Thierry Franza
email: thierry.franza@inrae.fr

Philippe Gaudu
email: philippe.gaudu@inrae.fr

Quinones: more than electron shuttles

Keywords:

Introduction

Quinones are redox-active organic compounds that are found in most living organisms. They are formed of unsaturated cyclic diketones that are usually prenylated by enzymes belonging to the UbiA superfamily of prenyltransferases; these enzymes add a lipid-soluble isoprenyl tail to the redox moiety that anchors it in membrane lipid bilayer (for a review see [START_REF] Li | Bringing bioactive compounds into membranes: the UbiA superfamily of intramembrane aromatic prenyltransferases[END_REF]). The number of isoprenoid units and modifications in the isoprenyl tail vary among species, and depending on whether the redox moiety undergoes reduction or oxidation, the molecule becomes either a quinol or quinone, respectively. The extensive degree of structural variation in bacterial isoprenoid quinones and elucidation of their complex biosynthetic pathways have been the focus of numerous studies and multiple recent reviews [START_REF] Nowicka | Occurrence, biosynthesis and function of isoprenoid quinones[END_REF][START_REF] Joshi | Novel enzymology in futalosine-dependent menaquinone biosynthesis[END_REF][START_REF] Kawamukai | Biosynthesis and applications of prenylquinones[END_REF][START_REF] Kazemzadeh | Advances in bacterial pathways for the biosynthesis of ubiquinone[END_REF][START_REF] Johnston | M Advances in menaquinone biosynthesis: sublocalisation and allosteric regulation[END_REF][START_REF] Salinas | N Rhodoquinone in bacteria and animals: two distinct pathways for biosynthesis of this key electron transporter used in anaerobic bioenergetics[END_REF].

In this review, we will focus on the two main structural groups of isoprenoid quinones found in bacteria: benzoquinones and naphthoquinones. Rare groups, such as methionaquinones, benzothiophenquinones, calderiellaquinones, and sulfolobus-type quinones, will not be addressed here. Benzoquinones can be divided into three types: ubiquinones (UQ), plastoquinones (PQ), and rhodoquinones (RQ) (Fig. 1A). Ubiquinones are widely distributed in both prokayotes and eukaryotes, while plastoquinones are restricted to cyanobacteria and plants. Rhodoquinones are structural analogs of ubiquinones in which one methoxyl group (CH 3 O) is replaced by an amino group (NH 2 ) (Fig. 1A); these are present in a limited number of bacterial species, such as some aerobic chemotrophic β-proteobacteria, as well as a few unicellular eukaryotic and animal species [START_REF] Salinas | N Rhodoquinone in bacteria and animals: two distinct pathways for biosynthesis of this key electron transporter used in anaerobic bioenergetics[END_REF]. Naphthoquinones, the second group of bacterial quinones, include demethylmenaquinones (DMK) and menaquinones (MK) (Fig. 1A), and are present mainly in Grampositive bacteria and archae; however, members of the former group, such as Enterococcus faecalis and Streptococcus agalatiae, produce only DMK because they lack a methyltransferase for converting DMK to MK. Certain bacteria, such as Escherichia coli, are able to produce both UQ and (D)MK [START_REF] Van Beilen | J All three endogenous quinone qpecies of Escherichia coli are involved in controlling the activity of the aerobic/anaerobic response regulator ArcA[END_REF]. DMKs and MKs are synthesized from the precursor 1,4dihydroxy-2-naphthoic acid (DHNA) or 1,4-dihydroxy-6-naphthoic acid, which are produced via the classical Men pathway or the futalosine pathway, respectively [START_REF] Joshi | Novel enzymology in futalosine-dependent menaquinone biosynthesis[END_REF]. Bacterial MKs belong to the vitamin K 2 group (Fig. 1A). In mammals, vitamin K 2 functions as an essential molecule required for the activation of several proteins involved in blood clotting and bone metabolism [START_REF] Liu | Structures of an intramembrane vitamin K epoxide reductase homolog reveal control mechanisms for electron transfer[END_REF].

The reduction or oxidation of quinones usually involves two electron transfers associated with the addition or release of two individual H + protons (Fig. 1B). Transfer or removal of only a single electron generates a semiquinone radical (Fig. 1C), which can become toxic in the presence of oxygen by yielding the superoxide anion • O 2 -(Fig. 1D). MK and RQ have low redox midpoint potentials (E m around -70 mV), whereas values for UQ and PQ are higher (E m of + 100 mV) and those for DMK are intermediate (E m of + 35 mV). Evolutionarily speaking, menaquinones are considered to be the ancestral type of quinones, while UQ and PQ are thought to have appeared more recently with the rise in oxygen concentrations on Earth. High redox-potential quinones, like UQ, are less toxic than MK in oxygen-rich environments [START_REF] Anand | Adaptive evolution reveals a tradeoff between growth rate and oxidative stress during naphthoquinone-based aerobic respiration[END_REF]. This review focuses on the diverse roles of quinones in bacterial physiology. In light of recent data supporting the importance of bacterial relationships in the functioning of various ecosystems, we will present multiple lines of evidence that these molecules can serve as key ecological resources in microbial communities, even for bacteria that do not produce quinone. A full consideration of both aspects of bacterial quinones in cellular physiology and community ecology opens new fields of investigation for biotechnological applications and human health management.

