AHPC_MYCTU
ID AHPC_MYCTU Reviewed; 195 AA.
AC P9WQB7; L0T9L3; Q79FE2; Q7BHK8; Q7D758;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 48.
DE RecName: Full=Alkyl hydroperoxide reductase C;
DE Short=MtAhpC;
DE EC=1.11.1.28 {ECO:0000269|PubMed:12084012, ECO:0000269|PubMed:14871480};
DE AltName: Full=Peroxiredoxin;
DE AltName: Full=Thioredoxin peroxidase;
GN Name=ahpC; OrderedLocusNames=Rv2428;
OS Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=83332;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=7604044; DOI=10.1073/pnas.92.14.6625;
RA Sherman D.R., Sabo P.J., Hickey M.J., Arain T.M., Mahairas G.G., Yuan Y.,
RA Barry C.E. III, Stover C.K.;
RT "Disparate responses to oxidative stress in saprophytic and pathogenic
RT mycobacteria.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:6625-6629(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=8596438; DOI=10.1111/j.1365-2958.1995.mmi_17050889.x;
RA Deretic V., Philipp W., Dhandayuthapani S., Mudd M.H., Curcic R., Garbe T.,
RA Heym B., Via L.E., Cole S.T.;
RT "Mycobacterium tuberculosis is a natural mutant with an inactivated
RT oxidative-stress regulatory gene: implications for sensitivity to
RT isoniazid.";
RL Mol. Microbiol. 17:889-900(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=An01, F07, Rm23, Rm24, and Rm30;
RA Orru G., Iona E., Memmi G., Oggioni M.R., Fattorini L., Orefici G.,
RA Pozzi G.;
RT "Mutation associated with isoniazid resistance in Italian isolates of
RT Mycobacterium tuberculosis.";
RL Submitted (OCT-2000) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=9634230; DOI=10.1038/31159;
RA Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E.,
RA Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K.,
RA Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K.,
RA Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K.,
RA Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J.,
RA Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S.,
RA Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S.,
RA Barrell B.G.;
RT "Deciphering the biology of Mycobacterium tuberculosis from the complete
RT genome sequence.";
RL Nature 393:537-544(1998).
RN [5]
RP PROTEIN SEQUENCE OF 2-16, LACK OF ACTION ON ISONIAZID, AND INDUCTION IN
RP DRUG-RESISTANT BACTERIA.
RC STRAIN=ATCC 35822;
RX PubMed=8658136; DOI=10.1126/science.272.5268.1641;
RA Sherman D.R., Mdluli K., Hickey M.J., Arain T.M., Morris S.L.,
RA Barry C.E. III, Stover C.K.;
RT "Compensatory ahpC gene expression in isoniazid-resistant Mycobacterium
RT tuberculosis.";
RL Science 272:1641-1643(1996).
RN [6]
RP FUNCTION, MUTAGENESIS OF CYS-61; CYS-174 AND CYS-176, AND DISULFIDE BOND.
RX PubMed=10766746; DOI=10.1074/jbc.m001001200;
RA Hillas P.J., del Alba F.S., Oyarzabal J., Wilks A.,
RA Ortiz De Montellano P.R.;
RT "The AhpC and AhpD antioxidant defense system of Mycobacterium
RT tuberculosis.";
RL J. Biol. Chem. 275:18801-18809(2000).
RN [7]
RP SUBUNIT.
RX PubMed=11171096; DOI=10.1042/0264-6021:3540209;
RA Chauhan R., Mande S.C.;
RT "Characterization of the Mycobacterium tuberculosis H37Rv alkyl
RT hydroperoxidase AhpC points to the importance of ionic interactions in
RT oligomerization and activity.";
RL Biochem. J. 354:209-215(2001).
RN [8]
RP INDUCTION BY HYPOXIA.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=11416222; DOI=10.1073/pnas.121172498;
RA Sherman D.R., Voskuil M., Schnappinger D., Liao R., Harrell M.I.,
RA Schoolnik G.K.;
RT "Regulation of the Mycobacterium tuberculosis hypoxic response gene
RT encoding alpha -crystallin.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:7534-7539(2001).
RN [9]
RP BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, FUNCTION AS ANTIOXIDANT,
RP MUTAGENESIS OF CYS-61; CYS-174; CYS-176 AND 174-CYS--CYS-176, AND DISULFIDE
RP BOND.
RX PubMed=12084012; DOI=10.1042/bj20020545;
RA Chauhan R., Mande S.C.;
RT "Site-directed mutagenesis reveals a novel catalytic mechanism of
RT Mycobacterium tuberculosis alkylhydroperoxidase C.";
RL Biochem. J. 367:255-261(2002).
