Cloning and Characterization of Three Differentially Expressed Peroxidoxin Genes from Leishmania chagasi

Antioxidants have been implicated in protecting cells from oxygen radicals produced as a result of aerobic metabolism and in response to foreign pathogens by phagocytic cells. The mechanisms allowing pathogens to withstand the toxic prooxidant environment within the phagolysosome are poorly understood. We have cloned and characterized three antioxidant genes belonging to the 2-Cys family of peroxidoxins from Leishmania chagasi that may prove to provide these parasites with an enhanced defense mechanism against toxic oxidants. The 5′-untranslated regions and coding regions of each gene are highly conserved, whereas the 3′-untranslated regions have diverged significantly. L. chagasi peroxidoxin 1 (LcPxn1) is predominantly expressed in the amastigote stage, whereas LcPxn2 and LcPxn3 are expressed mainly in the promastigote stage, with LcPxn3 being far less abundant than LcPxn2. LcPxn2 and LcPxn3 possess a nine-amino acid extension at the carboxyl terminus, which LcPxn1 lacks. LcPxn1 appears to exist as high molecular weight multimers in vivo, and recombinant LcPxn1 was shown to detoxify hydrogen peroxide and alkyl hydroperoxides. We also present strong evidence that recombinant LcPxn1 can enzymatically detoxify hydroxyl radicals, an activity never before clearly demonstrated for a protein. Antioxidants have been implicated in protecting cells from oxygen radicals produced as a result of aerobic metabolism and in response to foreign pathogens by phagocytic cells. The mechanisms allowing pathogens to withstand the toxic prooxidant environment within the phagolysosome are poorly understood. We have cloned and characterized three antioxidant genes belonging to the 2-Cys family of peroxidoxins from Leishmania chagasi that may prove to provide these parasites with an enhanced defense mechanism against toxic oxidants. The 5′-untranslated regions and coding regions of each gene are highly conserved, whereas the 3′-untranslated regions have diverged significantly. L. chagasi peroxidoxin 1 (LcPxn1) is predominantly expressed in the amastigote stage, whereas LcPxn2 and LcPxn3 are expressed mainly in the promastigote stage, with LcPxn3 being far less abundant than LcPxn2. LcPxn2 and LcPxn3 possess a nine-amino acid extension at the carboxyl terminus, which LcPxn1 lacks. LcPxn1 appears to exist as high molecular weight multimers in vivo, and recombinant LcPxn1 was shown to detoxify hydrogen peroxide and alkyl hydroperoxides. We also present strong evidence that recombinant LcPxn1 can enzymatically detoxify hydroxyl radicals, an activity never before clearly demonstrated for a protein. L. chagasi peroxidoxins 1–3 L. donovaniperoxidoxin 1 polymerase chain reaction glutathioneS-transferase isopropyl-1-thio-β-d-galactoside base pair(s) kilobase pair(s) untranslated region N-ethylmaleimide bovine serum albumin mixed function oxidation untranslated region iron-containing superoxide dismutase specific activity Peroxidoxins (also known as peroxiredoxins and thiol-specific antioxidants) comprise a family of antioxidants that have been recently discovered in numerous prokaryotes and eukaryotes. These proteins do not possess antioxidant activities found in other well known antioxidants. Peroxidoxins do not contain metal ions as seen in superoxide dismutases, they do not contain selenium-like glutathione peroxidases, nor do they contain heme like catalases (1Kim K. Kim I.H. Lee K-Y. Rhee S.G. Stadtman E.R. J. Biol. Chem. 1988; 263: 4704-4711Abstract Full Text PDF PubMed Google Scholar). The gene sequence and protein functions of peroxidoxins are highly conserved among organisms and are currently classified into two groups: 1-Cys and 2-Cys. The 1-Cys peroxidoxins contain a conserved cysteine residue in the amino-terminal region of the protein at amino acid position 47, whereas the 2-Cys peroxidoxin, in addition to the conserved cysteine 47 residue, also contains a second conserved cysteine residue in the carboxyl-terminal region of the protein at amino acid position 170. Peroxidoxins exist predominantly as homodimers arranged in a head-to-tail orientation; however, evidence exists of multimeric forms of peroxidoxins (2Alphey M.S. Bond C.S. Tetaud E. Fairlamb A.H. Hunter W.N. J. Mol. Biol. 2000; 300: 903-916Crossref PubMed Scopus (141) Google Scholar, 3Sch der E. Littlechild J.A. Lebedev A.A. Errington N. Vagin A.A. Isupov M.N. Structure. 