Structure and Mechanism of the Alkyl Hydroperoxidase AhpC, a Key Elementof the Mycobacterium tuberculosis Defense System against OxidativeStress

The peroxiredoxin AhpC from Mycobacterium tuberculosis (MtAhpC) isthe foremost element of a NADH-dependent peroxidase and peroxynitritereductase system, where it directly reduces peroxides and peroxynitrite and isin turn reduced by AhpD and other proteins. Overexpression of MtAhpC inisoniazid-resistant strains of M. tuberculosis harboring mutations inthe catalase/peroxidase katG gene provides antioxidant protection andmay substitute for the lost enzyme activities. We report here the crystalstructure of oxidized MtAhpC trapped in an intermediate oligomeric state ofits catalytic cycle. The overall structure folds into a ring-shaped hexamer ofdimers instead of the usual pentamer of dimers observed in other reducedperoxiredoxins. Although the general structure of the functional dimer issimilar to that of other 2-Cys peroxiredoxins, the α-helix containingthe peroxidatic cysteine Cys61 undergoes a unique rigid-bodymovement to allow the formation of the disulfide bridge with the resolvingcysteine Cys174. This conformational rearrangement creates a largeinternal cavity enclosing the active site, which might be exploited for thedesign of inhibitors that could block the catalytic cycle. Structural andmutagenesis evidence points to a model for the electron transfer pathway inMtAhpC that accounts for the unusual involvement of three cysteine residues incatalysis and suggests a mechanism by which MtAhpC can specifically interactwith different redox partners. The peroxiredoxin AhpC from Mycobacterium tuberculosis (MtAhpC) isthe foremost element of a NADH-dependent peroxidase and peroxynitritereductase system, where it directly reduces peroxides and peroxynitrite and isin turn reduced by AhpD and other proteins. Overexpression of MtAhpC inisoniazid-resistant strains of M. tuberculosis harboring mutations inthe catalase/peroxidase katG gene provides antioxidant protection andmay substitute for the lost enzyme activities. We report here the crystalstructure of oxidized MtAhpC trapped in an intermediate oligomeric state ofits catalytic cycle. The overall structure folds into a ring-shaped hexamer ofdimers instead of the usual pentamer of dimers observed in other reducedperoxiredoxins. Although the general structure of the functional dimer issimilar to that of other 2-Cys peroxiredoxins, the α-helix containingthe peroxidatic cysteine Cys61 undergoes a unique rigid-bodymovement to allow the formation of the disulfide bridge with the resolvingcysteine Cys174. This conformational rearrangement creates a largeinternal cavity enclosing the active site, which might be exploited for thedesign of inhibitors that could block the catalytic cycle. Structural andmutagenesis evidence points to a model for the electron transfer pathway inMtAhpC that accounts for the unusual involvement of three cysteine residues incatalysis and suggests a mechanism by which MtAhpC can specifically interactwith different redox partners. Mycobacterium tuberculosis, the leading cause of death from asingle bacterial pathogen, is restrained from proliferation in most infectedindividuals by the oxidative and nitrosative stress imposed by the immuneresponse (1Nathan C. Shiloh M.U. Proc.Natl. Acad. Sci. U. S. A. 2000; 97: 8841-8848Crossref PubMed Scopus (1158) Google Scholar). Yet M.tuberculosis is able to mount a stubborn antioxidant defense system thatallows the pathogen to persist and multiply within the highly oxidativeenvironment of host macrophages(2Sherman D.R. Sabo P.J. Hickey M.J. Arain T.M. Mahairas G.G. Yuan Y. Barry III, C.E. Stover C.K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 6625-6629Crossref PubMed Scopus (177) Google Scholar). This defense system isdirectly related to mycobacterial drug resistance and virulence. Thus,resistance to isoniazid(INH), 1The abbreviations used are: INH, isoniazid; MtAhpC, AhpC fromMycobacterium tuberculosis; SeMet, selenomethionine; StAhpC,Salmonella typhimurium AhpC; Tpx-B, thioredoxin peroxidase B; MAD,multiwavelength anomalous diffraction phasing; SAD, single wavelengthanomalous diffraction. a first lineanti-tuberculosis agent that inhibits cell wall synthesis after activation bythe catalase-peroxidase KatG(3Zhang Y. Dhandayuthapani S. Deretic V. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 13212-13216Crossref PubMed Scopus (100) Google Scholar, 4Slayden R.A. Barry III, C.E. Microbes Infect. 2000; 2: 659-669Crossref PubMed Scopus (169) Google Scholar, 5Rozwarski D.A. Grant G.A. Barton D.H.R. Jacobs W.R. Sacchettini J.C. Science. 1998; 279: 98-102Crossref PubMed Scopus (613) Google Scholar),usually arises from mutations in the katG gene that result in aprotein that is either inactive or has an impaired ability to activate INH(6Zhang Y. Heym B. Allen B. Young D. Cole S.T. Nature. 1992; 358: 591-593Crossref PubMed Scopus (1094) Google Scholar, 7Heym B. Alzari P.M. Honore N. Cole S.T. Mol. Microbiol. 1995; 15: 235-245Crossref PubMed Scopus (311) Google Scholar, 8Wengenack N.L. Rusnak F. Biochemistry. 2001; 40: 8990-8996Crossref PubMed Scopus (82) Google Scholar).Although not yet completely defined, the physiological function of KatGincludes protection of the mycobacterium against H2O2and other reactive oxygen species produced by the microbe and its host(2Sherman D.R. Sabo P.J. Hickey M.J. Arain T.M. Mahairas G.G. Yuan Y. Barry III, C.E. Stover C.K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 6625-6629Crossref PubMed Scopus (177) Google Scholar,9Manca C. Paul S. Barry III, C.E. Freedman V.H. Kaplan G. Infect. Immun. 1999; 67: 74-79Crossref PubMed Google Scholar). The pathogen needs tocompensate the catalase-peroxidase deficiency by alternative peroxidasesystems to remain virulent, and several lines of evidence point to the alkylhydroperoxidase AhpC (MtAhpC) as a key element in fulfilling that role. Thus,enhanced expression of MtAhpC is observed both in INH-resistant KatG-deficientstrains (10Sherman D.R. Mdluli K. Hickey M.J. Arain T.M. Morris S.L. Barry III, C.E. Stover C.K. Science. 1996; 272: 1641-1643Crossref PubMed Scopus (372) Google Scholar) as well as inINH-sensitive strains when challenged with the drug(11Wilson M. DeRisi J. Kristensen H.H. Imboden P. Rane S. Brown P.O. Schoolnik G.K. Proc. Natl.Acad. Sci. U. S. A. 1999; 96: 12833-12838Crossref PubMed Scopus (495) Google Scholar). Furthermore, thesaprophytic Mycobacterium smegmatis, naturally insensitive to INH,shows a dramatic increase of INH susceptibility after insertional inactivationof the ahpC gene(11Wilson M. DeRisi J. Kristensen H.H. Imboden P. Rane S. Brown P.O. Schoolnik G.K. Proc. Natl.Acad. Sci. U. S. A. 1999; 96: 12833-12838Crossref PubMed Scopus (495) Google Scholar). MtAhpC is a member of a large family of peroxidases, the peroxiredoxins,found in most living organisms. Peroxiredoxins are responsible for theantioxidant defense in bacteria, yeast, and trypanosomatids; they participatein balancing hydroperoxide production during photosynthesis in plants andappear to control cytokine-induced peroxide levels that mediate signaltransduction in mammalian cells (see Refs.12Hofmann B. Hecht H.J. Flohé L. Biol. Chem. 2002; 383: 347-364Crossref PubMed Scopus (773) Google Scholar and13Wood Z.A. Schröder E. Harris J.R. Poole L.B. Trends Biochem. Sci. 2003; 28: 32-40Abstract Full Text Full Text PDF PubMed Scopus (2121) Google Scholar for recent reviews). Inmycobacteria, AhpC can not only detoxify hydroperoxides but also affordsprotection to cells against reactive nitrogen intermediates(14Chen L. Xie Q. Nathan C. Mol. Cell. 1998; 1: 795-805Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar,15Master S.S. Springer B. Sander P. Boettger E.C. Deretic V. Timmins G.S. Microbiology. 2002; 148: 3139-3144Crossref PubMed Scopus (111) Google Scholar). MtAhpC specificallycatalyzes the conversion of peroxynitrite (OONO-) to nitrite fastenough to avoid the spontaneous decomposition of the former into thedeleterious nitrogen dioxide and hydroxyl radicals(16Bryk R. Griffin P. Nathan C. Nature. 