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Organic Cofactors Participated More Frequently Than Transition Metals in Redox Reactions of Primitive Proteins Hong-Fang Ji, Lei Chen, and Hong-Yu Zhang*

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Organic Cofactors Participated More Frequently Than Transition Metals in Redox Reactions of Primitive Proteins Hong-Fang Ji, Lei Chen, and Hong-Yu Zhang* http://www.paper.edu.cn Hypothesis Organic cofactors participated more frequently than transition metals in redox reactions of primitive proteins Hong-Fang Ji, Lei Chen, and Hong-Yu Zhang* Summary cobalt). Since transition metals were highly available in Protein redox reactions are one of the most basic and primordial world and NAD, NADP, FMN, FAD have been important biochemical actions. As amino acids are weak (1) redox mediators, most protein redox functions are under- considered vestiges of a previous RNA world, both kinds of taken by protein cofactors, which include organic ligands redox cofactors were likely to be accessible in the pre-protein and transition metal ions. Since both kinds of redox world (indeed, some of the organic redox cofactors can be cofactors were available in the pre-protein RNA world, it is synthesized by non-protein enzymatic catalysis(2,3)). Thus, challenging to explore which one was more involved in there is the intriguing question—which kinds of cofactors were redox processes of primitive proteins? In this paper, using an examination of the redox cofactor usage of more involved in redox processes of primitive proteins? putative ancient proteins, we infer that organic ligands Ten years ago, Daniel and Danson argued that, since the participated more frequently than transition metals in origin and early evolution of life occurred at high temperatures redox reactions of primitive proteins, at least as protein (>958C) and the organic redox cofactors are unstable at these cofactors. This is further supported by the relative temperatures, in the most primitive organisms, transition abundance of amino acids in the primordial world. metals (e.g. iron) were more likely than organic coenzymes Supplementary material for this article can be found on (4) the BioEssays website (http://www.mrw.interscience. (e.g. NAD/P(H)) to carry out the redox functions of proteins. wiley.com/suppmat/0265-9247/suppmat/index.html). However, to our knowledge whether the common ancestor BioEssays 30:766–771, 2008. ß 2008 Wiley Periodicals, of extant life liked it hot or not is still in debate.(5–7) More Inc. importantly, through analyzing the cofactor usage of redox proteins (with Enzyme Classification of E.C. 1._._._) derived Introduction from a hyperthermophile Pyrococcus furiosus (which is Protein redox reactions, consisting of a matched set (oxidation located at the root of the evolutionary tree, with an Optimal and reduction), have been recognized as one of the most basic Growth Temperature of 1008C), we found that most (82.4%) of and important biochemical actions in all organisms, because the redox cofactors are organic compounds (Table 1). Taken they are associated with energy production, material meta- together, we think that Daniel and Danson’s inference is not bolism and other key biological processes. As amino acids are conclusive and which kind of cofactors participated more weak redox mediators, most protein redox functions are frequently in redox reactions of primitive proteins deserves undertaken by protein cofactors, which include organic ligands further investigation. As this issue deals with the very early (e.g. nicotinamide-adenine-dinucleotide (NAD), nicotinamide- stage of life, there is no supporting fossil evidence. However, adenine-dinucleotide phosphate (NADP), flavin mononucleo- thanks to the rapid progress in genomics and bioinformatics, tide (FMN) and flavin-adenine dinucleotide (FAD)) and some putative ancient protein sets have been established from transition metals (e.g. copper, iron, manganese, nickel and which we can obtain some meaningful clues to this intriguing question. Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Center for Advanced Study, Shandong University of Redox cofactor usage in putative Technology, Zibo 255049, P. R. China. Funding agencies: This study was supported by the National Basic ancient proteins Research Program of China (grant 2003CB114400) and the National Through a large-scale phylogenomic analysis on 174 pro- Natural Science Foundation of China (grant 30570383 and 30700113). teomes, Caetano-Anolle´s and co-workers established a *Correspondence to: Hong-Yu Zhang, Center for Advanced Study, chronology for proteins.(8) The most ancient proteins (with Shandong University of Technology, Zibo 255049, P. R. China. Ancestry Value of 0 0.05) consist of 163 members, from E-mail: [email protected] DOI 10.1002/bies.20788 which 39 redox proteins (with Enzyme Classification of E.C. Published online in Wiley InterScience (www.interscience.wiley.com). 