Physiological functions of quinones

Electron shuttle in respiratory and photosynthetic chains

Early experiments on the physiological function of quinones (UQ, MK) in bacteria indicated that these molecules operate in electron transport chains [START_REF] Watanabe | Mode of action of vitamin K in microorganisms[END_REF]. Electron transfer generates a proton gradient across the cytosolic membrane, which is used by ATP synthase to produce ATP (for reviews see [START_REF] Lea-Smith | J Photosynthetic, respiratory and extracellular electron transport pathways in cyanobacteria[END_REF][START_REF] Magalon | Alberge F Distribution and dynamics of OXPHOS complexes in the bacterial cytosolic membrane[END_REF][START_REF] Melo | Teixeira M Supramolecular organization of bacterial aerobic respiratory chains: from cells and back[END_REF]). In vivo imaging experiments of E. coli established that ubiquinones can diffuse rapidly in membranes over long distance enabling electron transfer between multiple dehydrogenases and different electron transport complexes [START_REF] Llorente-Garcia | Single molecule in vivo imaging of bacterial respiratory complexes indicates delocalized oxidative phosphorylation[END_REF]. Thanks to their large repertoire of terminal electron transferases, bacteria can use a huge variety of compounds as direct electron acceptors, with the most common being oxygen, nitrite, nitrate, sulfate, sulfite, thiosulfate, trimethylamine, elemental sulfur, fumarate, and metals; this flexibility allows them to support growth and colonization in diverse environments [START_REF] Magalon | Alberge F Distribution and dynamics of OXPHOS complexes in the bacterial cytosolic membrane[END_REF][START_REF] Melo | Teixeira M Supramolecular organization of bacterial aerobic respiratory chains: from cells and back[END_REF]. In E. coli, high-redox-potential UQs are used under aerobiosis, whereas low-potential quinones like (D)MKs are rather involved in anaerobic respiratory chains. However, in Gram-positive bacteria, (D)MKs are used for both aerobic and anaerobic respiration. Likewise, some proteobacteria also employ UQs under anaerobic conditions [START_REF] Vo | The O 2independent pathway of ubiquinone biosynthesis is essential for denitrification in Pseudomonas aeruginosa[END_REF]. In cyanobacteria, plastoquinones (PQ) are used as electron carriers in thylakoid membranes, where they transfer electrons from the photosystem II reaction center to the cytochrome b 6 f complex. In addition, PQ replaces UQ in cyanobacterial respiratory electron transport chains [START_REF] Lea-Smith | J Photosynthetic, respiratory and extracellular electron transport pathways in cyanobacteria[END_REF]. Low-potential rhodoquinones RQ are thought to provide an advantage to some bacteria and protists for survival under anaerobic or anoxic conditions, but their exact role in anaerobic electron transfer chains remains to be fully understood [START_REF] Salinas | N Rhodoquinone in bacteria and animals: two distinct pathways for biosynthesis of this key electron transporter used in anaerobic bioenergetics[END_REF].

Extracellular electron transfer

Beyond these respiratory processes, under anaerobic or microaerobic conditions many bacterial species utilize an extracellular electron transfer (EET) mechanism through which they can transfer electrons outside of the cell envelope to distant electron acceptors such as minerals, independently of classical respiratory chains. EET has been thoroughly investigated in two species of Fe(III)-reducing Gram-negative bacteria, Shewanella oneidensis and Geobacter sulfurreducens (γ and δ proteobacteria, respectively). In these species, electrons originating from the intracellular metabolism are shuttled from the cytoplasmic membrane to the extracellular acceptor by distinct pathways involving quinones and surface multiheme cytochromes (for a review see [START_REF] Shi | Extracellular electron transfer mechanisms between microorganisms and minerals[END_REF]). Depending on the electron gradient, EET can be a bidirectional process (cells to minerals and vice-versa), in which quinols and quinones behave as electron donors or acceptors, respectively (Fig. 2A) [START_REF] Zhong | Genomic analyses of the quinol oxidases and/or quinone reductases involved in bacterial extracellular electron transfer[END_REF]. In the Gram-positive opportunistic pathogens Listeria monocytogenes and E. faecalis, EET is performed by a different set of proteins, using flavins instead of heme (Fig. 2B) [START_REF] Light | A flavinbased extracellular electron transfer mechanism in diverse Gram-positive bacteria[END_REF][START_REF] Pankratova | Hederstedt L Extracellular electron transfer by the Gram-positive bacterium Enterococcus faecalis[END_REF]. In the latter species, DMK-9 production is necessary for EET activity, while the former uses a specific but as-yetuncharacterized DMK. For L. monocytogenes, EET may be important under certain conditions, such as growth in the gastrointestinal tract [START_REF] Light | A flavinbased extracellular electron transfer mechanism in diverse Gram-positive bacteria[END_REF]. Genome analysis has revealed that homologs of the L. monocytogenes EET system are conserved in many species from the Firmicutes phylum, suggesting that these species are also quinone producers [START_REF] Pankratova | Hederstedt L Extracellular electron transfer by the Gram-positive bacterium Enterococcus faecalis[END_REF][START_REF] Light | Extracellular electron transfer powers flavinylated extracellular reductases in Gram-positive bacteria[END_REF].

EET can be accomplished by cell-to-cell transfer of electrons, electrical wire pili, or by redox proteins bound to extracellullar cell surfaces (Fig. 2C). EET can also occur at long distances from bacteria (millimeter to centimeter) thanks to diffusible aqueous redox carriers known as extracellular electron shuttles (EES) (Fig. 2D) [START_REF] Glasser | K The colorful world of extracellular electron shuttles[END_REF]. EESs can be quinones, flavins, phenazines, and pyocyanin, among others (Fig. 2E). EES can be essential in complex biofilm matrices where electron acceptors are at the periphery. These electron shuttles can be produced by bacteria (endogenous EES) or present in the environment (exogenous EES, like humic substances). The role of quinones in mediating EET was first discovered by Newman and Kolter [START_REF] Newman | Kolter R A role for excreted quinones in extracellular electron transfer[END_REF] in the model bacterium Shewanella putrefaciens (now S. oneidensis) MR-1, which uses insoluble ferric oxides as extracellular electron acceptors. The quinone involved was just recently identified as 2-amino-3-carboxyl-1,4-napthoquinone (ACNQ; Fig. 2E) [START_REF] Mevers | An elusive electron shuttle from a facultative anaerobe[END_REF]. ACNQ is formed through the spontaneous modification of DHNA in the presence of an amine donor (amino acid, ammonium salt); all DHNA-producing bacteria are potentially able to produce ACNQ for EET. As an example, Freguia and collaborators established that ACNQ plays a role in anodic electron transfer in Lactococcus lactis [START_REF] Freguia | Kano K Lactococcus lactis catalyses electricity generation at microbial fuel cell anodes via excretion of a soluble quinone[END_REF]. Both ACNQ and DHNA have also been identified as growth stimulators in bifidobacteria. Besides ACNQ, the benzoquinone 2,6-di-tertbutyl-p-benzoquinone (Fig. 2E) was found to be involved in EET in Klebsiella quasipneumoniae sp. 203 [START_REF] Guo | Effects of biofilm transfer and electron mediators transfer on Klebsiella quasipneumoniae sp. 203 electricity generation performance in MFCs[END_REF]. It is plausible that other soluble quinones, such as short isoprenoid chain quinones, anthraquinone derivatives (anthraquinone-2,7-disulfonic acid, AQDS), and pyrroloquinoline (PQQ) synthesized by proteobacteria can connect the intracellular metabolism to extracellular redox reactions via EET (Fig. 2E). Interestingly, the pathogenic bacterium Pseudomonas aeruginosa and the myxobacterium Stigmatella aurantiaca excrete structural MK analogs, such as the 2-heptyl-4-hydroxyquinoline N-oxide (HQNO) and the quinoline aurachin D, respectively (Fig. 1A), that inhibit electron transfer and respiration [START_REF] Yamamoto | Gaudu P Respiration metabolism of Group B Streptococcus is activated by environmental haem and quinone and contributes to virulence[END_REF][START_REF] Kunze | new quinoline antibiotics from myxobacteria: production, physico-chemical and biological properties[END_REF]. HQNO can alter the physiology of other bacteria and has demonstrated antibacterial activity, presumably by binding to and inhibiting cytochrome oxidases [START_REF] Machan | Wilson R 2-Heptyl-4hydroxyquinoline N-oxide, an antistaphylococcal agent produced by Pseudomonas aeruginosa[END_REF].