RN [10]
RP FUNCTION, AND SUBUNIT.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=11799204; DOI=10.1126/science.1067798;
RA Bryk R., Lima C.D., Erdjument-Bromage H., Tempst P., Nathan C.;
RT "Metabolic enzymes of mycobacteria linked to antioxidant defense by a
RT thioredoxin-like protein.";
RL Science 295:1073-1077(2002).
RN [11]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=14871480; DOI=10.1016/j.abb.2003.11.021;
RA Jaeger T., Budde H., Flohe L., Menge U., Singh M., Trujillo M., Radi R.;
RT "Multiple thioredoxin-mediated routes to detoxify hydroperoxides in
RT Mycobacterium tuberculosis.";
RL Arch. Biochem. Biophys. 423:182-191(2004).
RN [12]
RP MUTAGENESIS OF CYS-61; CYS-174 AND CYS-176, AND DISULFIDE BOND.
RX PubMed=15178486; DOI=10.1016/j.abb.2004.04.017;
RA Koshkin A., Knudsen G.M., Ortiz De Montellano P.R.;
RT "Intermolecular interactions in the AhpC/AhpD antioxidant defense system of
RT Mycobacterium tuberculosis.";
RL Arch. Biochem. Biophys. 427:41-47(2004).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=21969609; DOI=10.1074/mcp.m111.011627;
RA Kelkar D.S., Kumar D., Kumar P., Balakrishnan L., Muthusamy B., Yadav A.K.,
RA Shrivastava P., Marimuthu A., Anand S., Sundaram H., Kingsbury R.,
RA Harsha H.C., Nair B., Prasad T.S., Chauhan D.S., Katoch K., Katoch V.M.,
RA Kumar P., Chaerkady R., Ramachandran S., Dash D., Pandey A.;
RT "Proteogenomic analysis of Mycobacterium tuberculosis by high resolution
RT mass spectrometry.";
RL Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF MUTANT SER-176, DISULFIDE BONDS,
RP POSSIBLE CATALYTIC MECHANISM, AND SUBUNIT.
RX PubMed=15886207; DOI=10.1074/jbc.m503076200;
RA Guimaraes B.G., Souchon H., Honore N., Saint-Joanis B., Brosch R.,
RA Shepard W., Cole S.T., Alzari P.M.;
RT "Structure and mechanism of the alkyl hydroperoxidase AhpC, a key element
RT of the Mycobacterium tuberculosis defense system against oxidative
RT stress.";
RL J. Biol. Chem. 280:25735-25742(2005).
CC -!- FUNCTION: Thiol-specific peroxidase that catalyzes the reduction of
CC hydrogen peroxide and organic hydroperoxides to water and alcohols,
CC respectively. Plays a role in cell protection against oxidative stress
CC by detoxifying peroxides. Together with AhpD, DlaT and Lpd, constitutes
CC an NADH-dependent peroxidase active against hydrogen and alkyl
CC peroxides as well as serving as a peroxynitrite reductase, thus
CC protecting the bacterium against reactive nitrogen intermediates and
CC oxidative stress generated by the host immune system. Does not however
CC seem to play a role in detoxification of isoniazid.
CC {ECO:0000269|PubMed:10766746, ECO:0000269|PubMed:11799204,
CC ECO:0000269|PubMed:12084012}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R)-N(6)-dihydrolipoyl-L-lysyl-[lipoyl-carrier protein] + a
CC hydroperoxide = (R)-N(6)-lipoyl-L-lysyl-[lipoyl-carrier protein] + an
CC alcohol + H2O; Xref=Rhea:RHEA:62636, Rhea:RHEA-COMP:10502, Rhea:RHEA-
CC COMP:16355, ChEBI:CHEBI:15377, ChEBI:CHEBI:30879, ChEBI:CHEBI:35924,
CC ChEBI:CHEBI:83099, ChEBI:CHEBI:83100; EC=1.11.1.28;
CC Evidence={ECO:0000269|PubMed:12084012, ECO:0000269|PubMed:14871480};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=5.38 mM for tert-butyl hydroperoxide
CC {ECO:0000269|PubMed:12084012};
CC KM=0.2 uM for tert-butyl hydroperoxide (using AhpD as electron donor)
CC {ECO:0000269|PubMed:14871480};
CC KM=5.1 uM for tert-butyl hydroperoxide (using thioredoxin TrxC as
CC electron donor) {ECO:0000269|PubMed:14871480};
CC KM=65.7 uM for AhpD (using tert-butyl hydroperoxide as substrate)
CC {ECO:0000269|PubMed:14871480};
CC KM=5.6 uM for TrxC (using tert-butyl hydroperoxide as substrate)
CC {ECO:0000269|PubMed:14871480};
CC Note=kcat is 0.6 sec(-1) with tert-butyl hydroperoxide as substrate
CC and AhpD as reductant and 0.1 sec(-1) with tert-butyl hydroperoxide
CC as substrate and TrxC as reductant. {ECO:0000269|PubMed:14871480};
CC -!- SUBUNIT: Homodimer; disulfide-linked, upon oxidation. 6 homodimers
CC assemble to form a ring-like dodecamer (PubMed:11171096,
CC PubMed:15886207). Identified in a complex with AhpD, DlaT and Lpd
CC (PubMed:11799204). {ECO:0000269|PubMed:11171096,
CC ECO:0000269|PubMed:11799204, ECO:0000269|PubMed:15886207}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P0AE08}.
