adopt substantive positions on normative ethical theories. However, they can still influence these theories by examining their foundational principles.

Metaethics overlaps with various branches of philosophy. On the level of ontology, it examines whether there are objective moral facts. Concerning semantics, it asks what the meaning of moral terms are and whether moral statements have a truth value. The epistemological side of metaethics discusses whether and how people can acquire moral knowledge. Metaethics overlaps with psychology because of its interest in how moral judgments motivate people to act. It also overlaps with anthropology since it aims to explain how cross-cultural differences affect moral assessments.

Basic concepts

Metaethics examines basic ethical concepts and their relations. Ethics is concerned with normative statements about what ought to be the case, in contrast to descriptive statements, which are about what is the case. Duties and obligations express requirements of what people ought to do. Duties are sometimes defined as counterparts of the rights that always accompany them. According to this view, someone has a duty to benefit another person if this other person has the right to receive that benefit. Obligation and permission are contrasting terms that can be defined through each other: to be obligated to do something means that one is not permitted not to do it and to be permitted to do something means that one is not obligated not to do it. Some theorists define obligations in terms of values or what is good. When used in a general sense, good contrasts with bad. When describing people and their intentions, the term evil rather than bad is often employed.

Obligations are used to assess the moral status of actions, motives, and character traits. An action is morally right if it is in tune with a person's obligations and morally wrong if it violates them. Supererogation is a special moral status that applies to cases in which the agent does more than is morally required of them. To be morally responsible for an action usually means that the person possessed and exercised certain capacities or some form of control. If a person is morally responsible then it is appropriate to respond to them in certain ways, for example, by praising or blaming them.

Realism, relativism, and nihilism
A major debate in metaethics is about the ontological status of morality, questioning whether ethical values and principles are real. It examines whether moral properties exist as objective features independent of the human mind and culture rather than as subjective constructs or expressions of personal preferences and cultural norms.

Moral realists accept the claim that there are objective moral facts. This view implies that moral values are mind-independent aspects of reality and that there is an absolute fact about whether a given action is right or wrong. A consequence of this view is that moral requirements have the same ontological status as non-moral facts: it is an objective fact whether there is an obligation to keep a promise just as it is an objective fact whether a thing has a black color. Moral realism is often associated with the claim that there are universal ethical principles that apply equally to everyone. It implies that if two people disagree about a moral evaluation then at least one of them is wrong. This observation is sometimes taken as an argument against moral realism since moral disagreement is widespread in most fields.

Moral relativists reject the idea that morality is an objective feature of reality. They argue instead that moral principles are human inventions. This means that a behavior is not objectively right or wrong but only subjectively right or wrong relative to a certain standpoint. Moral standpoints may differ between persons, cultures, and historical periods. For example, moral statements like "slavery is wrong" or "suicide is permitted" may be true in one culture and false in another. Some moral relativists say that moral systems are constructed to serve certain goals such as social coordination. According to this view, different societies and different social groups within a society construct different moral systems based on their diverging purposes. A different explanation states that morality arises from moral emotions, which are not the same for everyone.

Moral nihilists deny the existence of moral facts. They are opposed to both objective moral facts defended by moral realism and subjective moral facts defended by moral relativism. They believe that the basic assumptions underlying moral claims are misguided. Some moral nihilists conclude from this that anything is allowed. A slightly different view emphasizes that moral nihilism is not itself a moral position about what is allowed and prohibited but the rejection of any moral position. Moral nihilism, like moral relativism, recognizes that people judge actions as right or wrong from different perspectives. However, it disagrees that this practice involves morality and sees it as just one type of human behavior.

Naturalism and non-naturalism
A central disagreement among moral realists is between naturalism and non-naturalism. Naturalism states that moral properties are natural properties accessible to empirical observation. They are similar to the natural properties investigated by the natural sciences, like color and shape. Some moral naturalists hold that moral properties are a unique and basic type of natural property. Another view states that moral properties are real but not a fundamental part of reality and can be reduced to other natural properties, such as properties describing the causes of pleasure and pain.

Non-naturalism accepts that moral properties form part of reality and argues that moral features are not identical or reducible to natural properties. This view is usually motivated by the idea that moral properties are unique because they express what should be the case. Proponents of this position often emphasize this uniqueness by claiming that it is a fallacy to define ethics in terms of natural entities or to infer prescriptive from descriptive statements.