Electron sink in metabolic pathways

In addition to electron transfer, quinones are also directly involved in certain biosynthetic and catabolic pathways.

Heme synthesis

In the E. coli heme biosynthesis pathway, the conversion of protoporphyrinogen IX into protoporphyrin IX is catalyzed by a protoporphyrinogen IX dehydrogenase/oxidase, HemG. This membrane flavoprotein catalyzes the oxidation of protoporphyrinogen IX, and in doing so, releases six electrons that are transferred to UQ or MK. The quinols then transfer their electrons to the appropriate terminal electron acceptor, determined by whether conditions are aerobic or anaerobic [START_REF] Möbius | Heme biosynthesis is coupled to electron transport chains for energy generation[END_REF].

Pyrimidine synthesis

In E. coli, the class 2 dihydroorotate dehydrogenase PyrD enzyme is a flavoprotein catalyzing oxidation of (S)-dihydroorotate to orotate during de novo biosynthesis of the pyrimidine nucleotide precursor UMP. PyrD interacts with the inner side of the cytosolic membrane via its hydrophobic N-terminal domain and requires ubiquinone under aerobic conditions (or (D)MK during anaerobic growth) as an electron acceptor [START_REF] Nørager | Escherichia coli dihydroorotate dehydrogenase reveals structural and functional distinctions between different classes of dihydroorotate dehydrogenases[END_REF]. Class 2 PyrD is highly conserved in both Gram-negative and -positive bacteria, meaning that PyrD should be present only in quinone producers.

Steroid degradative oxidation

In many bacteria, certain steroid compounds can serve as a carbon source for use in growth. The corresponding catabolic pathways involve oxidation of the steroid ring. In Pseudomonas N.C.I.B. 10590, Nocardia restrictus, and Corynebacterium simplex, it was shown that MK-7 acts as an efficient electron carrier during steroid ring dehydrogenation [START_REF] Williams | F Isolation of menaquinone 7 from Pseudomonas NCIB 10590: a natural electron acceptor for steroid A-ring dehydrogenations[END_REF]. However, the coupling of steroid oxidation with electron transfer via a respiratory chain has been demonstrated only in Arthrobacter globiformis [START_REF] Medentsev | K Regulation of 3-ketosteroid-1-en-dehydrogenase activity of Arthrobacter globiformis cells by a respiratory chain[END_REF].

Role in folding of extracytosolic proteins

In E. coli, oxidative formation of disulfide bonds that occurs during the folding of extracytosolic proteins is associated with an electron transport system (Dsb) and quinones (for a review see [START_REF] Landeta | Disulfide bond formation in prokaryotes[END_REF]). The enzyme DsbA oxidizes protein by introducing disulfide bonds, and in the process, becomes reduced. To start a new catalytic cycle, the membrane enzyme DsbB reoxidizes DsbA and transfers the electrons to quinones. In aerobiosis, DsbB uses ubiquinones to shuttle electrons to the cytochrome bo or bd oxidases, while under anaerobiosis, it uses menaquinones to transport electrons to alternative substrates like fumarate. The electrons for this process are coming from the periplasmic side of the membrane via DsbB protein modification, and not from metabolic reactions. Dsb-like homologs have been found in other bacteria, such as Bdb in the Gram-positive bacterium Bacillus subtilis, but they seem to use as-yet-unknown substrates instead of quinones [START_REF] Landeta | Disulfide bond formation in prokaryotes[END_REF]. Instead, in actinobacteria, cyanobacteria, and some δ-proteobacteria, DsbB is replaced by a protein homologous to the human enzyme vitamin K epoxide reductase (VKOR). In humans, membrane-bound VKOR regenerates vitamin K hydroquinone by reducing the vitamin K epoxide formed during gamma-carboxylation of glutamic acids in vitamin K-dependent proteins [START_REF] Liu | Structures of an intramembrane vitamin K epoxide reductase homolog reveal control mechanisms for electron transfer[END_REF]. Ke et al. [START_REF] Ke | Identification of the thioredoxin partner of vitamin K epoxide reductase in mycobacterial disulfide bond formation[END_REF] showed that in mycobacteria, VKOR contributes to DsbA oxidation by transferring electrons to menaquinones. Interestingly, E. coli DsbB can replace the VKOR protein in Mycobacterium smegmatis and, conversely, Mycobacterium tuberculosis VKOR can replace DsbB in E. coli. The close functional homology between these enzymes is further supported by the fact that warfarin, an inhibitor of human VKOR activity, also inhibits bacterial VKOR activity. These proteins appear to play an important role in the pathogenicity of certain plant-or animal-infecting bacteria, as many dsbA, dsbB, and vkor mutants have all demonstrated attenuated virulence in various infection models [START_REF] Landeta | Disulfide bond formation in prokaryotes[END_REF].