2000; 407: 211-215Crossref PubMed Scopus (568) Google Scholar). The NADH-dependentperoxidase and peroxynitrite reductase system of M. tuberculosisinvolves MtAhpC as the foremost element of a chain that also includes theMtAhpC-reducing protein, AhpD, dihydrolipoamide dehydrogenase, Lpd, anddihydrolipoamide succinyltransferase, SucB(17Bryk R. Lima C.D. Erdjument-Bromage H. Tempst P. Nathan C. Science. 2002; 295: 1073-1077Crossref PubMed Scopus (326) Google Scholar), although alternativethioredoxin-mediated pathways including MtAhpC have also been reported(18Jaeger T. Budde H. Flohé L. Menge U. Singh M. Trujillo M. Radi R. Arch. Biochem.Biophys. 2004; 432: 182-191Crossref Scopus (132) Google Scholar). Peroxiredoxins (EC 1.11.1.15) use redox-active cysteine residues to reducetheir substrates and can be classified into three classes (typical 2-Cys,atypical 2-Cys, and 1-Cys enzymes) based on the number and the sequencepositions of cysteinyl residues involved in catalysis(13Wood Z.A. Schröder E. Harris J.R. Poole L.B. Trends Biochem. Sci. 2003; 28: 32-40Abstract Full Text Full Text PDF PubMed Scopus (2121) Google Scholar). In all three classes,the first step of the peroxidase reaction involves a conserved N-terminalcysteine (the peroxidatic cysteine), which attacks the peroxide/peroxynitritesubstrate and is oxidized to a cysteine sulfenic acid (Cys-SOH). Typical 2-Cysperoxiredoxins like MtAhpC are obligate homodimers in which the second(C-terminal) cysteine from one subunit acts as the resolving cysteine toattack the peroxidatic cysteine sulfenic acid located in the other subunit.The ensuing condensation reaction results in the formation of a stableintersubunit disulfide bond, which is then reduced by one of severalcell-specific disulfide oxidoreductases, completing the catalytic cycle. Although MtAhpC is usually considered a typical 2-Cys peroxiredoxin, itdiffers in a number of important features from other members of the family.First, MtAhpC has three (rather than two) cysteine residues directly involvedin catalysis (19Hillas P.J. Soto del Alba F. Oyarzabal J. Wilks A. Ortiz de Montellano P.R. J. Biol.Chem. 2000; 275: 18801-18809Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar), theconserved peroxidatic cysteine Cys61, the putative resolvingcysteine Cys174, and a third cysteine, Cys176, whosecatalytic role is unclear (20Chauhan R. Mande S.C. Biochem. J. 2002; 367: 255-261Crossref PubMed Google Scholar,21Koshkin A. Knudsen G.M. Ortiz de Montellano P.R. Arch. Biochem. Biophys. 2004; 427: 41-47Crossref PubMed Scopus (30) Google Scholar). Second, it remained anenigma how MtAhpC is supplied with reduction equivalents because thethioredoxin system that reduces peroxiredoxins in eukaryoticH2O2 metabolism was reported to be inactive as areductant of MtAhpC (19Hillas P.J. Soto del Alba F. Oyarzabal J. Wilks A. Ortiz de Montellano P.R. J. Biol.Chem. 2000; 275: 18801-18809Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar), andthere is no homologue in the mycobacterial genome of the AhpF flavoproteinknown to reduce AhpC in Salmonella typhimurium(22Ellis H.R. Poole L.B. Biochemistry. 1997; 36: 13349-13356Crossref PubMed Scopus (177) Google Scholar). Instead, MtAhpC isreduced by a novel atypical system involving R. Lima C.D. Erdjument-Bromage H. Tempst P. Nathan C. Science. 2002; 295: 1073-1077Crossref PubMed Scopus (326) Google Scholar), a that is only in a number of organisms. report the structure of the point trapped in an intermediate state of its catalytic cycle. The of has a structure to of although the oxidized as in it in an oligomeric observed for other B. Hecht H.J. Flohé L. Biol. Chem. 2002; 383: 347-364Crossref PubMed Scopus (773) Google Z.A. Schröder E. Harris J.R. Poole L.B. Trends Biochem. Sci. 2003; 28: 32-40Abstract Full Text Full Text PDF PubMed Scopus (2121) Google Scholar). In the structure suggests a model for the that can the involvement of the three cysteine residues the formation of disulfide bond, the the peroxidatic cysteine is to instead of the observed inthe of other 2-Cys Z.A. Schröder E. Harris J.R. Poole L.B. Trends Biochem. Sci. 2003; 28: 32-40Abstract Full Text Full Text PDF PubMed Scopus (2121) Google Scholar). This unusual a large which the reaction