2000; 8: 605-615Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 4Hirotsu S. Abe Y. Okada K. Nagahara N. Hori H. Nishino T. Hakoshima T. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 12333-12338Crossref PubMed Scopus (236) Google Scholar, 5Logan C. Mayhew S.G. J. Biol. Chem. 2000; 275: 30019-30028Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). So far, the substrates of peroxidoxin include hydrogen peroxide, alkyl hydroperoxides (e.g. cumene andt-butyl hydroperoxides) (6McGonigle S. Dalton J.P. James E.R. Parasitol. Today. 1998; 14: 139-145Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar), and peroxynitrite (ONOO−) (7Bryk R. Griffin P. Nathan C. Nature. 2000; 407: 211-215Crossref PubMed Scopus (570) Google Scholar). The mechanism of action for the detoxification of these substrates involves the oxidation of the Cys47 residue to form a sulfenic acid intermediate, which then reacts with the adjacent thiol group of the opposing subunit (Cys47 for 1-Cys peroxidoxins and Cys170 for the 2-Cys peroxidoxins) to form an intermolecular disulfide bond (6McGonigle S. Dalton J.P. James E.R. Parasitol. Today. 1998; 14: 139-145Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar). Recently, a third type of peroxidoxin protein has been reported that resembles the 1-Cys peroxidoxins, where instead of forming an intermolecular disulfide bond with the adjacent monomer, it forms an intramolecular disulfide bond with a cysteine residue whose surrounding residues do not share homology with any of the conserved cysteine motifs found in other peroxidoxins from other species (8Seo M.S. Kang S.W. Kim K. Baines I.C. Lee T.H. Rhee S.G. J. Biol. Chem. 2000; 275: 20346-20354Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar). The reported substrates of peroxidoxins suggest that they may play key roles in the defense against oxidative stress. H2O2, hydroperoxides, and ONOO−are all extremely reactive by-products from the molecular reduction of O2 during normal cell metabolism and within the phagolysosomes of phagocytic cells during the respiratory burst. These molecules can be produced in many reactions such as Reactions 1–R4.O2+Fe2+→O⨪2+Fe3+2O⨪2+2H+→H2O2+O2O2+NO−→ONOO−NO⋅+O⨪2→ONOO−REACTIONS1–4A molecule that is of great concern to all cells is the hydroxyl radical (⋅OH). Due to its large reduction potential, ⋅OH is the most biologically reactive molecule known to exist. ⋅OH can be produced as a result of numerous reactions such as Reactions 5–R9.O2−+H2O2→⋅OH+O2+−OHO2−+H2O2→⋅OH+O2+−OHH2O2+UV→2⋅OHO2−+H2O2→⋅OH+O2+−OHO2−+H2O2→⋅OH+O2+−OHREACTIONS5–9⋅OH reacts with all biological targets at diffusion-limited rates and like other prooxidants can lead to the peroxidation of lipids, lethal damage to DNA, and the oxidation of sugars and protein thiols (9Halliwell B. Gutteridge J.M.C. Free Radicals in Biology and Medicine. 3rd Ed. Oxford University Press, Inc., New York2000Google Scholar). To date, no clear evidence for an enzymatic defense against⋅OH has been demonstrated. Most intracellular pathogens are heavily equipped with antioxidant defenses such as superoxide dismutase, catalases, and glutathione peroxidases in order to withstand the toxic prooxidant environment of the phagolysosome. However, many intracellular pathogens such asLeishmania lack detectable catalases and glutathione peroxidases. Leishmania is an obligate intracellular protozoan parasite of mammalian macrophages. The parasites exist in two forms during their life cycle. The extracellular promastigote form is found to survive in the gut of its sandfly vector and is inoculated into its host during the bite of the sandfly. It is phagocytosed by cells such as macrophages and transforms into the intracellular amastigote form. Phagocytosis of these parasites is accompanied by an oxidative burst that results in the production of all of the reactive prooxidants aforementioned in Reactions 1–R9 (10Robinson J.M. Badwey J.A. Immunol. Ser. 1994; 60: 159-178PubMed Google Scholar). Clearly, Leishmania parasites and other intracellular pathogens must evade the toxic effects of these prooxidants in order to survive and