Quinones in stress resistance

Oxidative stress

The work of Søballe and Poole [START_REF] Søballe | K Ubiquinone limits oxidative stress in Escherichia coli[END_REF] highlighted the ability of ubiquinone-8 (UQ-8) to act as an important antioxidant compound in E. coli. In vivo, UQ-8 is capable of reducing the accumulation of superoxides and peroxides by limiting undesirable direct single-electron donation to oxygen. Ubiquinol can also behave as a radical scavenger. Subsequently, Agrawal et al. [START_REF] Agrawal | Chaba R A genome-wide screen in Escherichia coli reveals that ubiquinone is a key antioxidant for metabolism of long-chain fatty acids[END_REF] provided further details on the antioxidant properties of UQ-8 in E. coli. Long-chain fatty acids (LCFAs) can be metabolized into acetyl-CoA via the β-oxidation pathway, an activity which requires the presence of terminal electron acceptors. During this process, electron leakage can occur via the enzyme FadE (acyl-CoA dehydrogenase), causing the formation of radical oxygen species (ROS) [START_REF] Agrawal | Chaba R A genome-wide screen in Escherichia coli reveals that ubiquinone is a key antioxidant for metabolism of long-chain fatty acids[END_REF]. To prevent this, UQ-8 is necessary for transferring these electrons to terminal oxidases, thus avoiding ROS production. Interestingly, in animals, ubiquinol-10 is an important antioxidant involved in protecting membrane phospholipids and serum low-density lipoproteins from lipid peroxidation [START_REF] Ernster | Biochemical, physiological and medical aspects of ubiquinone function[END_REF]. UQ-10 also protects mitochondrial components from free radicals. Furthermore, in E. coli UQ-8 is less toxic than MK-8 under high oxygen concentration [START_REF] Anand | Adaptive evolution reveals a tradeoff between growth rate and oxidative stress during naphthoquinone-based aerobic respiration[END_REF]. In Staphylococcus aureus, Wakemann et al. [START_REF] Wakeman | Menaquinone biosynthesis potentiates haem toxicity in Staphylococcus aureus[END_REF] demonstrated that menaquinones potentiate heme toxicity by generating semiquinones and reducing heme. Similarly, in L. lactis, MKs seem to control heme homeostasis; under low oxygen conditions, extracellular heme can be sequestered relatively safely in the membrane following its reduction by MK [START_REF] Joubert | Lechardeur D HrtBA and menaquinones control haem homeostasis in Lactococcus lactis[END_REF].

Osmotic stress

A link between ubiquinone and osmotic stress tolerance was first proposed by Sévin and Sauer [START_REF] Sévin | U Ubiquinone accumulation improves osmotic-stress tolerance in Escherichia coli[END_REF]. In their study of the BW25113 strain of E. coli, growth in high-salt solutions caused a 110-fold accumulation of UQ-8, and this effect was independent of the respiratory activity and antioxidant properties of this quinone. The authors hypothesized that UQ-8 accumulation might increase the hydrophobic thickness and/or stability of the inner membrane, contributing to the osmoprotection of cells. However, the results of Tempelhagen et al. [START_REF] Tempelhagen | M Cultivation at high osmotic pressure confers ubiquinone-8-independent protection of respiration on Escherichia coli[END_REF] contradicted this model. These authors argued that osmotolerance is not dependent on any UQ-8-induced modification of the membrane's physical properties, but is instead caused by protection of the respiratory chain. Despite this, investigations based on the use of lipid vesicles that mimic the E. coli plasma membrane have demonstrated that UQ-8 and UQ-10 do have an osmoprotective effect [START_REF] Eriksson | Osmoprotective effect of ubiquinone in lipid vesicles modelling the Escherichia coli plasma membrane[END_REF]. Interestingly, phylloquinone (vitamin K 1 ) was shown to increase the fluidity of dipalmitoylphosphatidylcholine membranes [START_REF] Asai | The interaction of vitamin K 1 with phospholipid membranes[END_REF]. This result was corroborated by work in the foodborne species L. monocytogenes, in which an increase in the concentration of the major menaquinone (MK-7) was shown to be important for membrane fluidity adaptation at low growth temperatures [START_REF] Seel | Lipski A Increased isoprenoid quinone concentration modulates membrane fluidity in Listeria monocytogenes at low growth temperatures[END_REF].

Cell differentiation

In B. subtilis, MK-7 production is required for the differentiation and formation of complex colony structures in which bacteria are held together by an extracellular matrix during growth on hard agar surfaces [START_REF] Pelchovich | Gophna U Menaquinone and iron are essential for complex colony development in Bacillus subtilis[END_REF]. This complex colony development (CCD) is not found in mutants of B. subtilis that are deficient in MK-7 synthesis, but the phenotype can be alleviated by the addition of exogenous MK-4. In the same species, MK-7 is also required for sporulation, but the cause of this requirement is still unknown.

Quinones as signaling molecules involved in transcriptional regulation

Because of their redox and chemical properties, quinones can be key signaling molecules detected by sensor and/or regulatory proteins.

Gene control by redox activity

In both Gram-negative and -positive species, the composition and/ or redox state of the quinone pool can serve as a regulatory signal that controls important physiological processes. The E. coli ArcB-ArcA pair, a two-component regulatory system (TCS), serves as a paradigm of this process. ArcA/B (aerobic respiration control) participates in a transcriptional regulatory network that is involved in the metabolic shift from anaerobic to aerobic growth, through which bacteria are able to respond to various environmental conditions [START_REF] Park | J The bacterial response regulator ArcA uses a diverse binding site architecture to regulate carbon oxidation globally[END_REF]. ArcB is a sensor membrane protein with histidine kinase/phosphatase activities, while ArcA is its cognate transcriptional regulator. When phosphorylated by ArcB on its Asp-54 aspartic residue, ArcA binds to the promoters of target genes and accelerates their transcriptional activity. When dephosphorylated by ArcB, ArcA loses its DNA binding activity and becomes inactive. The kinase activity of ArcB is governed by the redox states of the ubiquinone and menaquinone pools, which depend directly on aerobic respiratory chain activity. Specifically, quinones can generate intermolecular disulfide bonds between two ArcB monomers at the Cys-180/Cys-180′ and Cys-241/Cys-241' positions [START_REF] Malpica | Signaling by the arc two-component system provides a link between the redox state of the quinone pool and gene expression[END_REF], located in the Nterminal extremity downstream of the transmembrane domains. Formation of this intermolecular disulfide bond inhibits the kinase activity of ArcB dimers. Van Beilen and Hellingwerf [START_REF] Van Beilen | J All three endogenous quinone qpecies of Escherichia coli are involved in controlling the activity of the aerobic/anaerobic response regulator ArcA[END_REF] demonstrated that, when the oxygen tension decreases, the three quinol species of E. coli (UQH 2 , DMKH 2 , and MKH 2 ) reduce these disulfide bonds and concomitantly activate ArcB, leading to ArcA phosphorylation in vivo. Numerous histidine kinases with a similar regulatory system have been characterized in various species (Table 1). Quinone control has also been documented in Gram-positive bacteria like B. subtilis (ResDE) and S. aureus (SrrAB). Indeed, the TCS system SrrA/SrrB (Staphylococcus respiration response) is an important regulator of genes involved in virulence, anaerobic metabolism, resistance to oxidative and nitrosative stress, biofilm formation, and programmed cell death [START_REF] Mashruwala | M Impaired respiration elicits SrrABdependent programmed cell lysis and biofilm formation in Staphylococcus aureus[END_REF][START_REF] Tiwari | The SrrAB two-component system regulates Staphylococcus aureus pathogenicity through redox sensitive cysteines[END_REF]. By studying biofilm formation under hypoxia, Mashruwala et al. [START_REF] Mashruwala | M Impaired respiration elicits SrrABdependent programmed cell lysis and biofilm formation in Staphylococcus aureus[END_REF] showed that the redox states of MK control SrrB activity: membrane-bound SrrB is active when the menaquinol pool increases and inactive in the presence of menaquinone. This mechanism of SrrB activity was recently confirmed via structural analysis [START_REF] Tiwari | The SrrAB two-component system regulates Staphylococcus aureus pathogenicity through redox sensitive cysteines[END_REF]. In contrast to ArcB, kinase activity stimulation of the SrrB homodimer requires the reduction of the in- UQ-0: soluble oxidized ubiquinone-0 with no isoprenyl side chain (2,3dimethoxy-5-methyl-1,4-benzoquinone). MKH 2 : menaquinol (reduced form). a TodS, HskA, CikA and KaiA kinases are not integral membrane proteins.

