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Glycolysis

Glycolysis is the metabolic pathway that converts glucose (C6H12O6) into pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.

The wide occurrence of glycolysis in other species indicates that it is an ancient metabolic pathway. Indeed, the reactions that make up glycolysis and its parallel pathway, the pentose phosphate pathway, can occur in the oxygen-free conditions of the Archean oceans, also in the absence of enzymes, catalyzed by metal ions, meaning this is a plausible prebiotic pathway for abiogenesis.

The most common type of glycolysis is the Embden–Meyerhof–Parnas (EMP) pathway, which was discovered by Gustav Embden, Otto Meyerhof, and Jakub Karol Parnas. Glycolysis also refers to other pathways, such as the Entner–Doudoroff pathway and various heterofermentative and homofermentative pathways. However, the discussion here will be limited to the Embden–Meyerhof–Parnas pathway.

The glycolysis pathway can be separated into two phases:
 * 1) Investment phase – wherein ATP is consumed
 * 2) Yield phase – wherein more ATP is produced than originally consumed

Overview
The overall reaction of glycolysis is:

The use of symbols in this equation makes it appear unbalanced with respect to oxygen atoms, hydrogen atoms, and charges. Atom balance is maintained by the two phosphate (Pi) groups:
 * Each exists in the form of a hydrogen phosphate anion ([HPO4](2−)), dissociating to contribute 2H+ overall
 * Each liberates an oxygen atom when it binds to an adenosine diphosphate (ADP) molecule, contributing 2O overall

Charges are balanced by the difference between ADP and ATP. In the cellular environment, all three hydroxyl groups of ADP dissociate into −O− and H+, giving ADP3−, and this ion tends to exist in an ionic bond with Mg2+, giving ADPMg−. ATP behaves identically except that it has four hydroxyl groups, giving ATPMg2−. When these differences along with the true charges on the two phosphate groups are considered together, the net charges of −4 on each side are balanced.

For simple fermentations, the metabolism of one molecule of glucose to two molecules of pyruvate has a net yield of two molecules of ATP. Most cells will then carry out further reactions to "repay" the used NAD+ and produce a final product of ethanol or lactic acid. Many bacteria use inorganic compounds as hydrogen acceptors to regenerate the NAD+.

Cells performing aerobic respiration synthesize much more ATP, but not as part of glycolysis. These further aerobic reactions use pyruvate, and NADH + H+ from glycolysis. Eukaryotic aerobic respiration produces approximately 34 additional molecules of ATP for each glucose molecule, however most of these are produced by a mechanism vastly different from the substrate-level phosphorylation in glycolysis.

The lower-energy production, per glucose, of anaerobic respiration relative to aerobic respiration, results in greater flux through the pathway under hypoxic (low-oxygen) conditions, unless alternative sources of anaerobically oxidizable substrates, such as fatty acids, are found.

History
The pathway of glycolysis as it is known today took almost 100 years to fully elucidate. The combined results of many smaller experiments were required in order to understand the intricacies of the entire pathway.

The first steps in understanding glycolysis began in the nineteenth century with the wine industry. For economic reasons, the French wine industry sought to investigate why wine sometimes turned distasteful, instead of fermenting into alcohol. French scientist Louis Pasteur researched this issue during the 1850s, and the results of his experiments began the long road to elucidating the pathway of glycolysis. His experiments showed that fermentation occurs by the action of living microorganisms, yeasts, and that yeast's glucose consumption decreased under aerobic conditions of fermentation, in comparison to anaerobic conditions (the Pasteur effect).

Insight into the component steps of glycolysis were provided by the non-cellular fermentation experiments of Eduard Buchner during the 1890s. Buchner demonstrated that the conversion of glucose to ethanol was possible using a non-living extract of yeast, due to the action of enzymes in the extract. This experiment not only revolutionized biochemistry, but also allowed later scientists to analyze this pathway in a more controlled laboratory setting. In a series of experiments (1905–1911), scientists Arthur Harden and William Young discovered more pieces of glycolysis. They discovered the regulatory effects of ATP on glucose consumption during alcohol fermentation. They also shed light on the role of one compound as a glycolysis intermediate: fructose 1,6-bisphosphate.

The elucidation of fructose 1,6-bisphosphate was accomplished by measuring CO2 levels when yeast juice was incubated with glucose. CO2 production increased rapidly then slowed down. Harden and Young noted that this process would restart if an inorganic phosphate (Pi) was added to the mixture. Harden and Young deduced that this process produced organic phosphate esters, and further experiments allowed them to extract fructose diphosphate (F-1,6-DP).

Arthur Harden and William Young along with Nick Sheppard determined, in a second experiment, that a heat-sensitive high-molecular-weight subcellular fraction (the enzymes) and a heat-insensitive low-molecular-weight cytoplasm fraction (ADP, ATP and NAD+ and other cofactors) are required together for fermentation to proceed. This experiment begun by observing that dialyzed (purified) yeast juice could not ferment or even create a sugar phosphate. This mixture was rescued with the addition of undialyzed yeast extract that had been boiled. Boiling the yeast extract renders all proteins inactive (as it denatures them). The ability of boiled extract plus dialyzed juice to complete fermentation suggests that the cofactors were non-protein in character. In the 1920s Otto Meyerhof was able to link together some of the many individual pieces of glycolysis discovered by Buchner, Harden, and Young. Meyerhof and his team were able to extract different glycolytic enzymes from muscle tissue, and combine them to artificially create the pathway from glycogen to lactic acid.

In one paper, Meyerhof and scientist Renate Junowicz-Kockolaty investigated the reaction that splits fructose 1,6-diphosphate into the two triose phosphates. Previous work proposed that the split occurred via 1,3-diphosphoglyceraldehyde plus an oxidizing enzyme and cozymase. Meyerhoff and Junowicz found that the equilibrium constant for the isomerase and aldoses reaction were not affected by inorganic phosphates or any other cozymase or oxidizing enzymes. They further removed diphosphoglyceraldehyde as a possible intermediate in glycolysis.

With all of these pieces available by the 1930s, Gustav Embden proposed a detailed, step-by-step outline of that pathway we now know as glycolysis. The biggest difficulties in determining the intricacies of the pathway were due to the very short lifetime and low steady-state concentrations of the intermediates of the fast glycolytic reactions. By the 1940s, Meyerhof, Embden and many other biochemists had finally completed the puzzle of glycolysis. The understanding of the isolated pathway has been expanded in the subsequent decades, to include further details of its regulation and integration with other metabolic pathways.

Preparatory phase
The first five steps of Glycolysis are regarded as the preparatory (or investment) phase, since they consume energy to convert the glucose into two three-carbon sugar phosphates (G3P).

Once glucose enters the cell, the first step is phosphorylation of glucose by a family of enzymes called hexokinases to form glucose 6-phosphate (G6P). This reaction consumes ATP, but it acts to keep the glucose concentration inside the cell low, promoting continuous transport of blood glucose into the cell through the plasma membrane transporters. In addition, phosphorylation blocks the glucose from leaking out – the cell lacks transporters for G6P, and free diffusion out of the cell is prevented due to the charged nature of G6P. Glucose may alternatively be formed from the phosphorolysis or hydrolysis of intracellular starch or glycogen.

In animals, an isozyme of hexokinase called glucokinase is also used in the liver, which has a much lower affinity for glucose (Km in the vicinity of normal glycemia), and differs in regulatory properties. The different substrate affinity and alternate regulation of this enzyme are a reflection of the role of the liver in maintaining blood sugar levels.

Cofactors: Mg2+

G6P is then rearranged into fructose 6-phosphate (F6P) by glucose phosphate isomerase. Fructose can also enter the glycolytic pathway by phosphorylation at this point.