Cognitivism and non-cognitivism
The metaethical debate between cognitivism and non-cognitivism is about the meaning of moral statements and is a part of the study of semantics. According to cognitivism, moral statements like "Abortion is morally wrong" and "Going to war is never morally justified" are truth-apt, meaning that they all have a truth value: they are either true or false. Cognitivism only claims that moral statements have a truth value but is not interested in which truth value they have. It is often seen as the default position since moral statements resemble other statements, like "Abortion is a medical procedure" or "Going to war is a political decision", which have a truth value.

The semantic position of cognitivism is closely related to the ontological position of moral realism and philosophers who accept one often accept the other as well. An exception is error theory, which combines cognitivism with moral nihilism by claiming that all moral statements are false because there are no moral facts.

Non-cognitivism is the view that moral statements lack a truth value. According to this view, the statement "Murder is wrong" is neither true nor false. Some non-cognitivists claim that moral statements have no meaning at all. A different interpretation is that they express other types of meaning contents. Emotivism says that they articulate emotional attitudes. According to this view, the statement "Murder is wrong" expresses that the speaker has a negative moral attitude towards murder or dislikes it. Prescriptivism, by contrast, understands moral statements as commands. According to this view, stating that "Murder is wrong" expresses a command like "Do not commit murder".

Moral knowledge
The epistemology of ethics studies whether or how one can know moral truths. Foundationalist views state that some moral beliefs are basic and do not require further justification. Ethical intuitionism is one such view that says that humans have a special cognitive faculty through which they can know right from wrong. Intuitionists often argue that general moral truths, like "lying is wrong", are self-evident and that it is possible to know them without relying on empirical experience. A different foundationalist position focuses on particular observations rather than general intuitions. It says that if people are confronted with a concrete moral situation, they can perceive whether right or wrong conduct was involved.

In contrast to foundationalists, coherentists say that there are no basic moral beliefs. They argue that beliefs form a complex network and mutually support and justify one another. According to this view, a moral belief can only amount to knowledge if it coheres with the rest of the beliefs in the network. Moral skeptics say that people are unable to distinguish between right and wrong behavior, thereby rejecting the idea that moral knowledge is possible. Moral skepticism is often criticized based on the claim that it leads to immoral behavior.

Thought experiments are used as a method in ethics to decide between competing theories. They usually present an imagined situation involving an ethical dilemma and explore how people's intuitions of right and wrong change based on specific details in that situation. For example, in the trolley problem, a person can flip a switch to redirect a trolley from one track to another, thereby sacrificing the life of one person to save five. This scenario explores how the difference between doing and allowing harm affects moral obligations. Another thought experiment examines the moral implications of abortion by imagining a situation in which a person gets connected without their consent to an ill violinist. In this scenario, the violinist dies if the connection is severed, similar to how a fetus dies in the case of abortion. The thought experiment explores whether it would be morally permissible to sever the connection within the next nine months.

Moral motivation
On the level of psychology, metaethics is interested in how moral beliefs and experiences affect behavior. According to motivational internalists, there is a direct link between moral judgments and action. This means that every judgment about what is right motivates the person to act accordingly. For example, Socrates defends a strong form of motivational internalism by holding that a person can only perform an evil deed if they are unaware that it is evil. Weaker forms of motivational internalism say that people can act against moral judgments, for example, because of the weakness of the will. Motivational externalists accept that people can judge an act to be morally required without feeling a reason to engage in it. This means that moral judgments do not always provide motivational force. The debate between internalism and externalism is relevant for explaining the behavior of psychopaths or sociopaths, who fail to either judge that a behavior is wrong or translate their judgment into action. A closely related question is whether moral judgments can provide motivation on their own or need to be accompanied by other mental states, such as a desire to act morally.

Applied ethics
Applied ethics, also known as practical ethics, is the branch of ethics and applied philosophy that examines concrete moral problems encountered in real-life situations. Unlike normative ethics, it is not concerned with discovering or justifying universal ethical principles. Instead, it studies how those principles can be applied to specific domains of practical life, what consequences they have in these fields, and whether additional domain-specific factors need to be considered.

One of the main challenges of applied ethics is to breach the gap between abstract universal theories and their application to concrete situations. For example, an in-depth understanding of Kantianism or utilitarianism is usually not sufficient to decide how to analyze the moral implications of a medical procedure like abortion. One reason is that it may not be clear how the Kantian requirement of respecting everyone's personhood applies to a fetus and what the long-term consequences are in terms of the greatest good for the greatest number. This difficulty is particularly relevant to applied ethicists who employ a top-down methodology by starting from universal ethical principles and applying them to particular cases within a specific domain. A different approach is to use a bottom-up methodology, known as casuistry. This method does not start from universal principles but from moral intuitions about particular cases. It seeks to arrive at moral principles relevant to a specific domain, which may not be universally applicable to other domains. In either case, inquiry into applied ethics is often triggered by ethical dilemmas to solve cases in which a person is subject to conflicting moral requirements.