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tramolecular Cys-464-Cys-501 disulfide bond in each SrrB monomer. These two residues are located in the C-terminal extremity close to the ATP-binding catalytic domain. Finally, a different model of quinonedependent regulation was recently discovered in the α-proteobacterium Sinorhizobium meliloti. The smc01818 gene of S. meliloti encodes a 557-amino acid protein that shares similarities with class III adenylate cyclase (CyaC). This membrane protein is predicted to be folded into six transmembrane domains and acts as a dimeric adenylate cyclase [START_REF] Wissig | CyaC, a redox-regulated adenylate cyclase of Sinorhizobium meliloti with a quinone responsive diheme-B membrane anchor domain[END_REF].

CyaC also contains a cytosolic [2Fe-2S] ferredoxin-type domain and two molecules of heme b, which are necessary for its activity. Specifically, Wissig and collaborators demonstrated that CyaC activity is modulated in vitro by the reversible oxidation and reduction of these hemes, caused by addition of the exogenous benzoquinone decylubiquinone (UQ-0 with a decyl residue in position 6) [START_REF] Wissig | CyaC, a redox-regulated adenylate cyclase of Sinorhizobium meliloti with a quinone responsive diheme-B membrane anchor domain[END_REF]. Thus, in vivo, quinones or quinols can lead to stimulation or inhibition, respectively, of adenylate cyclase activity. In this case, the membrane quinone signal is transduced into an intracellular signal: cyclic adenosine monophosphate (cAMP). However, the exact nature of the endogenous quinones of S. meliloti interacting with CyaC remains to be determined.

Quinone toxicity control via electrophilic activity

As electrophiles, no-tailed quinones (usually benzoquinone-type compounds) can form S-adducts with thiol groups via thiol-(S)alkylation (Fig. 3A) [START_REF] Liebeke | Depletion of thiol-containing proteins in response to quinones in Bacillus subtilis[END_REF]. Gram-positive bacteria, like B. subtilis and S. aureus, have developed an array of defenses for the detoxification of no- tail quinones (degradation or reduction by reductases, generating lesstoxic hydroquinol) and for damage repair (replacement or depletion of thiol-containing proteins) [START_REF] Liebeke | Depletion of thiol-containing proteins in response to quinones in Bacillus subtilis[END_REF][START_REF] Hillion | Antelmann H Thiol-based redox switches in prokaryotes[END_REF]. This response depends on the activation of specific transcriptional regulators, for which the archetypes are YodB (B. subtilis) and QsrR (S. aureus) [START_REF] Ji | Molecular mechanism of quinone signaling mediated through S-quinonization of a YodB family repressor QsrR[END_REF][START_REF] Yoon | Two distinct mechanisms of transcriptional regulation by the redox sensor YodB[END_REF]. Both proteins belong to the MarR/DUF24 family of transcription factors and act as repressors. YodB and QsrR share 38% identity (60% similarity) and each forms a homodimer that senses quinones by thiol-S-alkylation in vitro (Fig. 3B) [START_REF] Ji | Molecular mechanism of quinone signaling mediated through S-quinonization of a YodB family repressor QsrR[END_REF][START_REF] Yoon | Two distinct mechanisms of transcriptional regulation by the redox sensor YodB[END_REF]. In their 2016 study, Lee and colleagues described how YodB is able to respond quickly to methyl-p-benzoquinone (MPBQ). The MPBQmediated S-alkylation of YodB results in the formation of a quinone adduct on the Cys-6 residue of YodB, which causes the dimer to dissociate from its target DNA site (Fig. 3B) [START_REF] Yoon | Two distinct mechanisms of transcriptional regulation by the redox sensor YodB[END_REF]. In S. aureus, QsrR (quinonesensing response repressor) controls the transcription of genes encoding quinone reductases, dioxygenases, and a nitroreductase [START_REF] Ji | Molecular mechanism of quinone signaling mediated through S-quinonization of a YodB family repressor QsrR[END_REF][START_REF] Yoon | Two distinct mechanisms of transcriptional regulation by the redox sensor YodB[END_REF]. In vitro, the binding of QsrR to its operator sequences is inhibited by menadione (abusively named vitamin K 3 ) and 2,3-dimethoxy-5-methyl-pbenzoquinone (a UQ precursor) [START_REF] Ji | Molecular mechanism of quinone signaling mediated through S-quinonization of a YodB family repressor QsrR[END_REF]. A crystal structure of QsrR with menadione revealed that the latter covalently binds to the thiol group of the Cys-5 residue in each QsrR monomer; in this way, menadione-Salkylation causes conformational changes that perturb QsrR dimerization and inhibit its binding to the DNA operator. Based on this, Squinonization of regulators has been proposed as a common mechanism of quinone sensing in bacteria. However, in a 2019 study of S. aureus, Fritsch and collaborators [START_REF] Fritsch | The MarRtype repressor mhqR confers quinone and antimicrobial resistance in Staphylococcus aureus[END_REF] suggested a new mechanism of quinone sensing based on the MhqR protein. MhqR also belongs to the MarR/ DUF24 protein family, but is not related to YodB and QsrR. It is a repressor of the mhqRED operon, which is involved in benzoquinone and antimicrobial drug resistance. Methylhydroquinone (MHQ), a benzoquinol, inhibits the binding of MhqR to its operator sequence in vitro. Unexpectedly, activation of MhqR does not require its sole cysteine

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residue (Cys-95). The authors thus proposed the existence of a putative pocket for quinone binding; the presence of MHQ in this binding site would inhibit MhqR DNA-binding activity [START_REF] Fritsch | The MarRtype repressor mhqR confers quinone and antimicrobial resistance in Staphylococcus aureus[END_REF]. Overall, the MarR/ DUF24 family of transcription factors is overrepresented in Grampositive bacteria, but their specific roles in the quinone response remain poorly investigated [START_REF] Hillion | Antelmann H Thiol-based redox switches in prokaryotes[END_REF]. Finally, a study of L. lactis strain IL1403 revealed that it possesses two enzymes, YaiA and YaiB, that are involved in quinone degradation [START_REF] Mancini | Solioz M A copper-induced quinone degradation pathway provides protection against combined copper/quinone stress in Lactococcus lactis IL1403[END_REF]. However, the corresponding genes for these enzymes are not regulated by a quinone sensor or a MarR-like regulator, but by the repressor CopR, which responds to levels of copper ions.