establish an infection. We have previously reported thatLeishmania chagasi possesses iron superoxide dismutases, which act as a first line of defense against O⨪2 (11Paramchuk W.J. Ismail S.O. Bhatia A. L. Mol. Parasitol. PubMed Scopus Google Scholar), no defense against H2O2, hydroperoxides, ⋅OH has been demonstrated. the and of three peroxidoxins from L. chagasi and is the first of the of peroxidoxins in We that of the recombinant L. can detoxify and alkyl present for the first clear evidence that LcPxn1 can enzymatically detoxify ⋅OH in and protein molecular weight from and molecular weight and parasite and from other of the and from acid the L. chagasi by promastigote parasites at in with and amino serum at for and at 1 and at to as previously J. PubMed Scopus Google Scholar). was chagasi and L. by parasites in was to the and at which was and at The was with a and the surrounding the two conserved cysteine residues and of the 2-Cys family of peroxidoxins previously from 1 sequence to T. peroxidoxin The amino acid sequence surrounding the conserved cysteine residues in the are as and 1 and to L. L. for of for 1 for for for a The was and a as the L. chagasi was to in J. T. Ed. Scholar). cloned into and as the The was with the and as a to the for an the peroxidoxin and to to J. T. Ed. Scholar), and was a The was with and a was the characterized by and and of amastigote chagasi and L. to from the was into vector an in and cells The of all have been in with the was with and a The was to action J. T. Ed. and with for The with and at with for which the with at for each was from the acid P. N. PubMed Scopus Google Scholar). of was in a and at for The with and at with for which the with at for each with as a by E. of to at with an The vector was to LcPxn1 as a cells. The coding region of LcPxn1 was by the and the a to of the into the vector J. T. Ed. Scholar). vector and the recombinant vector to E. cells. cells at in for which was to the and protein and protein by and a as by and 1988; PubMed Scopus Google Scholar). The protein was with of at and a to protein. was a and the was the protein of recombinant protein was from a in in and into New The first was in with in with an was for peroxide metabolism was as by R. J. PubMed Scopus Google Scholar). the reaction cumene and of protein. to the addition of the to the the recombinant peroxidoxin protein was with for at in order to the disulfide the cysteine The reaction was at with the addition of 1 of acid the protein was with a of and of to the reactions and mixed at known of peroxide as a before and to for at to ⋅OH as by Kim Kim K. Kim I.H. PubMed Scopus Google Scholar). recombinant protein with for at was then to the and at for was with N-ethylmaleimide for at before it to the of was then to each and at for The was a at before The production and the damage of the by and Gutteridge B. Gutteridge J.M.C. PubMed Scopus Google Scholar). reaction was to contain the to the as peroxidoxin in for at was to the and the at for of acid and of acid then to the and for and the was then in a a with before The amino acid surrounding the two cysteine residues of 2-Cys peroxidoxins from a of organisms are highly conserved (6McGonigle S. Dalton J.P. James E.R. Parasitol. Today. 1998; 14: 139-145Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar). of the conserved amino surrounding and from the 2-Cys peroxidoxin from The and are to the conserved Cys47 and Cys170 residues in other 2-Cys 1 and to was and sequence of the to the amino acid sequence the two conserved cysteine residues of the Leishmania peroxidoxin A. R. S.G. 1998; PubMed Google Tetaud E. Fairlamb A.H. J.M. Mol. Parasitol. 