The change in structure is an isomerization, in which the G6P has been converted to F6P. The reaction requires an enzyme, phosphoglucose isomerase, to proceed. This reaction is freely reversible under normal cell conditions. However, it is often driven forward because of a low concentration of F6P, which is constantly consumed during the next step of glycolysis. Under conditions of high F6P concentration, this reaction readily runs in reverse. This phenomenon can be explained through Le Chatelier's Principle. Isomerization to a keto sugar is necessary for carbanion stabilization in the fourth reaction step (below).

The energy expenditure of another ATP in this step is justified in 2 ways: The glycolytic process (up to this step) becomes irreversible, and the energy supplied destabilizes the molecule. Because the reaction catalyzed by phosphofructokinase 1 (PFK-1) is coupled to the hydrolysis of ATP (an energetically favorable step) it is, in essence, irreversible, and a different pathway must be used to do the reverse conversion during gluconeogenesis. This makes the reaction a key regulatory point (see below).

Furthermore, the second phosphorylation event is necessary to allow the formation of two charged groups (rather than only one) in the subsequent step of glycolysis, ensuring the prevention of free diffusion of substrates out of the cell.

The same reaction can also be catalyzed by pyrophosphate-dependent phosphofructokinase (PFP or PPi-PFK), which is found in most plants, some bacteria, archea, and protists, but not in animals. This enzyme uses pyrophosphate (PPi) as a phosphate donor instead of ATP. It is a reversible reaction, increasing the flexibility of glycolytic metabolism. A rarer ADP-dependent PFK enzyme variant has been identified in archaean species.

Cofactors: Mg2+

Destabilizing the molecule in the previous reaction allows the hexose ring to be split by aldolase into two triose sugars: dihydroxyacetone phosphate (a ketose), and glyceraldehyde 3-phosphate (an aldose). There are two classes of aldolases: class I aldolases, present in animals and plants, and class II aldolases, present in fungi and bacteria; the two classes use different mechanisms in cleaving the ketose ring.

Electrons delocalized in the carbon-carbon bond cleavage associate with the alcohol group. The resulting carbanion is stabilized by the structure of the carbanion itself via resonance charge distribution and by the presence of a charged ion prosthetic group.

Triosephosphate isomerase rapidly interconverts dihydroxyacetone phosphate with glyceraldehyde 3-phosphate (GADP) that proceeds further into glycolysis. This is advantageous, as it directs dihydroxyacetone phosphate down the same pathway as glyceraldehyde 3-phosphate, simplifying regulation.

Pay-off phase
The second half of glycolysis is known as the pay-off phase, characterised by a net gain of the energy-rich molecules ATP and NADH. Since glucose leads to two triose sugars in the preparatory phase, each reaction in the pay-off phase occurs twice per glucose molecule. This yields 2 NADH molecules and 4 ATP molecules, leading to a net gain of 2 NADH molecules and 2 ATP molecules from the glycolytic pathway per glucose.

The aldehyde groups of the triose sugars are oxidised, and inorganic phosphate is added to them, forming 1,3-bisphosphoglycerate.

The hydrogen is used to reduce two molecules of NAD+, a hydrogen carrier, to give NADH + H+ for each triose.

Hydrogen atom balance and charge balance are both maintained because the phosphate (Pi) group actually exists in the form of a hydrogen phosphate anion (HPO4(2−)), which dissociates to contribute the extra H+ ion and gives a net charge of -3 on both sides.

Here, arsenate ([AsO4](3-)), an anion akin to inorganic phosphate may replace phosphate as a substrate to form 1-arseno-3-phosphoglycerate. This, however, is unstable and readily hydrolyzes to form 3-phosphoglycerate, the intermediate in the next step of the pathway. As a consequence of bypassing this step, the molecule of ATP generated from 1-3 bisphosphoglycerate in the next reaction will not be made, even though the reaction proceeds. As a result, arsenate is an uncoupler of glycolysis.

This step is the enzymatic transfer of a phosphate group from 1,3-bisphosphoglycerate to ADP by phosphoglycerate kinase, forming ATP and 3-phosphoglycerate. At this step, glycolysis has reached the break-even point: 2 molecules of ATP were consumed, and 2 new molecules have now been synthesized. This step, one of the two substrate-level phosphorylation steps, requires ADP; thus, when the cell has plenty of ATP (and little ADP), this reaction does not occur. Because ATP decays relatively quickly when it is not metabolized, this is an important regulatory point in the glycolytic pathway.

ADP actually exists as ADPMg−, and ATP as ATPMg2−, balancing the charges at −5 both sides.

Cofactors: Mg2+

Phosphoglycerate mutase isomerises 3-phosphoglycerate into 2-phosphoglycerate.

Enolase next converts 2-phosphoglycerate to phosphoenolpyruvate. This reaction is an elimination reaction involving an E1cB mechanism.

Cofactors: 2 Mg2+, one "conformational" ion to coordinate with the carboxylate group of the substrate, and one "catalytic" ion that participates in the dehydration.

A final substrate-level phosphorylation now forms a molecule of pyruvate and a molecule of ATP by means of the enzyme pyruvate kinase. This serves as an additional regulatory step, similar to the phosphoglycerate kinase step.

Cofactors: Mg2+

Biochemical logic
The existence of more than one point of regulation indicates that intermediates between those points enter and leave the glycolysis pathway by other processes. For example, in the first regulated step, hexokinase converts glucose into glucose-6-phosphate. Instead of continuing through the glycolysis pathway, this intermediate can be converted into glucose storage molecules, such as glycogen or starch. The reverse reaction, breaking down, e.g., glycogen, produces mainly glucose-6-phosphate; very little free glucose is formed in the reaction. The glucose-6-phosphate so produced can enter glycolysis after the first control point.

In the second regulated step (the third step of glycolysis), phosphofructokinase converts fructose-6-phosphate into fructose-1,6-bisphosphate, which then is converted into glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. The dihydroxyacetone phosphate can be removed from glycolysis by conversion into glycerol-3-phosphate, which can be used to form triglycerides. Conversely, triglycerides can be broken down into fatty acids and glycerol; the latter, in turn, can be converted into dihydroxyacetone phosphate, which can enter glycolysis after the second control point.

Free energy changes
The change in free energy, ΔG, for each step in the glycolysis pathway can be calculated using ΔG = ΔG°′ + RTln Q, where Q is the reaction quotient. This requires knowing the concentrations of the metabolites. All of these values are available for erythrocytes, with the exception of the concentrations of NAD+ and NADH. The ratio of NAD+ to NADH in the cytoplasm is approximately 1000, which makes the oxidation of glyceraldehyde-3-phosphate (step 6) more favourable.

Using the measured concentrations of each step, and the standard free energy changes, the actual free energy change can be calculated. (Neglecting this is very common—the delta G of ATP hydrolysis in cells is not the standard free energy change of ATP hydrolysis quoted in textbooks).

From measuring the physiological concentrations of metabolites in an erythrocyte it seems that about seven of the steps in glycolysis are in equilibrium for that cell type. Three of the steps—the ones with large negative free energy changes—are not in equilibrium and are referred to as irreversible; such steps are often subject to regulation.

Step 5 in the figure is shown behind the other steps, because that step is a side-reaction that can decrease or increase the concentration of the intermediate glyceraldehyde-3-phosphate. That compound is converted to dihydroxyacetone phosphate by the enzyme triose phosphate isomerase, which is a catalytically perfect enzyme; its rate is so fast that the reaction can be assumed to be in equilibrium. The fact that ΔG is not zero indicates that the actual concentrations in the erythrocyte are not accurately known.