CC -!- INDUCTION: Induced in isoniazid (INH)-resistant, KatG-deficient strains
CC as well as in INH-sensitive strains when challenged with the drug.
CC Increased expression in these strains probably compensates for loss of
CC katG activity in detoxification of organic peroxides. A possible member
CC of the dormancy regulon. Induced in response to reduced oxygen tension
CC (hypoxia). It is hoped that this regulon will give insight into the
CC latent, or dormant phase of infection. {ECO:0000269|PubMed:11416222,
CC ECO:0000269|PubMed:8658136}.
CC -!- MISCELLANEOUS: The active site is a conserved redox-active cysteine
CC residue, the peroxidatic cysteine (C(P)), which makes the nucleophilic
CC attack on the peroxide substrate. The peroxide oxidizes the C(P)-SH to
CC cysteine sulfenic acid (C(P)-SOH), which then reacts with another
CC cysteine residue, the resolving cysteine (C(R)), to form a disulfide
CC bridge. The disulfide is subsequently reduced by an appropriate
CC electron donor to complete the catalytic cycle. In this typical 2-Cys
CC peroxiredoxin, C(R) is provided by the other dimeric subunit to form an
CC intersubunit disulfide (PubMed:15178486, PubMed:15886207). The
CC disulfide can subsequently be reduced through a mixed disulfide with
CC the C-terminal cysteine of AhpD, resolved by its second cysteine
CC (PubMed:15178486) or by thioredoxin (TrxC) (PubMed:14871480).
CC {ECO:0000269|PubMed:14871480, ECO:0000269|PubMed:15178486,
CC ECO:0000305|PubMed:15886207}.
CC -!- SIMILARITY: Belongs to the peroxiredoxin family. AhpC/Prx1 subfamily.
CC {ECO:0000305}.
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DR EMBL; U18264; AAA79919.1; -; Genomic_DNA.
DR EMBL; U16243; AAC43585.1; -; Genomic_DNA.
DR EMBL; AF313459; AAG34172.1; -; Genomic_DNA.
DR EMBL; AF313460; AAG34173.1; -; Genomic_DNA.
DR EMBL; AF313461; AAG34174.1; -; Genomic_DNA.
DR EMBL; AF313462; AAG34175.1; -; Genomic_DNA.
DR EMBL; AF313463; AAG34176.1; -; Genomic_DNA.
DR EMBL; AL123456; CCP45220.1; -; Genomic_DNA.
DR RefSeq; NP_216944.1; NC_000962.3.
DR RefSeq; WP_003412529.1; NZ_NVQJ01000024.1.
DR PDB; 2BMX; X-ray; 2.40 A; A/B/C=1-195.
DR PDBsum; 2BMX; -.
DR AlphaFoldDB; P9WQB7; -.
DR SMR; P9WQB7; -.
DR STRING; 83332.Rv2428; -.
DR PaxDb; P9WQB7; -.
DR DNASU; 885717; -.
DR GeneID; 45426418; -.
DR GeneID; 885717; -.
DR KEGG; mtu:Rv2428; -.
DR PATRIC; fig|83332.111.peg.2715; -.
DR TubercuList; Rv2428; -.
DR eggNOG; COG0450; Bacteria.
DR OMA; FWYPKDF; -.
DR PhylomeDB; P9WQB7; -.
DR BRENDA; 1.11.1.28; 3445.
DR Reactome; R-HSA-1222387; Tolerance of reactive oxygen produced by macrophages.
DR Reactome; R-HSA-1222538; Tolerance by Mtb to nitric oxide produced by macrophages.
DR Reactome; R-HSA-1222541; Cell redox homeostasis.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0009274; C:peptidoglycan-based cell wall; HDA:MTBBASE.
DR GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR GO; GO:0008785; F:alkyl hydroperoxide reductase activity; IDA:MTBBASE.
DR GO; GO:0032843; F:hydroperoxide reductase activity; IDA:MTBBASE.
DR GO; GO:0016491; F:oxidoreductase activity; IDA:MTBBASE.
DR GO; GO:0004601; F:peroxidase activity; IDA:MTBBASE.
DR GO; GO:0051920; F:peroxiredoxin activity; IDA:MTBBASE.
DR GO; GO:0045454; P:cell redox homeostasis; IDA:MTBBASE.