a for the of inhibitors and ahpC gene was and into which a or a of the with and was into and on was from several of the into the was Overexpression of MtAhpC was then in The was then the the to a single and a of the of was used with either to the single or with to the and MtAhpC and and a cells in with and The was by in a and a in a and The was with for and with and The was against and with the The and to in for use the in the E. S.L. J. J. Mol. Biol. PubMed Scopus Google Scholar). cells in and and and with as AhpC with and cell was The was for and was by on a system in and The or a of and the of or a of and of of of a in the of a (the with for with AhpC and the but for diffraction diffraction anomalous diffraction of on the different and from a of the a highly was asingle to the for the the and from the D. PubMed Scopus Google Scholar). The and three with a cell and in in a and structure was by a after with and of 2-Cysperoxiredoxins The three by and and with the G. C. C. M. 2003; PubMed Scopus Google Scholar). the anomalous in could be to with of after and a electron was with the M. A. PubMed Scopus Google Scholar). well in and a of residues of the three could be the the anomalous and large residues as including the resolving cysteine Cys174, and the α-helix the peroxidatic in the and not after A. 1999; PubMed Scopus Google Scholar) to a highly a single to with an overall of and after and the a disulfide bridge involving the from one of the was against the the of the electron and model with the A. Morris Biol. 1999; PubMed Scopus Google Scholar). model has an to of are as for of the not used from as for of the not used in a of the model includes three and The of of acid residues and and acid residues to in B. that the peroxidatic is in and and in all the by residues is to in the electron The model overall by the R.A. J. Google Scholar), all residues that within or of the The of of in on the of and are the third a The overall and and and and to other by a of the which might the structure acid of MtAhpC and all of which are in catalysis (19Hillas P.J. Soto del Alba F. Oyarzabal J. Wilks A. Ortiz de Montellano P.R. J. Biol.Chem. 2000; 275: 18801-18809Abstract Full Text Full Text PDF PubMed Scopus (113) Google R. Mande S.C. Biochem. J. 2002; 367: 255-261Crossref PubMed Google Scholar). The is conserved in all peroxiredoxins and peroxidatic cysteine to the on the was also to be and acts as the resolving produced MtAhpC, the single point that might the of of and the only the peroxidatic as E. of the role of disulfide in MtAhpC as in different from has been observed by (19Hillas P.J. Soto del Alba F. Oyarzabal J. Wilks A. Ortiz de Montellano P.R. J. Biol.Chem. 2000; 275: 18801-18809Abstract Full Text Full Text PDF PubMed Scopus (113) Google R. Mande S.C. Biochem. J. 2002; 367: 255-261Crossref PubMed Google Scholar). The as a dimer the an disulfide bridge Cys61 or the of that the third cysteine is highly reactive and in disulfide the other the of that is involved in disulfide the as a single to the that the is oxidized the used and the for In with the the of MtAhpC single point and MtAhpC as a of in the of the into a to a or not In as a single oligomeric species and In its oxidized the as which to a or the of that the of the is with a oligomeric a by E. J. Mol. Biol. 2000; PubMed Scopus Google Scholar) from of the reduced peroxidase from and for other members of Z.A. Schröder E. Harris J.R. Poole L.B. Trends Biochem. Sci. 2003; 28: 32-40Abstract Full Text Full Text PDF PubMed Scopus (2121) Google Scholar). The of structure in its oxidized state was by a different and to of In the to a ring-shaped with an of and an of a was for because all to as a because the oxidized as a dimer in This that the is trapped in an intermediate state ofits catalytic by in which reaction has but the oligomeric has not into the functional intermediate has for S. typhimurium AhpC Z.A. Poole L.B. Biochemistry. 2002; PubMed Scopus Google Scholar), where it was that to the oligomeric is the that MtAhpC of a hexamer than the pentamer of dimers observed in as E. J. Mol. Biol. 2000; PubMed Scopus Google Z.A. Poole L.B. Biochemistry. 