Regulation
The enzymes that catalyse glycolysis are regulated via a range of biological mechanisms in order to control overall flux though the pathway. This is vital for both homeostatsis in a static environment, and metabolic adaptation to a changing environment or need. The details of regulation for some enzymes are highly conserved between species, whereas others vary widely.

 * 1) Gene Expression: Firstly, the cellular concentrations of glycolytic enzymes are modulated via regulation of gene expression via transcription factors, with several glycolysis enzymes themselves acting as regulatory protein kinases in the nucleus.
 * 2) Allosteric inhibition and activation by metabolites: In particular end-product inhibition of regulated enzymes by metabolites such as ATP serves as negative feedback regulation of the pathway.
 * 3) Allosteric inhibition and activation by Protein-protein interactions (PPI). Indeed, some proteins interact with and regulate multiple glycolytic enzymes.
 * 4) Post-translational modification (PTM). In particular, phosphorylation and dephosphorylation is a key mechanism of regulation of pyruvate kinase in the liver.
 * 5) Localization

Regulation by insulin in animals
In animals, regulation of blood glucose levels by the pancreas in conjunction with the liver is a vital part of homeostasis. The beta cells in the pancreatic islets are sensitive to the blood glucose concentration. A rise in the blood glucose concentration causes them to release insulin into the blood, which has an effect particularly on the liver, but also on fat and muscle cells, causing these tissues to remove glucose from the blood. When the blood sugar falls the pancreatic beta cells cease insulin production, but, instead, stimulate the neighboring pancreatic alpha cells to release glucagon into the blood. This, in turn, causes the liver to release glucose into the blood by breaking down stored glycogen, and by means of gluconeogenesis. If the fall in the blood glucose level is particularly rapid or severe, other glucose sensors cause the release of epinephrine from the adrenal glands into the blood. This has the same action as glucagon on glucose metabolism, but its effect is more pronounced. In the liver glucagon and epinephrine cause the phosphorylation of the key, regulated enzymes of glycolysis, fatty acid synthesis, cholesterol synthesis, gluconeogenesis, and glycogenolysis. Insulin has the opposite effect on these enzymes. The phosphorylation and dephosphorylation of these enzymes (ultimately in response to the glucose level in the blood) is the dominant manner by which these pathways are controlled in the liver, fat, and muscle cells. Thus the phosphorylation of phosphofructokinase inhibits glycolysis, whereas its dephosphorylation through the action of insulin stimulates glycolysis.

Regulated Enzymes in Glycolysis
The three regulatory enzymes are hexokinase (or glucokinase in the liver), phosphofructokinase, and pyruvate kinase. The flux through the glycolytic pathway is adjusted in response to conditions both inside and outside the cell. The internal factors that regulate glycolysis do so primarily to provide ATP in adequate quantities for the cell's needs. The external factors act primarily on the liver, fat tissue, and muscles, which can remove large quantities of glucose from the blood after meals (thus preventing hyperglycemia by storing the excess glucose as fat or glycogen, depending on the tissue type). The liver is also capable of releasing glucose into the blood between meals, during fasting, and exercise thus preventing hypoglycemia by means of glycogenolysis and gluconeogenesis. These latter reactions coincide with the halting of glycolysis in the liver.

In addition hexokinase and glucokinase act independently of the hormonal effects as controls at the entry points of glucose into the cells of different tissues. Hexokinase responds to the glucose-6-phosphate (G6P) level in the cell, or, in the case of glucokinase, to the blood sugar level in the blood to impart entirely intracellular controls of the glycolytic pathway in different tissues (see below).

When glucose has been converted into G6P by hexokinase or glucokinase, it can either be converted to glucose-1-phosphate (G1P) for conversion to glycogen, or it is alternatively converted by glycolysis to pyruvate, which enters the mitochondrion where it is converted into acetyl-CoA and then into citrate. Excess citrate is exported from the mitochondrion back into the cytosol, where ATP citrate lyase regenerates acetyl-CoA and oxaloacetate (OAA). The acetyl-CoA is then used for fatty acid synthesis and cholesterol synthesis, two important ways of utilizing excess glucose when its concentration is high in blood. The regulated enzymes catalyzing these reactions perform these functions when they have been dephosphorylated through the action of insulin on the liver cells. Between meals, during fasting, exercise or hypoglycemia, glucagon and epinephrine are released into the blood. This causes liver glycogen to be converted back to G6P, and then converted to glucose by the liver-specific enzyme glucose 6-phosphatase and released into the blood. Glucagon and epinephrine also stimulate gluconeogenesis, which converts non-carbohydrate substrates into G6P, which joins the G6P derived from glycogen, or substitutes for it when the liver glycogen store have been depleted. This is critical for brain function, since the brain utilizes glucose as an energy source under most conditions. The simultaneously phosphorylation of, particularly, phosphofructokinase, but also, to a certain extent pyruvate kinase, prevents glycolysis occurring at the same time as gluconeogenesis and glycogenolysis.

Hexokinase and glucokinase
All cells contain the enzyme hexokinase, which catalyzes the conversion of glucose that has entered the cell into glucose-6-phosphate (G6P). Since the cell membrane is impervious to G6P, hexokinase essentially acts to transport glucose into the cells from which it can then no longer escape. Hexokinase is inhibited by high levels of G6P in the cell. Thus the rate of entry of glucose into cells partially depends on how fast G6P can be disposed of by glycolysis, and by glycogen synthesis (in the cells which store glycogen, namely liver and muscles).

Glucokinase, unlike hexokinase, is not inhibited by G6P. It occurs in liver cells, and will only phosphorylate the glucose entering the cell to form G6P, when the glucose in the blood is abundant. This being the first step in the glycolytic pathway in the liver, it therefore imparts an additional layer of control of the glycolytic pathway in this organ.

Phosphofructokinase
Phosphofructokinase is an important control point in the glycolytic pathway, since it is one of the irreversible steps and has key allosteric effectors, AMP and fructose 2,6-bisphosphate (F2,6BP).

F2,6BP is a very potent activator of phosphofructokinase (PFK-1) that is synthesized when F6P is phosphorylated by a second phosphofructokinase (PFK2). In the liver, when blood sugar is low and glucagon elevates cAMP, PFK2 is phosphorylated by protein kinase A. The phosphorylation inactivates PFK2, and another domain on this protein becomes active as fructose bisphosphatase-2, which converts F2,6BP back to F6P. Both glucagon and epinephrine cause high levels of cAMP in the liver. The result of lower levels of liver F2,6BP is a decrease in activity of phosphofructokinase and an increase in activity of fructose 1,6-bisphosphatase, so that gluconeogenesis (in essence, "glycolysis in reverse") is favored. This is consistent with the role of the liver in such situations, since the response of the liver to these hormones is to release glucose to the blood.

ATP competes with AMP for the allosteric effector site on the PFK enzyme. ATP concentrations in cells are much higher than those of AMP, typically 100-fold higher, but the concentration of ATP does not change more than about 10% under physiological conditions, whereas a 10% drop in ATP results in a 6-fold increase in AMP. Thus, the relevance of ATP as an allosteric effector is questionable. An increase in AMP is a consequence of a decrease in energy charge in the cell.

Citrate inhibits phosphofructokinase when tested in vitro by enhancing the inhibitory effect of ATP. However, it is doubtful that this is a meaningful effect in vivo, because citrate in the cytosol is utilized mainly for conversion to acetyl-CoA for fatty acid and cholesterol synthesis.