1998; 96: PubMed Scopus Google Scholar). the as a was from L. chagasi that was to The of the peroxidoxin appears to be L. chagasi and L. The in 1 also that the peroxidoxins are of a family and that the peroxidoxin is within a in with and suggest that are peroxidoxin genes all present in L. chagasi and L. not it was that the L. chagasi peroxidoxin is within a order to peroxidoxin a was large the as a a the peroxidoxin was The was with and a was and for peroxidoxin of three peroxidoxin LcPxn2 and LcPxn3 and amastigote from L. chagasi The sequence of from each to the sequence of LcPxn1 that was from the The coding and of the from amastigote to the LcPxn1 of and LcPxn3 amino acid homology to other 2-Cys peroxidoxins from other the amino acid sequence surrounding and LcPxn1 of amino with a molecular of and LcPxn2 and LcPxn3 of amino each with molecular of and a of The coding region of LcPxn1 is to the coding regions of LcPxn2 and whereas LcPxn2 and LcPxn3 are to each the being a amino acid at amino acid position in in The carboxyl of LcPxn2 and LcPxn3 have diverged from The carboxyl of LcPxn2 and LcPxn3 contains a nine-amino acid extension that is not present in the of extension in LcPxn3 is a sequence J.M. Mol. Biol. PubMed Scopus Google Scholar). the amino acid for at the carboxyl of LcPxn2 not to for a sequence any other sequence J.M. Mol. Biol. PubMed Scopus Google Scholar). LcPxn1 the nine-amino acid extension found in LcPxn2 and LcPxn3 and not to possess any The of the of each peroxidoxin gene are not whereas the are and L. These results suggest that are at three highly conserved, 2-Cys peroxidoxins in L. To the of peroxidoxin as the parasites their life from parasites at and amastigote by The of in each was with a expressed of the LcPxn1 coding region as the the of two and that expressed from LcPxn1 to a into the a in from the to the amastigote from LcPxn2 to a demonstrated a in from the to the amastigote from LcPxn3 to a and a of to the LcPxn2 with a in from the to the amastigote LcPxn3 to be less abundant than LcPxn2 into the specific activity of the and that the to be to for to a with to LcPxn1 and LcPxn2. The of the LcPxn3 in the the coding region of LcPxn1 was a not These results clearly that LcPxn1 is predominantly expressed in the amastigote stage, LcPxn2 and LcPxn3 are expressed predominantly in the promastigote with from L. an of peroxidoxin not The coding region of LcPxn1 was cloned into the E. vector and to E. cells. of the protein with at in a of the protein being expressed in the form 1 protein was by with and by LcPxn1 protein with a molecular of which well with the molecular of To LcPxn1 is into protein within L. parasite was a LcPxn1 in a in The of a be of a high of LcPxn1 protein of the with other peroxidoxin Peroxidoxins are known to exist predominantly as homodimers in many organisms (6McGonigle S. Dalton J.P. James E.R. Parasitol. Today. 1998; 14: 139-145Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar), to was the with L. chagasi LcPxn1 protein was an of three from to To was an from of the a recombinant LcPxn1 and parasite was from to these results suggest that L. may exist as high molecular weight multimers in vivo, a also for peroxidoxins in (2Alphey M.S. Bond C.S. Tetaud E. Fairlamb A.H. Hunter W.N. J. Mol. Biol. 2000; 300: 903-916Crossref PubMed Scopus (141) Google Scholar), der E. Littlechild J.A. Lebedev A.A. Errington N. Vagin A.A. Isupov M.N. Structure. 2000; 8: 605-615Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar), and C. Mayhew S.G. J. Biol. Chem. 2000; 275: 30019-30028Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). The highly conserved amino acid sequence of peroxidoxins among organisms a conserved function in metabolism for all peroxidoxin We have the of recombinant LcPxn1 to detoxify hydrogen peroxide, cumene and in the activities of recombinant LcPxn1 hydrogen peroxide at a of cumene at a of andt-butyl at a of each LcPxn1 not any of the at a and also not any of the not These results the highly conserved detoxification activities in most peroxidoxins from other activities of recombinant is the of are the of three are the of three are the of three are the of three are the of three of activity are in of recombinant is the of are the of three in a of activity are in of recombinant protein. oxygen species have been implicated in a of such as lethal damage to the of cells. reactive oxygen it appears that O⨪2 and are not of at K. PubMed Scopus Google Scholar, B. Scopus Google Scholar). of the of O⨪2 and in from their into ⋅OH and B. Gutteridge J.M.C. Sci. 1998; Scholar, L. PubMed Scopus Google Scholar, H. Y. A. J. PubMed Scopus Google Scholar). It has been demonstrated that ⋅OH can in as well as to the and C. Mol. PubMed Scopus Google Scholar). a function oxidation to ⋅OH in B. PubMed Scopus Google Scholar), have the of L. to and from and the of the the of the in the form LcPxn1 protein no the in the of the the of