2002; PubMed Scopus Google Scholar), and peroxidase E. N. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). several lines to that formation of be a general 2-Cys peroxiredoxins in which the oligomeric is with enzyme Z.A. Schröder E. Harris J.R. Poole L.B. Trends Biochem. Sci. 2003; 28: 32-40Abstract Full Text Full Text PDF PubMed Scopus (2121) Google Scholar). recent and that the is a that to R. Mande S.C. Biochem. J. 2001; PubMed Scopus Google Scholar), and for that in with the redox state of the the and of the reduced in and in an to the the results not Although a model the not it was to the of from in the structure of MtAhpC of in of is including and the of and from dimers in MtAhpC also the and in the other and and the in MtAhpC is observed in conserved residues and for which a of is with the in E. J. Mol. Biol. 2000; PubMed Scopus Google E. N. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), the in the and that a also be in that the observed MtAhpC by to a of the in The functional MtAhpC is of other 2-Cys with an overall The of a of a and three with and and and in of is highly in the electron of in typical the dimer is by the of the involving the formation of an as well as by the and the and The three cysteine residues of MtAhpC are the the first in the disulfide bridge conserved in typical In the structure of the point disulfide is well in the electron Cys61 from and from a rigid-bodymovement of that is for disulfide formation is observed in the three that the is oxidized in the with the This oxidized an intermediate of reaction by 2-Cys peroxiredoxins and was observed inthe of 2-Cys peroxiredoxin S. Y. K. N. H. T. T. Proc. Natl. Acad. Sci. A. 1999; 96: PubMed Scopus Google Scholar) and Z.A. Poole L.B. Biochemistry. 2002; PubMed Scopus Google Scholar). Although the is and by several residues in the in MtAhpC it is to the and its is The is by the of and the and and the and decomposition a to cysteine as well as an acid to the although have yet to be The of MtAhpC be from the structure has been trapped in an intermediate state of the reaction reduction by Cys61 and the condensation reaction the active residues in Z.A. Schröder E. Harris J.R. Poole L.B. Trends Biochem. Sci. 2003; 28: 32-40Abstract Full Text Full Text PDF PubMed Scopus (2121) Google Scholar), and are in the mycobacterial enzyme and are to a the of the of peroxiredoxins, the sulfenic acid the peroxidatic cysteine peroxide reduction as in the structure of the H.J. Biol. 1998; PubMed Scopus Google by the resolving cysteine from the other to disulfide This condensation reaction conformational both in in which of the is to cysteine Z.A. Schröder E. Harris J.R. Poole L.B. Trends Biochem. Sci. 2003; 28: 32-40Abstract Full Text Full Text PDF PubMed Scopus (2121) Google Scholar), the to the resolving cysteine This is observed in the structure in the of and from the residues are from third is observed in the of the reaction in which the condensation reaction has but the have not yet the of intermediate is of observed in oxidized the to the for disulfide is in MtAhpC by a rigid-bodymovement of the that Cys61 This not to be by the in the because it is not observed in a and in oligomeric is also by The that the isdirectly related to the MtAhpC mechanism of can the peroxidatic cysteine either with the resolving cysteine as in or to the active of in which the of the observed in the other peroxiredoxin are for to for rearrangement of three a Cys61 of and of in with the both and active for peroxide for system to an important role in M.tuberculosis resistance against the oxidative and nitrosative by the host R. Lima C.D. Erdjument-Bromage H. Tempst P. Nathan C. Science. 2002; 295: 1073-1077Crossref PubMed Scopus (326) Google Scholar). for novel for INH-resistant M. tuberculosis strains where MtAhpC to for the catalase-peroxidase S.S. Springer B. Sander P. Boettger E.C. Deretic V. Timmins G.S. Microbiology. 2002; 148: 3139-3144Crossref PubMed Scopus (111) Google R. Griffin P. Nathan C. Nature. 