Quinone roles in bacterial ecosystems

Although quinones fulfill important physiological functions, early investigations clearly demonstrated that several bacterial species do not produce quinone [START_REF] Bentley | Biosynthesis of vitamin K in bacteria[END_REF]. Nevertheless, several studies revealed that a majority of these auxotrophic species were able to use exogenous quinones or their biosynthetic precursors for growth, suggesting that some species possess a partial quinone biosynthetic pathway. Indeed, quinone production was found to be restored by intraspecies crossfeeding between different auxotrophic mutants of E. coli, B. subtilis, and the γ-proteobacterium S. oneidensis [START_REF] Myers | M Shewanella oneidensis MR-1 restores menaquinone synthesis to a menaquinone-negative mutant[END_REF]. In particular, Hammer et al. [START_REF] Hammer | Inter-and intraspecies metabolite exchange promotes virulence of antibioticresistant Staphylococcus aureus[END_REF] reported an important role for intraspecies quinone complementation in pathogenic bacteria. By coculturing a heme auxotroph of S. aureus together with quinone auxotrophs, they were able to enhance the growth and fitness of both types of mutants. In this way, quinone exchange may increase the fitness and virulence of small colony variant cells (SCV) of S. aureus, which have mutations in the biosynthetic pathways for menaquinone or heme, and are frequently isolated from hosts [START_REF] Proctor | Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections[END_REF]. Quinone nutritional exchange can also occur between species of different genera. For example, our group characterized interpecific metabolic crossfeeding in Streptococcus agalactiae (Group B streptococcus, GBS), a Gram-positive bacterium colonizing the gastrointestinal and urogenital tracts in humans. Under certain conditions, GBS causes severe infections in neonates, pregnant women, immunocompromised patients, and the elderly. In the presence of exogenous heme and MK-4, GBS can shift from a fermentative metabolism toward a respiratory metabolism [START_REF] Yamamoto | Gaudu P Respiration metabolism of Group B Streptococcus is activated by environmental haem and quinone and contributes to virulence[END_REF][START_REF] Franza | A partial metabolic pathway enables group b streptococcus to overcome quinone deficiency in a host bacterial community[END_REF]. Specifically, heme and menaquinones activate a CydACydB cytochrome bd oxidase, which reduces oxygen from NADH dehydrogenase. Cells of E. faecalis, L. lactis, and E. coli, but not S. aureus, are all able to crossfeed GBS and thus induce a shift to respiration (Fig. 4A) [START_REF] Franza | A partial metabolic pathway enables group b streptococcus to overcome quinone deficiency in a host bacterial community[END_REF][START_REF] Rezaïki | Gaudu P Lactococcus lactis produces short-chain quinones that cross-feed Group B Streptococcus to activate respiration growth[END_REF]; this enhances growth, increases the final pH of the culture, and promotes the survival of GBS cells in vitro. Furthermore, respiration plays an important role in host colonization, as demonstrated by the finding that a cydA mutant of GBS displayed reduced virulence in a neonate rat model [START_REF] Yamamoto | Gaudu P Respiration metabolism of Group B Streptococcus is activated by environmental haem and quinone and contributes to virulence[END_REF]. We determined that GBS uses the menaquinone precursor 1,4-dihydroxy-2-naphthoic acid (DHNA) to synthesize its own DMK-10, specifically using the menA gene which encodes a 1,4dihydroxy-2-naphthoate prenyltransferase enzyme (Fig. 4B) [START_REF] Franza | A partial metabolic pathway enables group b streptococcus to overcome quinone deficiency in a host bacterial community[END_REF]. This gene is clustered in an operon that also contains gbs1788, coding for a type-2 NADH dehydrogenase, and the cydAB genes, which encode the cytochrome bd oxidase. The adjacent gene gbs1783 encodes an IspB polyprenyldiphosphate synthase, which is responsible for synthesizing the isoprenoid side tail. Many species of the human gut microbiota produce the intermediate metabolite DHNA [START_REF] Ravcheev | Genomic analysis of the human gut microbiome suggests novel enzymes involved in quinone biosynthesis[END_REF], which has the advantage of being more diffusible than MK. In this ecological niche, certain pathogenic bacteria may thus acquire DHNA in order to perform respiration and enhance their ability to colonize, persist, and thrive in vivo.

Since the pioneering work of Gustafsson and collaborators [START_REF] Gustafsson | J Effects of vitamin K-active compounds and intestinal microorganisms in vitamin K-deficient germfree rats[END_REF] on gnotobiotic rats in 1962, it has been well known that the gut microbiota participates in the production of certain vitamins, notably vitamin K (menaquinones MK-6 to MK-12). More recently, Fenn et al. [START_REF] Fenn | Quinones are growth factors for the human gut microbiota[END_REF] investigated growth factors that enabled the cultivation and identification of as-yet-uncultured gut bacterial species. They determined that quinones produced by cultivable bacteria act as required growth factors for several microorganisms of the gut microbiota. Indeed, their work showed that diverse bacterial species of the human microbiome can only grow in the presence of quinone-producing gut bacteria. These quinonerequiring species belong to the genera Bacteroides, Faecalibacterium, Bilophila, Gordonibacter, and Sutterella, and can be crossfed by "quinone helpers" such as E. coli, Eggerthella lenta, Eubacterium rectale, and several Bacteroides species. Genome analysis revealed that some of the "uncultured" bacteria possess at least one menA-like gene, indicating that they can use DHNA to produce their own (demethyl)menaquinones. A particularly interesting example is Faecalibacterium, a genus of Grampositive anaerobic bacteria of the human gut microbiota that has been proposed to be beneficial for health because of its anti-inflammatory properties [START_REF] Sokol | Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients[END_REF]. Members of this genus are devoid of genes involved in quinone biosynthesis and may instead use quinones directly from other species. Indeed, Fenn and collaborators suggested that this may be true for the majority of these species, i.e., that exogenous menaquinones may be important for performing anaerobic respiration in the gut (Fig. 4C) [START_REF] Fenn | Quinones are growth factors for the human gut microbiota[END_REF]. This hypothesis was supported by a genome survey that uncovered the presence of numerous genes involved in anaerobic respiration. Thus, it seems likely that the production and presence of substantial levels of quinones (or their biosynthetic precursors) in the gut enable the persistence of quinone-auxotrophic bacteria. Furthermore, variations in quinone level and diversity can disturb the composition of the gut flora. Depending on the conditions at hand, quinone nutritional complementation may favor pathogenic bacteria as well as, or instead of, beneficial bacteria, creating a "Dr. Jekyll and Mr. Hyde" effect. Vitamin K supplementation in the human diet must thus be undertaken with caution [START_REF] Fu | Dietary vitamin K is remodeled by gut microbiota and influences community composition[END_REF].