TIGAR, a p53 induced enzyme, is responsible for the regulation of phosphofructokinase and acts to protect against oxidative stress. TIGAR is a single enzyme with dual function that regulates F2,6BP. It can behave as a phosphatase (fructuose-2,6-bisphosphatase) which cleaves the phosphate at carbon-2 producing F6P. It can also behave as a kinase (PFK2) adding a phosphate onto carbon-2 of F6P which produces F2,6BP. In humans, the TIGAR protein is encoded by C12orf5 gene. The TIGAR enzyme will hinder the forward progression of glycolysis, by creating a build up of fructose-6-phosphate (F6P) which is isomerized into glucose-6-phosphate (G6P). The accumulation of G6P will shunt carbons into the pentose phosphate pathway.

Pyruvate kinase

The final step of glycolysis is catalysed by pyruvate kinase to form pyruvate and another ATP. It is regulated by a range of different transcriptional, covalent and non-covalent regulation mechanisms, which can vary widely in different tissues. For example, in the liver, pyruvate kinase is regulated based on glucose availability. During fasting (no glucose available), glucagon activates protein kinase A which phosphorylates pyruvate kinase to inhibit it. An increase in blood sugar leads to secretion of insulin, which activates protein phosphatase 1, leading to dephosphorylation and re-activation of pyruvate kinase. These controls prevent pyruvate kinase from being active at the same time as the enzymes that catalyze the reverse reaction (pyruvate carboxylase and phosphoenolpyruvate carboxykinase), preventing a futile cycle. Conversely, the isoform of pyruvate kinasein found in muscle is not affected by protein kinase A (which is activated by adrenaline in that tissue), so that glycolysis remains active in muscles even during fasting.

Post-glycolysis processes
The overall process of glycolysis is:

 * Glucose + 2 NAD+ + 2 ADP + 2 Pi → 2 Pyruvate + 2 NADH + 2 H+ + 2 ATP + 2 H2O

If glycolysis were to continue indefinitely, all of the NAD+ would be used up, and glycolysis would stop. To allow glycolysis to continue, organisms must be able to oxidize NADH back to NAD+. How this is performed depends on which external electron acceptor is available.

Anoxic regeneration of NAD+
One method of doing this is to simply have the pyruvate do the oxidation; in this process, pyruvate is converted to lactate (the conjugate base of lactic acid) in a process called lactic acid fermentation:

 * Pyruvate + NADH + H+ → Lactate + NAD+

This process occurs in the bacteria involved in making yogurt (the lactic acid causes the milk to curdle). This process also occurs in animals under hypoxic (or partially anaerobic) conditions, found, for example, in overworked muscles that are starved of oxygen. In many tissues, this is a cellular last resort for energy; most animal tissue cannot tolerate anaerobic conditions for an extended period of time.

Some organisms, such as yeast, convert NADH back to NAD+ in a process called ethanol fermentation. In this process, the pyruvate is converted first to acetaldehyde and carbon dioxide, and then to ethanol.

Lactic acid fermentation and ethanol fermentation can occur in the absence of oxygen. This anaerobic fermentation allows many single-cell organisms to use glycolysis as their only energy source.

Anoxic regeneration of NAD+ is only an effective means of energy production during short, intense exercise in vertebrates, for a period ranging from 10 seconds to 2 minutes during a maximal effort in humans. (At lower exercise intensities it can sustain muscle activity in diving animals, such as seals, whales and other aquatic vertebrates, for very much longer periods of time.) Under these conditions NAD+ is replenished by NADH donating its electrons to pyruvate to form lactate. This produces 2 ATP molecules per glucose molecule, or about 5% of glucose's energy potential (38 ATP molecules in bacteria). But the speed at which ATP is produced in this manner is about 100 times that of oxidative phosphorylation. The pH in the cytoplasm quickly drops when hydrogen ions accumulate in the muscle, eventually inhibiting the enzymes involved in glycolysis.

The burning sensation in muscles during hard exercise can be attributed to the release of hydrogen ions during the shift to glucose fermentation from glucose oxidation to carbon dioxide and water, when aerobic metabolism can no longer keep pace with the energy demands of the muscles. These hydrogen ions form a part of lactic acid. The body falls back on this less efficient but faster method of producing ATP under low oxygen conditions. This is thought to have been the primary means of energy production in earlier organisms before oxygen reached high concentrations in the atmosphere between 2000 and 2500 million years ago, and thus would represent a more ancient form of energy production than the aerobic replenishment of NAD+ in cells.

The liver in mammals gets rid of this excess lactate by transforming it back into pyruvate under aerobic conditions; see Cori cycle.

Fermentation of pyruvate to lactate is sometimes also called "anaerobic glycolysis", however, glycolysis ends with the production of pyruvate regardless of the presence or absence of oxygen.

In the above two examples of fermentation, NADH is oxidized by transferring two electrons to pyruvate. However, anaerobic bacteria use a wide variety of compounds as the terminal electron acceptors in cellular respiration: nitrogenous compounds, such as nitrates and nitrites; sulfur compounds, such as sulfates, sulfites, sulfur dioxide, and elemental sulfur; carbon dioxide; iron compounds; manganese compounds; cobalt compounds; and uranium compounds.

Aerobic regeneration of NAD+ and further catabolism of pyruvate
In aerobic eukaryotes, a complex mechanism has developed to use the oxygen in air as the final electron acceptor, in a process called oxidative phosphorylation. Aerobic prokaryotes, which lack mitochondria, use a variety of simpler mechanisms.
 * Firstly, the NADH + H+ generated by glycolysis has to be transferred to the mitochondrion to be oxidized, and thus to regenerate the NAD+ necessary for glycolysis to continue. However the inner mitochondrial membrane is impermeable to NADH and NAD+.  Use is therefore made of two “shuttles” to transport the electrons from NADH across the mitochondrial membrane. They are the malate-aspartate shuttle and the glycerol phosphate shuttle. In the former the electrons from NADH are transferred to cytosolic oxaloacetate to form malate. The malate then traverses the inner mitochondrial membrane into the mitochondrial matrix, where it is reoxidized by NAD+ forming intra-mitochondrial oxaloacetate and NADH. The oxaloacetate is then re-cycled to the cytosol via its conversion to aspartate which is readily transported out of the mitochondrion. In the glycerol phosphate shuttle electrons from cytosolic NADH are transferred to dihydroxyacetone to form glycerol-3-phosphate which readily traverses the outer mitochondrial membrane. Glycerol-3-phosphate is then reoxidized to dihydroxyacetone, donating its electrons to FAD instead of NAD+. This reaction takes place on the inner mitochondrial membrane, allowing FADH2 to donate its electrons directly to coenzyme Q (ubiquinone) which is part of the electron transport chain which ultimately transfers electrons to molecular oxygen O2, with the formation of water, and the release of energy eventually captured in the form of ATP.
 * The glycolytic end-product, pyruvate (plus NAD+) is converted to acetyl-CoA, CO2 and NADH + H+ within the mitochondria in a process called pyruvate decarboxylation.
 * The resulting acetyl-CoA enters the citric acid cycle (or Krebs Cycle), where the acetyl group of the acetyl-CoA is converted into carbon dioxide by two decarboxylation reactions with the formation of yet more intra-mitochondrial NADH + H+.
 * The intra-mitochondrial NADH + H+ is oxidized to NAD+ by the electron transport chain, using oxygen as the final electron acceptor to form water. The energy released during this process is used to create a hydrogen ion (or proton) gradient across the inner membrane of the mitochondrion.
 * Finally, the proton gradient is used to produce about 2.5 ATP for every NADH + H+ oxidized in a process called oxidative phosphorylation.