Applied ethics covers issues belonging to both the private sphere, like right conduct in the family and close relationships, and the public sphere, like moral problems posed by new technologies and duties toward future generations. Major branches include bioethics, business ethics, and professional ethics. There are many other branches, and their domains of inquiry often overlap.

Bioethics
Bioethics is a wide field that covers moral problems associated with living organisms and biological disciplines. A key problem in bioethics is how features such as consciousness, being able to feel pleasure and pain, rationality, and personhood affect the moral status of entities. These differences concern, for example, how to treat non-living entities like rocks and non-sentient entities like plants in contrast to animals and whether humans have a different moral status than other animals. According to anthropocentrism, only humans have a basic moral status. This suggests that all other entities possess a derivative moral status only insofar as they impact human life. Sentientism, by contrast, extends an inherent moral status to all sentient beings. Further positions include biocentrism, which also covers non-sentient lifeforms, and ecocentrism, which states that all of nature has a basic moral status.

Bioethics is relevant to various aspects of life and many professions. It covers a wide range of moral problems associated with topics like abortion, cloning, stem cell research, euthanasia, suicide, animal testing, intensive animal farming, nuclear waste, and air pollution.

Bioethics can be divided into medical ethics, animal ethics, and environmental ethics based on whether the ethical problems relate to humans, other animals, or nature in general. Medical ethics is the oldest branch of bioethics and has its origins in the Hippocratic Oath, which establishes ethical guidelines for medical practitioners like a prohibition to harm the patient. Medical ethics often addresses issues related to the start and end of life. One debate focuses on the moral status of fetuses, for example, whether they are full-fledged persons and whether abortion is a form of murder. At the end of life, ethical issues arise about whether a person has the right to end their life in cases of terminal illness and if doctors may help them do so. Other topics in medical ethics include medical confidentiality, informed consent, research on human beings, organ transplantation, and access to healthcare.

Animal ethics examines how humans should treat other animals. This field often emphasizes the importance of animal welfare while arguing that humans should avoid or minimize the harm done to animals. There is wide agreement that it is wrong to torture animals for fun. The situation is more complicated in cases where harm is inflicted on animals as a side effect of the pursuit of human interests. This happens, for example, during factory farming, when using animals as food, and for research experiments on animals. A key topic in animal ethics is the formulation of animal rights. Animal rights theorists assert that animals have a certain moral status and that humans should respect this status when interacting with them. Examples of suggested animal rights include the right to life, the right to be free from unnecessary suffering, and the right to natural behavior in a suitable environment.

Environmental ethics deals with moral problems relating to the natural environment including animals, plants, natural resources, and ecosystems. In its widest sense, it covers the whole cosmos. In the domain of agriculture, this concerns the circumstances under which the vegetation of an area may be cleared to use it for farming and the implications of planting genetically modified crops. On a wider scale, environmental ethics addresses the problem of global warming and people's responsibility on the individual and collective levels, including topics like climate justice and duties towards future generations. Environmental ethicists often promote sustainable practices and policies directed at protecting and conserving ecosystems and biodiversity.

Business and professional ethics
Business ethics examines the moral implications of business conduct and how ethical principles apply to corporations and organizations. A key topic is corporate social responsibility, which is the responsibility of corporations to act in a manner that benefits society at large. Corporate social responsibility is a complex issue since many stakeholders are directly and indirectly involved in corporate decisions, such as the CEO, the board of directors, and the shareholders. A closely related topic is the question of whether corporations themselves, and not just their stakeholders, have moral agency. Business ethics further examines the role of honesty and fairness in business practices as well as the moral implications of bribery, conflict of interest, protection of investors and consumers, worker's rights, ethical leadership, and corporate philanthropy.

Professional ethics is a closely related field that studies ethical principles applying to members of a specific profession, like engineers, medical doctors, lawyers, and teachers. It is a diverse field since different professions often have different responsibilities. Principles applying to many professions include that the professional has the required expertise for the intended work and that they have personal integrity and are trustworthy. Further principles are to serve the interest of their target group, follow client confidentiality, and respect and uphold the client's rights, such as informed consent. More precise requirements often vary between professions. A cornerstone of engineering ethics is to protect public safety, health, and well-being. Legal ethics emphasizes the importance of respect for justice, personal integrity, and confidentiality. Key factors in journalism ethics include accuracy, truthfulness, independence, and impartiality as well as proper attribution to avoid plagiarism.