the most of the was into the form the The addition of recombinant LcPxn1 and the ⋅OH and to the the of the into the form and proteins and no against of the To the by LcPxn1 was to its to H2O2, LcPxn1 in the of a of not to the the addition of 1 of to the not the from whereas the addition of recombinant LcPxn1 and was to the the of a to a that at with acid B. Gutteridge J.M.C. PubMed Scopus Google Scholar, J.M.C. PubMed Scopus Google Scholar). The addition of ⋅OH such as and to the results in and of the from 1 the of recombinant of the was LcPxn1 LcPxn1 and in a in and To of the be to the of protein of and in the and not and of which hydrogen peroxide at a to recombinant LcPxn1 the to the We found no evidence that LcPxn1 with the of the and peroxidoxins have been shown not to iron which in the reaction (1Kim K. Kim I.H. Lee K-Y. Rhee S.G. Stadtman E.R. J. Biol. Chem. 1988; 263: 4704-4711Abstract Full Text PDF PubMed Google Scholar). These results well with the results and suggest that LcPxn1 can enzymatically detoxify the of and with a in and are of a defense against organisms S. S. Nathan C. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). that reactive oxygen such as produced during the respiratory burst of are key in the of foreign pathogens such chagasi that survive and within these of the cells are not to withstand the reactive they however, they do possess antioxidant mechanisms such as superoxide dismutase J.M. J. PubMed Scopus Google Scholar), J. PubMed Scopus Google Scholar), and J. Biol. Chem. Full Text PDF PubMed Google that their to a of in that the foreign to their The molecular mechanism L. within macrophages is poorly understood. We chagasi possesses a strong antioxidant defense against the by the which the of the parasites to and establish an infection. We have previously shown that L. chagasi possesses iron superoxide that act as a first line of defense against O⨪2 (11Paramchuk W.J. Ismail S.O. Bhatia A. L. Mol. Parasitol. PubMed Scopus Google Scholar). suggest that a of in these parasites results in a reduction in in and L. that an antioxidant defense is for within macrophages. Recently, a peroxidoxin gene has been cloned and characterized which is for the form of A. R. S.G. 1998; PubMed Google Scholar, Tetaud E. Fairlamb A.H. J.M. Mol. Parasitol. 1998; 96: PubMed Scopus Google Scholar). L. has been shown to be expressed in these and no evidence of other peroxidoxins has been found Tetaud E. Fairlamb A.H. J.M. Mol. Parasitol. 1998; 96: PubMed Scopus Google Scholar). To peroxidoxins are present within L. chagasi and are any in the of peroxidoxins a and lethal of and characterized three peroxidoxins from L. chagasi and present and that It is to that the three peroxidoxins that present are in their function from the previously antioxidants and from L. chagasi (11Paramchuk W.J. Ismail S.O. Bhatia A. L. Mol. Parasitol. PubMed Scopus Google Scholar), the parasites a of LcPxn1 from the promastigote to the amastigote stage, whereas the of LcPxn2 and LcPxn3 the that of the peroxidoxin from L. which appears to be expressed in the of two L. in the amastigote peroxidoxin as to a peroxidoxin like that in L. The of the peroxidoxin genes in L. chagasi that may be a function for the Leishmania parasites exist in their life cycle. the in the gut of the they may and as they to be inoculated into their LcPxn2 and LcPxn3 have to the from oxidative that may result as in the parasites in response to of activity in response to has been previously reported N. Y. Acad. Sci. PubMed Scopus Google Scholar). the parasites the it is that they are to a oxidative environment with the gut of the sandfly. The LcPxn1 not may have to provide a enhanced and defense against and of The of each of the three peroxidoxins functions for these It be to the of three expressed peroxidoxins, is a to the the form and the form of the The of of peroxidoxin genes chagasi and L. may provide key into the mechanism of gene in within the the region and of many genes have been shown to be in gene R. S. 1994; PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, L. P. A. S. E. J. 14: PubMed Scopus Google Scholar, H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of all three L. chagasi peroxidoxins and the from L. highly conserved and coding regions and It is to that the