Conversion of carbohydrates into fatty acids and cholesterol
The pyruvate produced by glycolysis is an important intermediary in the conversion of carbohydrates into fatty acids and cholesterol. This occurs via the conversion of pyruvate into acetyl-CoA in the mitochondrion. However, this acetyl CoA needs to be transported into cytosol where the synthesis of fatty acids and cholesterol occurs. This cannot occur directly. To obtain cytosolic acetyl-CoA, citrate (produced by the condensation of acetyl CoA with oxaloacetate) is removed from the citric acid cycle and carried across the inner mitochondrial membrane into the cytosol. There it is cleaved by ATP citrate lyase into acetyl-CoA and oxaloacetate. The oxaloacetate is returned to mitochondrion as malate (and then back into oxaloacetate to transfer more acetyl-CoA out of the mitochondrion). The cytosolic acetyl-CoA can be carboxylated by acetyl-CoA carboxylase into malonyl CoA, the first committed step in the  synthesis of fatty acids, or it can be combined with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) which is the rate limiting step controlling the synthesis of cholesterol. Cholesterol can be used as is, as a structural component of cellular membranes, or it can be used to synthesize the steroid hormones, bile salts, and vitamin D.

Conversion of pyruvate into oxaloacetate for the citric acid cycle
Pyruvate molecules produced by glycolysis are actively transported across the inner mitochondrial membrane, and into the matrix where they can either be oxidized and combined with coenzyme A to form CO2, acetyl-CoA, and NADH, or they can be carboxylated (by pyruvate carboxylase) to form oxaloacetate. This latter reaction "fills up" the amount of oxaloacetate in the citric acid cycle, and is therefore an anaplerotic reaction (from the Greek meaning to "fill up"), increasing the cycle's capacity to metabolize acetyl-CoA when the tissue's energy needs (e.g. in heart and skeletal muscle) are suddenly increased by activity. In the citric acid cycle all the intermediates (e.g. citrate, iso-citrate, alpha-ketoglutarate, succinate, fumarate, malate and oxaloacetate) are regenerated during each turn of the cycle. Adding more of any of these intermediates to the mitochondrion therefore means that that additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other. Hence the addition of oxaloacetate greatly increases the amounts of all the citric acid intermediates, thereby increasing the cycle's capacity to metabolize acetyl CoA, converting its acetate component into CO2 and water, with the release of enough energy to form 11 ATP and 1 GTP molecule for each additional molecule of acetyl CoA that combines with oxaloacetate in the cycle.

To cataplerotically remove oxaloacetate from the citric cycle, malate can be transported from the mitochondrion into the cytoplasm, decreasing the amount of oxaloacetate that can be regenerated. Furthermore, citric acid intermediates are constantly used to form a variety of substances such as the purines, pyrimidines and porphyrins.

Intermediates for other pathways
This article concentrates on the catabolic role of glycolysis with regard to converting potential chemical energy to usable chemical energy during the oxidation of glucose to pyruvate. Many of the metabolites in the glycolytic pathway are also used by anabolic pathways, and, as a consequence, flux through the pathway is critical to maintain a supply of carbon skeletons for biosynthesis.

The following metabolic pathways are all strongly reliant on glycolysis as a source of metabolites: and many more.
 * Pentose phosphate pathway, which begins with the dehydrogenation of glucose-6-phosphate, the first intermediate to be produced by glycolysis, produces various pentose sugars, and NADPH for the synthesis of fatty acids and cholesterol.
 * Glycogen synthesis also starts with glucose-6-phosphate at the beginning of the glycolytic pathway.
 * Glycerol, for the formation of triglycerides and phospholipids, is produced from the glycolytic intermediate glyceraldehyde-3-phosphate.
 * Various post-glycolytic pathways:
 * Fatty acid synthesis
 * Cholesterol synthesis
 * The citric acid cycle which in turn leads to:
 * Amino acid synthesis
 * Nucleotide synthesis
 * Tetrapyrrole synthesis

Although gluconeogenesis and glycolysis share many intermediates the one is not functionally a branch or tributary of the other. There are two regulatory steps in both pathways which, when active in the one pathway, are automatically inactive in the other. The two processes can therefore not be simultaneously active. Indeed, if both sets of reactions were highly active at the same time the net result would be the hydrolysis of four high energy phosphate bonds (two ATP and two GTP) per reaction cycle.

NAD+ is the oxidizing agent in glycolysis, as it is in most other energy yielding metabolic reactions (e.g. beta-oxidation of fatty acids, and during the citric acid cycle). The NADH thus produced is primarily used to ultimately transfer electrons to O2 to produce water, or, when O2 is not available, to produce compounds such as lactate or ethanol (see Anoxic regeneration of NAD+ above). NADH is rarely used for synthetic processes, the notable exception being gluconeogenesis. During fatty acid and cholesterol synthesis the reducing agent is NADPH. This difference exemplifies a general principle that NADPH is consumed during biosynthetic reactions, whereas NADH is generated in energy-yielding reactions. The source of the NADPH is two-fold. When malate is oxidatively decarboxylated by “NADP+-linked malic enzyme" pyruvate, CO2 and NADPH are formed. NADPH is also formed by the pentose phosphate pathway which converts glucose into ribose, which can be used in synthesis of nucleotides and nucleic acids, or it can be catabolized to pyruvate.

Diabetes
Cellular uptake of glucose occurs in response to insulin signals, and glucose is subsequently broken down through glycolysis, lowering blood sugar levels. However, insulin resistance or low insulin levels seen in diabetes result in hyperglycemia, where glucose levels in the blood rise and glucose is not properly taken up by cells. Hepatocytes further contribute to this hyperglycemia through gluconeogenesis. Glycolysis in hepatocytes controls hepatic glucose production, and when glucose is overproduced by the liver without having a means of being broken down by the body, hyperglycemia results.

Genetic diseases
Glycolytic mutations are generally rare due to importance of the metabolic pathway; the majority of occurring mutations result in an inability of the cell to respire, and therefore cause the death of the cell at an early stage. However, some mutations (glycogen storage diseases and other inborn errors of carbohydrate metabolism) are seen with one notable example being pyruvate kinase deficiency, leading to chronic hemolytic anemia.

Cancer
Malignant tumor cells perform glycolysis at a rate that is ten times faster than their noncancerous tissue counterparts. During their genesis, limited capillary support often results in hypoxia (decreased O2 supply) within the tumor cells. Thus, these cells rely on anaerobic metabolic processes such as glycolysis for ATP (adenosine triphosphate). Some tumor cells overexpress specific glycolytic enzymes which result in higher rates of glycolysis. Often these enzymes are Isoenzymes, of traditional glycolysis enzymes, that vary in their susceptibility to traditional feedback inhibition. The increase in glycolytic activity ultimately counteracts the effects of hypoxia by generating sufficient ATP from this anaerobic pathway. This phenomenon was first described in 1930 by Otto Warburg and is referred to as the Warburg effect. The Warburg hypothesis claims that cancer is primarily caused by dysfunctionality in mitochondrial metabolism, rather than because of the uncontrolled growth of cells. A number of theories have been advanced to explain the Warburg effect. One such theory suggests that the increased glycolysis is a normal protective process of the body and that malignant change could be primarily caused by energy metabolism.

This high glycolysis rate has important medical applications, as high aerobic glycolysis by malignant tumors is utilized clinically to diagnose and monitor treatment responses of cancers by imaging uptake of 2-18F-2-deoxyglucose (FDG) (a radioactive modified hexokinase substrate) with positron emission tomography (PET).

There is ongoing research to affect mitochondrial metabolism and treat cancer by reducing glycolysis and thus starving cancerous cells in various new ways, including a ketogenic diet.

Interactive pathway map
The diagram below shows human protein names. Names in other organisms may be different and the number of isozymes (such as HK1, HK2, ...) is likely to be different too.

Alternative nomenclature
Some of the metabolites in glycolysis have alternative names and nomenclature. In part, this is because some of them are common to other pathways, such as the Calvin cycle.