The idea of quinones as exported growth factors is quite paradoxical, since isoprenoid quinones are poorly hydrosoluble. Quinone excretion or secretion is thus a topic of much debate [START_REF] Fenn | Quinones are growth factors for the human gut microbiota[END_REF][START_REF] Ikeda | A vitamin-K 2 -binding factor secreted from Bacillus subtilis[END_REF]. For quinone diffusion in the environment, it has been proposed that these compounds can be modified into a water-soluble form, or excreted in vesicles or by nanotubes. Interestingly, bacterial proteins from the YceI family are able to bind polyprenyl molecules, including UQ-8 [START_REF] Handa | Crystal structure of a novel polyisoprenoid-binding protein from Thermus thermophilus HB8[END_REF][START_REF] Donnarumma | Neisseria meningitis GNA1030 is a ubiquinone-8 binding protein[END_REF][START_REF] El-Halfawy | Antibiotic capture by bacterial lipocalins uncovers an extracellular mechanism of intrinsic antibiotic resistance[END_REF]. These proteins belong to the large, diverse group of lipocalins, which have an affinity for small hydrophobic molecules. YceI homologs are found in a large number of Gram-negative and -positive bacteria, where they can be periplasmic or extracellular proteins. The work of Ikeda and Doi [START_REF] Ikeda | A vitamin-K 2 -binding factor secreted from Bacillus subtilis[END_REF] in B. subtilis provided evidence for exportation, as they reported that 40% of all menaquinone (MK-7) produced was present outside the bacterial cells during the stationary phase. The cell supernatant also contained a 100-kDa glycoprotein that demonstrated binding affinity for MK-4 and MK-7 but not for menadione [START_REF] Ikeda | A vitamin-K 2 -binding factor secreted from Bacillus subtilis[END_REF]. Thus, it seems likely that quinones with a polyprenyl side chain may be effectively excreted/ secreted in the environment. Quinone nutritional exchanges can occur within a microbial community and impact its stability and function.

Conclusion and perspectives

The aim of this review is to discuss recent advances in our understanding of the crucial roles of quinones in bacterial metabolism, physiology, regulation, and syntrophy (summarized in Fig. 5). Notably, the experimental works presented here suggest that quinones may contribute to host colonization and virulence, with evidence obtained from pathogenic bacteria such as Salmonella enterica, M. tuberculosis, L. monocytogenes, and Francisella tularensis [START_REF] Ernster | Biochemical, physiological and medical aspects of ubiquinone function[END_REF][START_REF] Aussel | UbiJ, a new gene required for aerobic growth and proliferation in macrophage, is involved in coenzyme Q biosynthesis in Escherichia coli and Salmonella enterica serovar Typhimurium[END_REF][START_REF] Sogi | R Biosynthesis and regulation ofsulfomenaquinone, a metabolite associated with virulence in Mycobacterium tuberculosis[END_REF][START_REF] Smith | D Listeria monocytogenes MenI encodes a DHNA-CoA thioesterase necessary for menaquinone biosynthesis, cytosolic survival, and virulence[END_REF][START_REF] Kazemzadeh | The biosynthetic pathway of ubiquinone contributes to pathogenicity of Francisella[END_REF]. Because menaquinone biosynthesis pathways are absent in humans, they represent an appealing target for efforts to design new antibacterial drugs [START_REF] Johnston | M Advances in menaquinone biosynthesis: sublocalisation and allosteric regulation[END_REF]. Such works have already resulted in the discovery of new enzymes that catalyze the synthesis of MK derivatives, including two class C radical Sadenosylmethionine methyltransferases in Coriobacteriia that performs specific methylations of 8-methylmenaquinone and dimethylmenaquinone [START_REF] Wilkens | Sequence analysis and specificity of distinct types of menaquinone methyltransferases indicate the widespread potential of methylmenaquinone production in bacteria and archaea[END_REF]. Members of this class are present in the gastrointestinal tract and can be pathogenic, but the precise functions of these novel quinones are not known and require further investigation. Interestingly, in the anaerobic γ-proteobacterium Syntrophus aciditrophicus, 8methylmenaquinone (8-MMK-7) has been proposed to participate in fatty acid β-oxidation coupled to CO 2 reduction during syntrophic methane formation from fatty acids [START_REF] Agne | The missing enzymatic link in syntrophic methane formation from fatty acids[END_REF]. In addition, the MenJ oxidoreductase, a novel enzyme belonging to the geranylgeranyl reductase enzyme family, was found to reduce a single C = C double bond of the second prenyl group in the isoprenyl side-chain of the mycobacterial menaquinone MK-9 [START_REF] Upadhyay | Mycobacterial MenJ, an oxidoreductase involved in menaquinone biosynthesis[END_REF]. However, the physiological function of this partial saturation of the MK-9 isoprenoid side chain is not understood. Recent structural analyses of E. coli cytochrome bd oxidases have revealed a new structural stabilizing role for ubiquinone-8, and, in B. subtilis, the characterization of a new type of formate dehydrogenase utilizing MK-7 has expanded our knowledge of quinone roles [START_REF] Grauel | Structure of Escherichia coli cytochrome bd-II type oxidase with bound aurachin D[END_REF][START_REF] Arias-Cartin | Identification and characterization of a non-canonical menaquinone-linked formate dehydrogenase[END_REF]. Generally speaking, recent advances have highlighted the importance of quinones in bacterial life and ecology, which raises the question of their evolutionary history. The presence of quinone-like molecules in stellar dust supports the hypothesis that these compounds were essential in the earliest chemical reactions on Earth [START_REF] Kissel | C The cometary and interstellar dust analyzer at comet 81P/Wild 2[END_REF]. Their redox and chemical properties could have enabled simple life forms to carry out energy me-