1._._._) can be identified (Table 2). According to the catalytic reactions presented in the comments of SWISS-PROT/ 766 BioEssays 30.8 BioEssays 30:766–771, ß 2008 Wiley Periodicals, Inc. 转载 中国科技论文在线 http://www.paper.edu.cn Hypothesis Table 1. Redox proteins contained in hyperthermophile Pyrococcus furiosus Redox proteins (EC number)a Entry namea Cofactorb Shikimate dehydrogenase (1.1.1.25) AROE_PYRFU NADP,NADPH Ketol-acid reductoisomerase (1.1.1.86) ILVC_PYRFU NADP,NADPH Histidinol dehydrogenase (1.1.1.23) HISX_PYRFU NAD, NADH Glyoxylate reductase (1.1.1.26) GYAR_PYRFU NAD, NADH Probable L-threonine 3-dehydrogenase (1.1.1.103) TDH_PYRFU NAD, NADH Inosine-50-monophosphate dehydrogenase (1.1.1.205) IMDH_PYRFU NAD, NADH Coenzyme A disulfide reductase (1.8.1.14) CDR_PYRFU NAD(P), NAD(P)H Glycerol-1-phosphate dehydrogenase [NAD(P)] (1.1.1.261) EGSA_PYRFU NAD(P), NAD(P)H Glyceraldehyde-3-phosphate dehydrogenase (1.2.1.59) G3P_PYRFU NAD(P), NAD(P)H Glutamate dehydrogenase (1.4.1.3) DHE3_PYRFU NAD(P), NAD(P)H Pyruvate/ketoisovalerate oxidoreductases common subunit gamma (1.2.7.7) PORC_PYRFU CoA, acetyl-CoA L-aspartate oxidase (1.4.3.16) NADB_PYRFU FADc Dihydroorotate dehydrogenase (1.3.3.1) PYRD_PYRFU FMNc Probable glycine dehydrogenase [decarboxylating] subunit 2 (1.4.4.2) GCSPB_PYRFU Pyridoxal phosphatec Superoxide reductase (1.15.1.2) SOR_PYRFU Ironc Tungsten-containing aldehyde ferredoxin oxidoreductase (1.2.7.5) AOR_PYRFU Fe-Sc Hydrogenase (1.12.2.1) Q59667_PYRFU Fe2þ,Ni2þc Sarcosine oxidase subunit alpha (1.5.3.1) Q8U025_PYRFU —d Probable peroxiredoxin (1.11.1.15) TDXH_PYRFU —d Prephenate dehydrogenase (1.3.1.12) Q8U096_PYRFU —d Glucose 1-dehydrogenase (1.1.1.47) Q8TZX2_PYRFU —d Pyruvate synthase subunit porA (1.2.7.1) PORA_PYRFU —d Phosphoglycerate dehydrogenase (1.1.1.95) Q8U3T5_PYRFU —d Ribonucleoside-diphosphate reductase (1.17.4.1) P95484_PYRFU —d aData from SWISS-PROT/TrEMBL.9 bAccording to the catalytic reactions presented in the comments of SWISS-PROT/TrEMBL.9 cAccording to the cofactor information presented in the comments of SWISS-PROT/TrEMBL.9 dCofactor information is absent in the comments of SWISS-PROT/TrEMBL.9 TrEMBL,(9) the redox cofactors were pinpointed for 34 redox agree well with a recent discovery based on the pattern analysis proteins (Table 2). It can be found that most (94.1%) of the of ligand-protein mapping that NAD and NADP are among the proteins depend on organic cofactors rather than metallic earliest cofactors bound to proteins and the predicted most counterparts, in which NAD/P(H) are most widely shared ancient host proteins of these ligands pertain to c.2 fold.(12) (96.9%). Recently, Prachumwat and Li provided another set of early Elucidation of redox cofactor preference in proteins by classifying the yeast proteome into five age primitive proteins groups.(10) The oldest age group includes yeast proteins that It is of obvious interest to elucidate why transition metals can be traced back to eubacterial genomes, which consists of were less popular than organic cofactors to undertake the 1806 members (according to Saccharomyces Genome Data- redox functions of primitive proteins. Thirty years ago, White base (SGD), Oct 18, 2006),(11) from which 100 redox proteins proposed that coenzyme-binding sites of contemporary (with Enzyme Classification of E.C. 1._._._) can be extracted. enzymes may be relics of the earliest proteins,(1) which According to the catalytic reaction annotations provided by inspired us to speculate that the clues to elucidating the redox SWISS-PROT/TrEMBL,(9) the redox cofactors were deter- cofactor preference in primitive proteins may reside in the mined for 95 proteins, in which organic cofactors (82) are cofactor-binding residues of contemporary redox proteins. dominant and NAD/P(H) (67) are most popular (See Table S1 Recently, based on an extensive analysis of metal-binding in Supplementary Material). sites of metalloproteins, Kasampalidis et al. indicated that the The predominance of organic cofactors in two relatively copper and iron-coordinating residues are much more con- independently established putative ancient protein datasets served than those of other positions during evolution and the strongly suggests that organic cofactors were more involved metal-binding sites mainly consist of reducing amino acids, i.e. than metallic counterparts in the redox functions of primitive His, Cys and Met.(13) This conclusion is further supported by proteins and NAD/P(H) were the most widely used redox our analyses. Through identifying the metal-binding residues cofactors. In addition, as shown in Table 2, most (64.3%) of redox metalloproteins (with Enzyme Classification of E.C. of NAD/P(H)-containing redox proteins belong to NAD(P)- 1._._._, containing copper,iron, manganese, nickel, cobalt and binding Rossmann-fold domain fold (c.2). All of these findings selected from PDB at a non-redundant level), we found that BioEssays 30.8 767 中国科技论文在线 http://www.paper.edu.cn
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