Structure of glycolysis components in Fischer projections and polygonal model
The intermediates of glycolysis depicted in Fischer projections show the chemical changing step by step. Such image can be compared to polygonal model representation.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Glycolysis


text:
Gary North (economist)

Gary Kilgore North (February 11, 1942 – February 24, 2022) was an American writer, Austrian School economic historian, and leading figure in the Christian reconstructionist movement. North authored or coauthored over fifty books on topics including Reformed Protestant theology, economics, and history. He was an Associated Scholar of the Mises Institute.

He is known for his advocacy of biblical or "radically libertarian" free-market economics and also as a theorist of dominionism and theonomy. North often invoked the Protestant work ethic to advance these views. He supported the establishment and enforcement of Bible-based religious law, a view which put him in conflict with other libertarians. He believed that capital punishment is appropriate punishment for male homosexuality, adultery, blasphemy, abortion, and witchcraft.

Early life and education
North was born in Los Angeles, California, on February 11, 1942, and grew up in Southern California, the son of FBI special agent Samuel W. North Jr. and his wife Peggy. North converted to Christianity in high school and, after attending a rally where anti-communist activist Fred Schwarz spoke, began frequenting conservative book-stores in the Los Angeles area during his college years. Between 1961 and 1963, while an undergraduate student at University of California, Riverside, North became acquainted with the works of Wilhelm Röpke, Rose Wilder Lane, Cornelius Van Til, Austrian School economists Eugen Böhm von Bawerk, Ludwig von Mises, F. A. Hayek and Murray Rothbard, and also read the works of Calvinist philosopher Rousas John Rushdoony. Later he married Rushdoony's daughter, collaborated with him and eulogized Rushdoony in a blog post on LewRockwell.com.

Career
Starting in 1967, North became a contributor to the libertarian journal The Freeman where he had first read the work of Ludwig von Mises and Friedrich Hayek. In the 1970s, he was the director of seminars for the Foundation for Economic Education (FEE). North received a PhD in history from the University of California, Riverside in 1972. His dissertation was The Concept of Property in Puritan New England, 1630–1720.

He served as research assistant for libertarian Republican Congressman Ron Paul in Paul's first term (1976). North was a regular contributor to the LewRockwell.com website, which lists an extensive archive of his articles there. North's own website, Garynorth.com, posts commentary on religious, social, and political issues and offers paid access to investment advice and other premium content. North also published a blog called Deliverance from Debt which provided advice about relief from debt. Another North website, "Free Christian Curriculum", seeks to provide a free Christian homeschooling curriculum for children from age 3 through grade 12.

Ron Paul curriculum
In addition, North offered the Ron Paul Curriculum, a home school online curriculum associated with former U.S. Congressman Ron Paul, which is free for grades K–5 and available to paid members from grades 6–12. As director of curriculum development, North outlined four goals of the educational project: providing a "detailed study" of the "history of liberty"; teaching a "thorough understanding of Austrian economics"; serving as "an academically rigorous curriculum that is tied to primary source" material rather than textbooks; and teaching "the Biblical principle of self-government and personal responsibility", which North called "the foundation of the market economy".

Christian, Bible-based economic methodology
North wrote that the "starting point for all economic analysis" lies in accepting that "God [has] cursed the earth" in the Book of Genesis 3:17–19; this "made scarcity an inescapable fact of man's existence". In his 1982 Dominion Covenant: Genesis, North wrote that mainstream modern economics, whether libertarian, conservative or liberal, is "in disintegration" because it is "humanist" in its approach and consequently rejects the notion that "biblical revelation" is necessary for sound economic theory. He also wrote that economics "must begin with the [Biblical] story of creation" if it is not to collapse into "total chaos".

Proposed "Christian theocratic" political and social order
A 2011 article in The New York Times identified North as a central figure in Christian reconstructionism, the philosophy which advocates the institution of "a Christian theocracy under Old Testament law [as] the best form of government, and a radically libertarian one." North wrote: "I certainly believe in biblical theocracy."

The article also described North as "the leading proponent of 'Christian economics,' which applies biblical principles to economic issues and the free market." North supported the abolition of the fractional-reserve banking system and a return to the gold standard. According to the Times, North believed that the Bible forbids inflation, welfare programs, and also writes that "God would prefer gold money to paper".

Range of capital offenses
North favored capital punishment for a range of offenders, including murderers, blasphemers, children who curse their parents, male homosexuals, and other people who commit some of the acts deemed capital offenses in the Old Testament. (North believed that the death penalty for sabbath breaking and some other crimes no longer applies. ) North stated that the biblical admonition to kill homosexuals in the Book of Leviticus is God's "law and its morally appropriate sanction", arguing that "God is indeed a homophobe" who "hates the practice [of homosexuality] and those who practice it" and "hates the sin and hates the sinner."

North said that capital punishment should be carried out by stoning, because it is the biblically approved method of execution and it is cheap due to the plentiful and convenient supply of stones.

Religious liberty
North said: "We must use the doctrine of religious liberty to gain independence for Christian schools until we train up a generation of people who know that there is no religious neutrality, no neutral law, no neutral education, and no neutral civil government. Then they will get busy in constructing a Bible-based social, political and religious order which finally denies the religious liberty of the enemies of God."

Adam C. English suggests that this quote implies that "religious liberty is a useful tool to Christians in the present, yet is ultimately to be denied to anyone who is not Christian once the Christians are in power". English argues that although this may seem inconsistent (advocating religious liberty but denying the reality of the notion), North and his fellow reconstructionists understand "liberty" in a theological sense. According to the reconstructionists, "anyone outside of the Christian faith is in bondage," and so "government by rigorous theonomy is not oppressive but liberating".

Y2K
North was also a prominent promoter of exaggerated predictions of computer failure from the Year 2000 problem (Y2K) during the late 1990s,    earning him the nickname "Scary Gary." His main website became dominated by links to extremist predictions for Y2K damage, including widespread collapse of governments and financial institutions. North declared on his home page that Y2K "may be the biggest problem that the modern world has ever faced" and labeled 2000 as "The Year the Earth Stands Still".

Critics said the motivation for North's predictions was linked to his Christian reconstructionist aims, which require widespread societal collapse to set the stage for a new theocratic order. North made the connection explicit in communications with fellow reconstructionists: "The Y2K crisis is systemic. It cannot possibly be fixed. I think it will wipe out every national government in the West. Not just modify them—destroy them...That is what I have wanted all my adult life. In my view, Y2K is our deliverance."

Death
North was diagnosed with prostate cancer in 2017, and underwent treatment for about five years. He died in Dallas, Georgia, on February 24, 2022, at the age of 80.

Institute for Christian Economics
North was the founder of the Institute for Christian Economics (ICE), which publishes online books and magazines focusing on Christian ethics. ICE, along with Dominion Press in Tyler, Texas, are important sources for reconstructionist publications.

Books and newsletters
North authored or coauthored more than fifty books, many of which are available for free download. For many years, North was the author and editor of the newsletter The Remnant Review. He also provided Gary North's Reality Check, a free e-newsletter.

Documentary and educational film

 * Unknown History of the 20th Century (DVD) (2006)

title: Gary North (economist)


text:
Guernica

Guernica, officially Gernika in Basque, is a town in the province of Biscay, in the Autonomous Community of the Basque Country, Spain. The town of Guernica is one part (along with neighbouring Lumo) of the municipality of Gernika-Lumo (Guernica y Luno), whose population is 16,224.

On April 26, 1937, Guernica was bombed by Nazi Germany's Condor Legion, in one of the first aerial bombings. The attack inspired Pablo Picasso's painting Guernica, depicting his outrage at the attack.