Other subfields
Many other fields of applied ethics are discussed in the academic literature. Communication ethics covers moral principles of communicative conduct. Two key issues in it are freedom of speech and speech responsibility. Freedom of speech concerns the ability to articulate one's opinions and ideas without the threats of punishment and censorship. Speech responsibility is about being accountable for the consequences of communicative action and inaction. A closely related field is information ethics, which focuses on the moral implications of creating, controlling, disseminating, and using information.

The ethics of technology examines the moral issues associated with the creation and use of any artifact, from simple spears to high-tech computers and nanotechnology. Central topics in the ethics of technology include the risks associated with creating new technologies, their responsible use, and questions about human enhancement through technological means, such as performance-enhancing drugs and genetic enhancement. Important subfields include computer ethics, ethics of artificial intelligence, machine ethics, ethics of nanotechnology, and nuclear ethics.

The ethics of war investigates moral problems of war and violent conflicts. According to just war theory, waging war is morally justified if it fulfills certain conditions. These conditions are commonly divided into requirements concerning the cause to initiate violent activities, such as self-defense, and the way those violent activities are conducted, such as avoiding excessive harm to civilians in the pursuit of legitimate military targets. Military ethics is a closely related field that is interested in the conduct of military personnel. It governs questions of the circumstances under which they are permitted to kill enemies, destroy infrastructure, and put the lives of their own troops at risk. Additional topics are recruitment, training, and discharge of military personnel.

Further fields of applied ethics include political ethics, which examines the moral dimensions of political decisions, educational ethics, which covers ethical issues related to proper teaching practices, and sexual ethics, which addresses the moral implications of sexual behavior.

Value theory
Value theory, also called axiology, is the philosophical study of value. It examines the nature and types of value. A central distinction is between intrinsic and instrumental value. An entity has intrinsic value if it is good in itself or good for its own sake. An entity has instrumental value if it is valuable as a means to something else, for example, by causing something that has intrinsic value. Further topics include what kinds of things have value and how valuable they are. For instance, axiological hedonists say that pleasure is the only source of intrinsic value with the magnitude of value corresponding to the degree of pleasure. Axiological pluralists, by contrast, hold that there are different sources of intrinsic value.

There are disagreements about the exact relation between value theory and ethics. Some philosophers characterize value theory as a subdiscipline of ethics while others see value theory as the broader term that encompasses other fields besides ethics, such as aesthetics and political philosophy. A different characterization sees the two disciplines as overlapping but distinct fields. The term axiological ethics is sometimes used for the discipline studying this overlap, that is, the part of ethics that studies values. The two disciplines are sometimes distinguished based on their focus: ethics is about moral behavior or what is right while value theory is about value or what is good. Some ethical theories, like consequentialism, stand very close to value theory by defining what is right in terms of what is good. But this is not true for ethics in general and deontological theories tend to reject the idea that what is good can be used to define what is right.

Moral psychology
Moral psychology explores the psychological foundations and processes involved in moral behavior. It is an empirical science that studies how humans think and act in moral contexts. It is interested in how moral reasoning and judgments take place, how moral character forms, what sensitivity people have to moral evaluations, and how people attribute and react to moral responsibility.

One of its key topics is moral development or the question of how morality develops on a psychological level from infancy to adulthood. According to Lawrence Kohlberg, children go through different stages of moral development as they understand moral principles first as fixed rules governing reward and punishment, then as conventional social norms, and later as abstract principles of what is objectively right across societies. A closely related question is whether and how people can be taught to act morally.

Evolutionary ethics, a closely related field, explores how evolutionary processes have shaped ethics. One of its key ideas is that natural selection is responsible for moral behavior and moral sensitivity. It interprets morality as an adaptation to evolutionary pressure that augments fitness by offering a selective advantage. Altruism, for example, can provide benefits to group survival by improving cooperation. Some theorists, like Mark Rowlands, argue that morality is not limited to humans, meaning that some non-human animals act based on moral emotions. Others explore evolutionary precursors to morality in non-human animals.

Descriptive ethics
Descriptive ethics, also called comparative ethics, studies actually existing moral codes, practices, and beliefs. It investigates and compares moral phenomena in different societies and different groups within a society. It aims to provide a value-neutral and empirical description without judging or justifying which practices are objectively right. For instance, the question of how nurses think about the ethical implications of abortion belongs to descriptive ethics. Another example is descriptive business ethics, which describes ethical standards in the context of business, including common practices, official policies, and employee opinions. Descriptive ethics also has a historical dimension by exploring how moral practices and beliefs have changed over time.