three peroxidoxin genes of L. chagasi and the L. peroxidoxin, are of gene The LcPxn1 gene in the amastigote stage, LcPxn2 and LcPxn3 LcPxn3 is in and the L. peroxidoxin appears to be It be to the of all of these genes to are sequence for the of gene is an molecule that can and and proteins and T. J. 1988; PubMed Scopus Google Scholar, H. Chem. Ed. Scopus Google Scholar). It has been reported that the within the can as high as Mol. Biol. PubMed Scopus Google Scholar). can also lead to the production of high of toxic ⋅OH molecules and it is that an intracellular must possess a strong defense against and ⋅OH it is to a strong defense in L. chagasi has not been peroxidoxins to have been shown to detoxify H2O2, and have demonstrated that recombinant LcPxn1 protein also in We found it that LcPxn1 the amastigote stage, a found within the in an environment where that of the functions of LcPxn1 is in an in the of LcPxn1 that the parasites may be LcPxn1 protein for they the high of within the phagolysosome. of organisms in for the of oxidative have been reported J. C. R. J. Nature. 1999; PubMed Scopus Google Scholar, A. A. Free Biol. PubMed Scopus Google Scholar, 1994; Scopus Google Scholar). can also it is a for the of ⋅OH and ⋅OH can peroxidation hydrogen is for L. an of be a peroxidases are the for in many other no glutathione peroxidases have been discovered to Most peroxidoxins have been shown to detoxify alkyl hydroperoxides such and cumene hydroperoxides (6McGonigle S. Dalton J.P. James E.R. Parasitol. Today. 1998; 14: 139-145Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar), and have demonstrated that LcPxn1 is no We that LcPxn1 may be a key in the of in L. the peroxidoxin from L. not detoxify cumene Tetaud E. Fairlamb A.H. J.M. Mol. Parasitol. 1998; 96: PubMed Scopus Google Scholar). The coding region of LcPxn1 is to the coding region of the L. peroxidoxin with the being in the carboxyl It is that the nine-amino acid extension of the L. peroxidoxin and LcPxn2 and LcPxn3 of the hydroperoxides to the We have not a of the LcPxn2 LcPxn3 it be to they are to detoxify hydroperoxides. The mechanism that peroxidoxins in the form in is in however, it is that a may be Tetaud E. Fairlamb A.H. J.M. Mol. Parasitol. 1998; 96: PubMed Scopus Google Scholar, A.H. A. PubMed Scopus Google Scholar). It has been reported that the of reduction of by glutathione is that of the glutathione was as the instead (1Kim K. Kim I.H. Lee K-Y. Rhee S.G. Stadtman E.R. J. Biol. Chem. 1988; 263: 4704-4711Abstract Full Text PDF PubMed Google Scholar). the the and it is that rates of are in a is of its extremely high reduction potential, it has been that ⋅OH is reactive to be by any type of We present evidence that recombinant LcPxn1 can enzymatically detoxify is enzymatic activity has never before been clearly demonstrated with any other and such activity is conserved within the parasites in it may to L. chagasi can withstand environment of the phagolysosome. We found it that in an environment of H2O2, recombinant LcPxn1 was to detoxify ⋅OH and from mechanisms of detoxification in 2-Cys peroxidoxins that reaction with and the a sulfenic acid forms before a with the the opposing subunit Rhee S.G. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). It is that of its high reduction potential, ⋅OH can for to the to form a sulfenic acid before being However, the of a second We are currently the mechanism by which recombinant LcPxn1 and ⋅OH by and molecular which lead to and The the first clear for a protein an enzymatic defense against hydroxyl with the that peroxidoxins can detoxify peroxynitrite (7Bryk R. Griffin P. Nathan C. Nature. 2000; 407: 211-215Crossref PubMed Scopus (570) Google Scholar), peroxidoxins to play an as the line of defense against oxidative peroxidoxins from pathogens such as Leishmania be targets for and for the first in the of of be a in the sequence of the of each of these genes for sequence that may be in gene The and activities of peroxidoxins in lead to that by such L. chagasi has an enhanced defense for within macrophages. We are the of the peroxidoxin gene in L. chagasi and L. in order to the of the which in the of is to the that these peroxidoxins play in Leishmania and We for in the and

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