Location
The village is situated in the region of Busturialdea, in the valley of the Oka river. The river ends in an estuary that gives its name to the village of Guernika. Its mouth is known as the Urdaibai's estuary's heart. Gernika borders on the following townships:
 * North: Forua, Kortezubi and Arratzu
 * East: Ajangiz
 * South: Muxika
 * West: Errigoiti

1366-1936
The town of Guernica was founded by Tello Alfonso, Lord of Biscay, on April 28, 1366, at the intersection of the road from Bermeo to Durango with the road from Bilbao to Elantxobe and Lekeitio. The strategic importance of the site was increased by the fact that it lay on a major river estuary, where vessels could dock at the port of Suso.

In time, it took on the typical shape of a Basque town, comprising a series of parallel streets (Goienkale, Azokekale, Artekale and Barrenkale; respectively: ‘upper, market, between, lower roads’) and a transverse street called Santa María, with a church at each end of the built-up area.

Life in the town became rigidly structured, with the aim being to preserve the privileges of the dominant middle classes. This pattern continued practically unaltered until the late 17th century.

On a small hillock in the town, stands the Meeting House and the Tree of Gernika. By ancient tradition, Basques, and indeed other peoples in Medieval Europe, held assemblies under a tree, usually an oak, to discuss matters affecting the community.

In Biscay, each administrative district (known as a merindad) had its appointed tree, but over the centuries, the Tree of Guernica acquired particular importance. It stood in the parish of Lumo, on a site known as Gernikazarra, beside a small shrine.

The laws of Biscay continued to be drawn up under this tree until 1876, with each town and village in the province sending two representatives to the sessions, known as General Assemblies. This early form of democracy was recorded by the philosopher Rousseau, by the poet William Wordsworth, by the dramatist Tirso de Molina and by the composer Iparragirre, who wrote the piece called Gernikako Arbola ("The Tree of Gernika" in Basque).

When the Domain of Biscay was incorporated into the kingdom of Castile, the king of Castile visited Guernica and swore an oath under the Tree promising to uphold the fueros or local laws of Biscay. The oath of King Ferdinand, known as the "Catholic Monarch", on June 30, 1476, is depicted in a painting by Francisco de Mendieta popularly known as "El besamanos" ("The Royal audience"). On July 3, 1875, during the Carlist Wars, the pretender to the throne, Don Carlos, also visited Guernica and swore the oath. Throughout the 19th century, there were frequent meetings under the Tree, including both General Assemblies and other political events.

By the 18th century, there was a square at the centre of the town, flanked by the town hall, a public gaol housing prisoners from all over the Lordship of Biscay, a hospital and a poor-house for local people. Day-to-day life comprised agriculture (growing of cereals, vegetable and fruit), crafts (menders, tailors, cobblers, flax manufacturers) and trade (transportation and sale of goods and produce).

This was also a time of continual conflicts with the neighbouring parish of Lumo over disputed land. These disputes were not finally settled until 1882, when the two parishes joined to form Gernika-Lumo.

The first industrial factories were set up in the early years of the 20th century. This encouraged population growth, and the town grew from 4,500 inhabitants in 1920 to 6,000 in 1936.

Civil War: 1937 bombing
On April 26, 1937, during the Spanish Civil War, Guernica was the scene of a massive aerial bombing attack by the Condor Legion of Nazi Germany's Luftwaffe and the Italian Aviazione Legionaria. According to official Basque figures, 1,654 civilians were killed, but German sources report a round figure of 300 civilians killed in the bombing, according to the German Bundeswehr Magazine (published in April 2007, page 94). The raid was requested by Francisco Franco to aid in his overthrowing the Basque Government and the Spanish Republican government. The town was devastated, though the Biscayan assembly and the Oak of Guernica survived. The Bombing of Guernica, which went on continuously for three hours, is considered the beginning of the Luftwaffe doctrine of terror bombing civilian targets in order to demoralize the enemy.

In art
Pablo Picasso painted his Guernica painting to commemorate the horrors of the bombing and René Iché made a violent sculpture the day after the bombing. It has inspired musical compositions by Octavio Vazquez (Gernika piano trio), René-Louis Baron, Lenny White, and Mike Batt (performed by Katie Melua), and poems by Paul Eluard (Victory of Guernica), and Uys Krige (Nag van die Fascistiese Bomwerpers; English translation from the Afrikaans: Night of the Fascist Bombers). There is also a short film from 1950, by Alain Resnais, titled Guernica.

Celebrations were staged in 1966 to mark the 600th anniversary of the founding of the town. As part of these celebrations, a statue of Count Tello, made by local sculptor Agustín Herranz, was set up in the Fueros Square.

21st century
As of 2009, Gernika-Lumo had 16,244 inhabitants. It is a town with a prosperous service sector, and is also home to industrial companies, as well as good cultural and educational amenities.

Cultural importance
Guernica is historically the seat of the parliament of the province of Biscay, whose executive branch is located in nearby Bilbao.

In prior centuries, Lumo had been the meeting place of the traditional Biscayan assembly, Urduña and chartered towns like Guernica were under the direct authority of the Lord of Biscay, and Enkarterri and the Durango area had separate assemblies. All would hold assemblies under local big trees. As time passed, the role of separate assemblies was superseded by the single assembly in Guernica, and by 1512, its oak, known as the Gernikako Arbola, became symbolic of the traditional rights of the Basque people as a whole.

The trees are always renewed from their own acorns. One of these trees (the "Old Tree") lived until the 19th century, and may be seen, as a dry stump, near the assembly house. A tree planted in 1860 to replace it died in 2004 and was in turn replaced; the sapling that had been chosen to become the official Oak of Guernica is also sick so the tree will not be replaced until the earth around the site has been restored to health.

A hermitage was built beside the Gernikako Arbola to double as an assembly place, followed by the current house of assembly (Biltzar Jauregia in Basque), built in 1826.

Symbol for peace
On April 26, 1937, during the Spanish Civil War, the town was razed to the ground by German aircraft belonging to the Condor Legion, sent by Hitler to support Franco's troops. For almost four hours bombs rained down on Guernica in an "experiment" for the blitzkrieg tactics and bombing of civilians seen in later wars.

In 1987 the 50th anniversary of the bombing was commemorated as the town hosted the Preliminary Congress of the World Association of Martyr Cities. The full congress was held subsequently in Madrid, bringing together representatives of cities all over the world. Since then, Gernika-Lumo has been a member of this association. 1988 saw the setting up of the monument Gure Aitaren Etxea, by Basque sculptor Eduardo Chillida, and in 1990 Large Figure in a Shelter, by British sculptor Henry Moore, was erected beside it. These monuments are symbolic of Gernika-Lumo as a city of peace.

As part of the "Symbol for Peace" movement, Gernika has twinned with several towns, including Berga (Catalonia – 1986), Pforzheim (Germany – 1988) and Boise, Idaho (United States – 1993). The twinning agreements include co-operation in the fields of culture, education and industry.

Market day
There is a popular saying in Guernica which runs as follows: "lunes gerniqués, golperik ez". A combination of both local languages (Castillian and Basque) into a single sentence, this translates roughly as "not a stroke of work gets done on Mondays". The Monday market day has for decades been considered as a holiday in the town.

People would flock to Guernica not just from the immediate vicinity, but from all over the province, so that the town was packed. They came not just to buy or sell at the produce market, but also to eat at the town's renowned restaurants and afterwards perhaps to watch a pelota game at the local court. The Monday market has been fulfilling its age-old function of bringing people together since the times when people could not afford to travel far and it provided them with a chance to socialise. The bombing of Guernica by Nazi Germany's Luftwaffe and the Italian Aviazione Legionaria was deliberately chosen to occur on a Monday (April 26, 1937), because it was known that the Basque people who lived outside of Guernica proper would travel into town for the Market Day, thus affording the pilots of the German and Italian aircraft the opportunity to murder as many people as possible.