Descriptive ethics is a multidisciplinary field that is covered by disciplines such as anthropology, sociology, psychology, and history. Its empirical outlook contrasts with the philosophical inquiry into normative questions, such as which ethical principles are correct and how to justify them.

History
The history of ethics studies how moral philosophy has developed and evolved in the course of history. It has its origin in ancient civilizations. In ancient Egypt, the concept of Maat was used as an ethical principle to guide behavior and maintain order by emphasizing the importance of truth, balance, and harmony. In ancient India, the Vedas and Upanishads were written as the foundational texts of Hindu philosophy and discussed the role of duty and the consequences of one's actions. Buddhist ethics also originated in ancient India and advocated compassion, non-violence, and the pursuit of enlightenment. Ancient China saw the emergence of Confucianism, which focuses on moral conduct and self-cultivation by acting in agreement with virtues, and Daoism, which teaches that human behavior should be in harmony with the natural order of the universe.

In ancient Greece, Socrates emphasized the importance of inquiry into what a good life is by critically questioning established ideas and exploring concepts like virtue, justice, courage, and wisdom. According to Plato, to lead a good life means that the different parts of the soul are in harmony with each other. For Aristotle, a good life is associated with being happy by cultivating virtues and flourishing. The close relation between right action and happiness was also explored by the Hellenistic schools of Epicureanism, which recommended a simple lifestyle without indulging in sensory pleasures, and Stoicism, which advocated living in tune with reason and virtue while practicing self-mastery and becoming immune to disturbing emotions.

Ethical thought in the medieval period was strongly influenced by religious teachings. Christian philosophers interpreted moral principles as divine commands originating from God. Thomas Aquinas developed natural law ethics by claiming that ethical behavior consists in following the laws and order of nature, which he believed were created by God. In the Islamic world, philosophers like Al-Farabi and Avicenna synthesized ancient Greek philosophy with the ethical teachings of Islam while emphasizing the harmony between reason and faith. In medieval India, philosophers like Adi Shankara and Ramanuja saw the practice of spirituality to attain liberation as the highest goal of human behavior.

Moral philosophy in the modern period was characterized by a shift toward a secular approach to ethics. Thomas Hobbes identified self-interest as the primary drive of humans. He concluded that it would lead to "a war of every man against every man" unless a social contract is established to avoid this outcome. David Hume thought that only moral sentiments, like empathy, can motivate ethical actions while he saw reason not as a motivating factor but only as what anticipates the consequences of possible actions. Immanuel Kant, by contrast, saw reason as the source of morality. He formulated a deontological theory, according to which the ethical value of actions depends on their conformity with moral laws independent of their outcome. These laws take the form of categorical imperatives, which are universal requirements that apply to every situation. Georg Wilhelm Friedrich Hegel saw Kant's categorical imperative on its own as an empty formalism and emphasized the role of social institutions in providing concrete content to moral duties. According to the Christian philosophy of Søren Kierkegaard, the demands of ethical duties are sometimes suspended when doing God's will. Friedrich Nietzsche formulated criticisms of both Christian and Kantian morality. Another influential development in this period was the formulation of utilitarianism by Jeremy Bentham and John Stuart Mill. According to the utilitarian doctrine, actions should promote happiness while reducing suffering and the right action is the one that produces the greatest good for the greatest number of people.

An important development in 20th-century ethics in analytic philosophy was the emergence of metaethics. Significant early contributions to this field were made by G. E. Moore, who argued that moral values are essentially different from other properties found in the natural world. R. M. Hare followed this idea in formulating his prescriptivism, which states that moral statements are commands that, unlike regular judgments, are neither true nor false. J. L. Mackie suggested that every moral statement is false since there are no moral facts. An influential argument for moral realism was made by Derek Parfit, who argued that morality concerns objective features of reality that give people reasons to act in one way or another. Bernard Williams agreed with the close relation between reasons and ethics but defended a subjective view instead that sees reasons as internal mental states that may or may not reflect external reality. Another development in this period was the revival of ancient virtue ethics by philosophers like Philippa Foot. In the field of political philosophy, John Rawls relied on Kantian ethics to analyze social justice as a form of fairness. In continental philosophy, phenomenologists such as Max Scheler and Nicolai Hartmann built ethical systems based on the claim that values have objective reality that can be investigated using the phenomenological method. Existentialists like Jean-Paul Sartre and Simone de Beauvoir, by contrast, held that values are created by humans and explored the consequences of this view in relation to individual freedom, responsibility, and authenticity. This period also saw the emergence of feminist ethics, which questions traditional ethical assumptions associated with a male perspective and puts alternative concepts, like care, at the center.

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title: Ethics