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tabolisms, facilitating the colonization of diverse environments. For instance, quinone profiling (abundance and distribution patterns) in marine water and sediments is a useful way to investigate and understand biogeochemical element cycling and energy flow processes such as respiration, photosynthesis, nitrification, and methanotrophy in these ecosystems [START_REF] Becker | Isoprenoid quinones resolve the stratification of redox processes in a biogeochemical continuum from the photic zone to deep anoxic sediments of the black sea[END_REF]. Similarly, quinones may have assisted bacteria in adapting to the anaerobic reductive environment of the human gut. The ecophysiological functions of the numerous quinones present in the gut microbiota require much additional investigation. For example, there is now evidence that several bacteria in the human microbiota, such as enterococci, Faecalibacterium prausnitzii, and K. pneumoniae, are also capable of performing EET [START_REF] Naradasu | Okamoto A Isolation and characterization of human gut bacteria capable of extracellular electron transport by electrochemical techniques[END_REF]. Future inquiries into quinone biosynthesis and functions thus constitute a promising and exciting field of microbial research.

  https://doi.org/10.1016/j.resmic.2022.103953 0923-2508/© 20XX Note: Low-resolution images were used to create this PDF. The original images will be used in the final composition.

Fig. 1 .

 1 Fig. 1. Chemical structures and properties of quinones. A: Chemical structures of the major bacterial quinones and K vitamins. Some chemical changes between the different quinone structures are highlighted with circles. Vitamin K 1 (phylloquinone) is present in cyanobacteria and most photosynthetic eukaryotes. Vitamin K 2 (MK-4) is synthesized by mammals by conversion from vitamins K 1 or K 3 . Potent inhibitors of respiratory electron transfer are presented in the solid box: HQNO (2heptyl-4-hydroxyquinoline-N-oxide) is a quinoline-N-oxide (arrow), whereas aurachin D is a quinoline terpenoid (arrow) similar to (D)MK. Both molecules have no redox capacity. B: Reduction/oxidation of benzoquinone. C: Formation of a benzosemiquinone radical. D: Generation of superoxide anion from the semiquinone radical.

Fig. 2 .

 2 Fig. 2. Extracellular electron transfer in bacteria. A: Simplified drawing of the multiheme c-type cytochrome proteins (black arrow) involved in bidirectional extracellular electron transport (EET). White cylinders represent quinol oxidase (left) and reductase (right). Q: quinones (UQ or MK). QH 2 : quinols (UQH 2 or MKH 2 ). im: inner membrane. om: outer membrane. B: Schematic representation of the EET system of the Gram-positive bacterium Listeria monocytogenes. The two membrane proteins EetA and EetB and the lipoprotein PplA transfer electrons from DMKH 2 to an unknown extracellular terminal acceptor. PplA is FMNylated (small black circles) and the flavins are in charge of the electron flow. C and D: Different means of extracellular electron transfer, by contact or nanowires to another bacterium or a mineral (C), or by extracellular electron shuttles (EES) (D). E: Chemical structures of some EESs, including quinones, flavins, and phenazines. EET can be performed by EES diffusion (concentration gradient) or by electron hopping between EESs (electron gradient).

Fig. 3 .

 3 Fig. 3. S-quinonization. A: Electrophilic properties of benzoquinone lead to the formation of S-adducts with thiol-compounds or cysteines from protein (gray rectangles). B: Model of YodB regulation in Bacillus subtilis. YodB is a transcriptional repressor belonging to the MarR/DUF24 family of transcription factors. In the presence of methyl-p-benzoquinone (MPBQ), there is MPBQ-mediated S-alkylation of YodB, causing dissociation of the YodB dimer from its target DNA.

Fig. 4 .

 4 Fig. 4. Quinones and crossfeeding in bacteria. A: DHNA crossfeeding and DMK-10 biosynthesis in Streptococcus agalactiae (GBS). The ubiA menA mutant of Escherichia coli releases DHNA, which stimulates GBS growth via activation of its respiration metabolism. B: GBS converts DHNA into DMK-10 via the activities of the IspB (prenyl synthase) and MenA (prenyl transferase) enzymes. C: Hypothetical model for quinone crossfeeding in the gut microbiota. As populations of "quinone helper" bacteria (blue cells producing red triangles) increase, quinone-auxotroph bacteria (brown cells) can grow and shift their metabolism(s) (green cells). These bacteria may in turn provide new nutrients (black circles, dotted arrow) to helper cells. In a polymicrobial population, metabolic differentiation and cooperation can happen via exchange of quinones or their biosynthetic precursors.

Fig. 5 .

 5 Fig. 5. Schematic summary of the different roles attributed to bacterial quinones.

Table 1

 1 Histidine kinases regulated by quinone sensing.

	2 Component System: Regulator Sensor/ Kinase	Organism	Regulon function	Signal and in vitro mechanism	References
	RegB/RegA BvgS/BvgA EvgS/EvgA AccS/AccR TodS a /todT HskA a / unknown CikA a KaiA a SrrB/SrrA ResE/ResD	Rhodobacter capsulatus Bordetella pertussis Escherichia coli Azoarcus sp. Pseudomonas putida Pseudomonas putida Synechococcus elongatus Staphylococcus aureus Bacillus subtilis	control of metabolism colonization/ virulence acid stress/ drug resistance carbon catabolite repression toluene/ benzene degradation electron transport chain composition circadian clock control (circadian oscillator) virulence, biofilm anaerobic metabolism anaerobic regulatory network, NO response	RegB kinase activity inhibition by UQ-0 BvgS kinase activity inhibition by UQ-0 EvgS kinase activity inhibition by UQ-0 AccS kinase inhibition by UQ-0 thiol oxidation menadione TodS inhibition by a cysteine-dependent uncharacterized mechanism autophosphorylation inhibited by UQ-0 oxidized plastoquinone would reduce CikA and KaiA stability? activation of kinase, activity by intrasubunit disulfide bond reduction by MKH 2 uncharacterized mechanism	Wu and Bauer 2010 [51] Bock and Gross 2002 [52] Bock and Gross 2002 [52] Valderrama et al., 2019 [53] Silva-Jiménez et al., 2015 [54] Sevilla et al., 2013 [55] Ivleva et al., 2006 Wood et al., 2010 [56,57] Tiwari et al., 2020 [50] Härtig and Jahn 2012 [58]

Acknowledgments

We are grateful to the Editor for having taken our review into consideration. Thanks are due to the reviewers for insightful comments that improved the quality of the manuscript. We would also like to thank our colleagues for their help and fruitful discussions. We apologize to all colleagues whose studies could not be discussed owing to space constraints. We also thank L. Higgins for English reading of the manuscript.

Declaration of competing interest

The authors declare no conflict of interest for this work.