Sports

Jai alai (cesta-punta) is a form of pelota. The Guernica jai alai court is the biggest operational court of its type in the world. It was designed by Secundino Zuano, one of Spain's leading architects of the 20th century and first opened in 1963. It is acknowledged by players of the game to be the world's finest court.

Bare-handed pelota games are held at the Santanape court. This is the most popular form of the sport.

Twin towns – sister cities

 * 🇪🇸 Berga, Catalonia, Spain
 * 🇮🇶 Halabja, Kurdistan Region, Iraq
 * 🇩🇪 Pforzheim, Germany
 * 🇺🇸 Boise, Idaho, United States
 * 🇺🇦 Irpin, Ukraine (2022)

Notable people

 * Manuel Allendesalazar y Muñoz de Salazar (1856-1923), conservative politician
 * Teodoro de Arana y Beláustegui (1858-1945), Carlist politician
 * Rafael Iriondo (1918-2016), footballer and manager
 * Mauricio Ugartemendia Lauzirika (1934-2022), footballer
 * Sofía Gandarias (1957-2016), painter
 * Fernando Lamikiz Garai (born 1959), lawyer, economist and sports manager
 * Enrique Guerrikagoitia (born 1967), cyclist
 * Ainhoa Ibarra Astellara (born 1968), alpine skier
 * Roberto Laiseka (born 1969), cyclist
 * Yolanda Alzola (born 1970), actress
 * Joane Somarriba (born 1972), cyclist
 * Gorka Gerrikagoitia (born 1973), cyclist
 * Rubén Oarbeascoa (born 1975), cyclist
 * Lander Euba (born 1977), cyclist
 * Andoni Lafuente (born 1985), cyclist
 * Pello Bilbao (born 1990), cyclist
 * Gorka Larrucea (born 1993), footballer
 * Koldo Obieta (born 1993), footballer
 * Iker Amorrortu (born 1995), footballer
 * Asier Villalibre (born 1997), footballer

title: Guernica


text:
Gerrit Rietveld

Gerrit Rietveld (24 June 1888 – 25 June 1964) was a Dutch furniture designer and architect.

Early life
Rietveld was born in Utrecht on 24 June 1888 as the son of a joiner. He left school at 11 to be apprenticed to his father and enrolled at night school before working as a draughtsman for C. J. Begeer, a jeweller in Utrecht, from 1906 to 1911.

De Stijl
By the time he opened his own furniture workshop in 1917, Rietveld had taught himself drawing, painting and model-making. He afterwards set up in business as a cabinet-maker.

Rietveld designed his Red and Blue Chair in 1917 which has become an iconic piece of modern furniture. Hoping that much of his furniture would eventually be mass-produced rather than handcrafted, Rietveld aimed for simplicity in construction. In 1918, he started his own furniture factory, and changed the chair's colours after becoming influenced by the De Stijl movement, of which he became a member in 1919, the same year in which he became an architect. The contacts that he made at De Stijl gave him the opportunity to exhibit abroad as well. In 1923, Walter Gropius invited Rietveld to exhibit at the Bauhaus.

He built the Rietveld Schröder House, in 1924, in close collaboration with the owner Truus Schröder-Schräder. Built in Utrecht on the Prins Hendriklaan 50, the house has a conventional ground floor, but is radical on the top floor, lacking fixed walls but instead relying on sliding walls to create and change living spaces. The house has been a UNESCO World Heritage Site since 2000. His involvement in the Schröder House exerted a strong influence on Truus' daughter, Han Schröder, who became one of the first female architects in the Netherlands.

Nieuwe Zakelijkheid

Rietveld broke with De Stijl in 1928 and became associated with a more functionalist style of architecture, known as either Nieuwe Zakelijkheid or Nieuwe Bouwen. The same year he joined the Congrès Internationaux d'Architecture Moderne. From the late 1920s he was concerned with social housing, inexpensive production methods, new materials, prefabrication and standardisation. In 1927 he was already experimenting with prefabricated concrete slabs, a very unusual material at that time. In the 1920s and 1930s, however, all his commissions came from private individuals, and it was not until the 1950s that he was able to put his progressive ideas about social housing into practice, in projects in Utrecht and Reeuwijk.

Rietveld designed the Zig-Zag Chair in 1934 and started the design of the Van Gogh Museum in Amsterdam, which was finished after his death.

De Stijl revival

In 1951 Rietveld designed a retrospective exhibition about De Stijl which was held in Amsterdam, Venice and New York. Interest in his work revived as a result. In subsequent years he was given many commissions, including the Dutch pavilion for the Venice Biennale (1953), the art academies in Amsterdam and Arnhem, and the press room for the UNESCO building in Paris. Designed for the display of small sculptures at the Third International Sculpture Exhibition in Arnhem's Sonsbeek Park in 1955, Rietveld's 'Sonsbeek Pavilion' was rebuilt at the Kröller-Müller Museum in 1965. Due to irreparable damages caused by regular decay, it was once again rebuilt, this time with new materials, in 2010. In order to handle all these projects, in 1961 Rietveld set up a partnership with the architects Johan van Dillen and J. van Tricht built hundreds of homes, many of them in the city of Utrecht.

His work was neglected when rationalism came into vogue, but he later benefited from a revival of the style of the 1920s thirty years later.

Death
Rietveld died on 25 June 1964 in Utrecht.

His son Wim Rietveld also became a renowned industrial designer.

Recognition
Rietveld had his first retrospective exhibition devoted to his architectural work at the Central Museum, Utrecht, in 1958. When the art academy in Amsterdam became part of the higher professional education system in 1968 and was given the status of an Academy for Fine Arts and Design, the name was changed to the Gerrit Rietveld Academy in honour of Rietveld. "Gerrit Rietveld: A Centenary Exhibition" at the Barry Friedman Gallery, New York, in 1988 was the first comprehensive presentation of the Dutch architect's original works ever held in the U.S. The highlight of a celebratory "Rietveld Year" in Utrecht, the exhibition "Rietveld's Universe" opened at the Centraal Museum and compared him and his work with famous contemporaries like Wright, Le Corbusier and Mies van der Rohe.

Two software tools,           both for code review, have been named after Gerrit Rietveld: Gerrit and Rietveld.

title: Gerrit Rietveld


text:
Gary

Gary may refer to:
 * Gary (given name), a common masculine given name, including a list of people and fictional characters with the name
 * Gary, Indiana, the largest city named Gary

Places

 * Iran
 * Gary, Iran, Sistan and Baluchestan Province
 * United States
 * Gary (Tampa), Florida
 * Gary, Maryland
 * Gary, Minnesota
 * Gary, South Dakota
 * Gary, West Virginia
 * Gary – New Duluth, a neighborhood in Duluth, Minnesota
 * Gary Air Force Base, San Marcos, Texas
 * Gary City, Texas

Ships

 * USS Gary (DE-61), a destroyer escort launched in 1943
 * USS Gary (CL-147), scheduled to be a light cruiser, but canceled prior to construction in 1945
 * USS Gary (FFG-51), a frigate, commissioned in 1984
 * USS Thomas J. Gary (DE-326), a destroyer escort commissioned in 1943

People and fictional characters

 * Gary (surname), including a list of people with the name
 * Gary (rapper), South Korean rapper and entertainer
 * Gary (Argentine singer), Argentine singer of cuarteto songs

Other uses

 * Gary: Tank Commander, a British television sitcom
 * Gary (mango), a mango cultivar
 * 4735 Gary, an asteroid
 * Gary Elks, an American football team from 1920 to 1923

title: Gary