2000; 407: 211-215Crossref PubMed Scopus (568) Google Scholar). a was to be to the M. tuberculosis in A. P. Barry III, C.E. Ortiz de Montellano P.R. 2004; PubMed Scopus Google Scholar). A. P. Barry III, C.E. Ortiz de Montellano P.R. 2004; PubMed Scopus Google Scholar) that a to MtAhpC the the is the for drug against The structure of MtAhpC that of a which is in and might a putative for drug during the catalytic a that into could block the its intermediate state by of the catalytic the enzyme could be specifically with the catalytic which is the peroxiredoxin The of MtAhpC and the of model of the peroxiredoxin catalytic from and Z.A. Schröder E. Harris J.R. Poole L.B. Trends Biochem. Sci. 2003; 28: 32-40Abstract Full Text Full Text PDF PubMed Scopus (2121) Google Z.A. Poole L.B. Biochemistry. 2002; PubMed Scopus Google Scholar), although in the different reaction the three catalytic be to for its reduction by the redox peroxide the peroxidatic cysteine in sulfenic acid which is in turn by the resolving cysteine, either or This mechanism is by that both Cys61 and to be for R. Mande S.C. Biochem. J. 2002; 367: 255-261Crossref PubMed Google Scholar) and is able to substitute for in A. Knudsen G.M. Ortiz de Montellano P.R. Arch. Biochem. Biophys. 2004; 427: 41-47Crossref PubMed Scopus (30) Google Scholar). in the of and could be for by the of which can Cys61 to in the or the condensation reaction has in typical 2-Cysperoxiredoxins a by an is to reduce on the formation of A. Knudsen G.M. Ortiz de Montellano P.R. Arch. Biochem. Biophys. 2004; 427: 41-47Crossref PubMed Scopus (30) Google Scholar) also for to the to an for a mechanism to the conformational the of the cysteine residues in the and R. Lima C.D. Erdjument-Bromage H. Tempst P. Nathan C. Science. 2002; 295: 1073-1077Crossref PubMed Scopus (326) Google S. P.J. Ortiz de Montellano P.R. J. Biol.Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The structure of suggests an involving the of the three cysteine residues In the the of for in the is and from the of the of a disulfide involving during the reduction by an not conformational could be the of the the of to disulfide in from its state in the intermediate structure to in other the disulfide be located in the a single to and highly for an where the residues the residues and are in of the three a the could the of MtAhpC with redox a from AhpD, M. tuberculosis thioredoxin can reduce T. Budde H. Flohé L. Menge U. Singh M. Trujillo M. Radi R. Arch. Biochem.Biophys. 2004; 432: 182-191Crossref Scopus (132) Google Scholar). In with the A. Knudsen G.M. Ortiz de Montellano P.R. Arch. Biochem. Biophys. 2004; 427: 41-47Crossref PubMed Scopus (30) Google Scholar) observed that the not of MtAhpC could be trapped as with AhpD, leading to that formation of Cys61 and is step in MtAhpC the of the the peroxide reduction all electron transfer which of a intermediate for the to involvement of Cys61 in the the the of as resolving might the formation for the point and the peroxidase system by AhpD, and MtAhpC an atypical with a the oxidative activation hydroperoxide as T. Budde H. Flohé L. Menge U. Singh M. Trujillo M. Radi R. Arch. Biochem.Biophys. 2004; 432: 182-191Crossref Scopus (132) Google Scholar). This to when MtAhpC and AhpD with the other of the the first involves no the oxidized and reduced of the AhpD R. Lima C.D. Erdjument-Bromage H. Tempst P. Nathan C. Science. 2002; 295: 1073-1077Crossref PubMed Scopus (326) Google Scholar). The with the of a which could the into with the of of the AhpD active R. Lima C.D. Erdjument-Bromage H. Tempst P. Nathan C. Science. 2002; 295: 1073-1077Crossref PubMed Scopus (326) Google S. P.J. Ortiz de Montellano P.R. J. Biol.Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar) and in the atypical structure of in an intermediate state of the catalytic an instead of the observed of reducedperoxiredoxins. The condensation reaction an unusual of the the peroxidatic cysteine, which creates a cavity catalytic that might be for drug the alternative reaction can be for the reduction of MtAhpC by its redox peroxidase We G. and M. for with the and

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