DR GO; GO:0051409; P:response to nitrosative stress; IMP:MTBBASE.
DR GO; GO:0006979; P:response to oxidative stress; IEA:InterPro.
DR InterPro; IPR017559; AhpC.
DR InterPro; IPR000866; AhpC/TSA.
DR InterPro; IPR024706; Peroxiredoxin_AhpC-typ.
DR InterPro; IPR036249; Thioredoxin-like_sf.
DR InterPro; IPR013766; Thioredoxin_domain.
DR PANTHER; PTHR10681:SF121; PTHR10681:SF121; 1.
DR Pfam; PF00578; AhpC-TSA; 1.
DR PIRSF; PIRSF000239; AHPC; 1.
DR SUPFAM; SSF52833; SSF52833; 1.
DR PROSITE; PS51352; THIOREDOXIN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Antioxidant; Cytoplasm; Direct protein sequencing;
KW Disulfide bond; Oxidoreductase; Peroxidase; Redox-active center;
KW Reference proteome; Stress response.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:8658136"
FT CHAIN 2..195
FT /note="Alkyl hydroperoxide reductase C"
FT /id="PRO_0000392913"
FT DOMAIN 4..170
FT /note="Thioredoxin"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00691"
FT ACT_SITE 61
FT /note="Cysteine sulfenic acid (-SOH) intermediate"
FT /evidence="ECO:0000305|PubMed:10766746,
FT ECO:0000305|PubMed:12084012, ECO:0000305|PubMed:15178486"
FT DISULFID 61
FT /note="Interchain (with C-133 in AhpD); transient"
FT /evidence="ECO:0000269|PubMed:15178486"
FT DISULFID 61
FT /note="Interchain (with C-174); in linked form"
FT /evidence="ECO:0000269|PubMed:10766746,
FT ECO:0000269|PubMed:15178486, ECO:0000269|PubMed:15886207,
FT ECO:0007744|PDB:2BMX"
FT DISULFID 174
FT /note="Interchain (with C-61); in linked form"
FT /evidence="ECO:0000269|PubMed:10766746,
FT ECO:0000269|PubMed:15178486, ECO:0000269|PubMed:15886207,
FT ECO:0007744|PDB:2BMX"
FT MUTAGEN 61
FT /note="C->A,S: No enzyme activity."
FT /evidence="ECO:0000269|PubMed:10766746,
FT ECO:0000269|PubMed:12084012, ECO:0000269|PubMed:15178486"
FT MUTAGEN 174..176
FT /note="CAC->AAA: 50% reduction in oxidation activity of
FT dithiothreitol and 60% reduction in oxidation of
FT thiocyanate."
FT /evidence="ECO:0000269|PubMed:12084012"
FT MUTAGEN 174
FT /note="C->A: Very poor oxidation activity of dithiothreitol
FT and thiocyanate."
FT /evidence="ECO:0000269|PubMed:10766746,
FT ECO:0000269|PubMed:12084012, ECO:0000269|PubMed:15178486"
FT MUTAGEN 174
FT /note="C->S: In reconstituted in vitro system retains no
FT enzyme activity."
FT /evidence="ECO:0000269|PubMed:10766746,
FT ECO:0000269|PubMed:12084012, ECO:0000269|PubMed:15178486"
FT MUTAGEN 176
FT /note="C->A: 50% reduction in oxidation activity of
FT dithiothreitol and thiocyanate."
FT /evidence="ECO:0000269|PubMed:10766746,
FT ECO:0000269|PubMed:12084012, ECO:0000269|PubMed:15178486"
FT MUTAGEN 176
FT /note="C->S: Retains about 10% activity with tert-
FT butylhydroperoxide. In reconstituted in vitro system
FT retains 30% enzyme activity."
FT /evidence="ECO:0000269|PubMed:10766746,
FT ECO:0000269|PubMed:12084012, ECO:0000269|PubMed:15178486"
FT STRAND 14..18
FT /evidence="ECO:0007829|PDB:2BMX"
FT HELIX 23..25
FT /evidence="ECO:0007829|PDB:2BMX"
FT HELIX 31..34
FT /evidence="ECO:0007829|PDB:2BMX"
FT STRAND 35..39
FT /evidence="ECO:0007829|PDB:2BMX"
FT STRAND 47..52
FT /evidence="ECO:0007829|PDB:2BMX"
FT HELIX 62..70
FT /evidence="ECO:0007829|PDB:2BMX"
FT HELIX 72..76
FT /evidence="ECO:0007829|PDB:2BMX"
FT TURN 77..79
FT /evidence="ECO:0007829|PDB:2BMX"
FT STRAND 80..88
FT /evidence="ECO:0007829|PDB:2BMX"
FT HELIX 90..99
FT /evidence="ECO:0007829|PDB:2BMX"
FT HELIX 103..105
FT /evidence="ECO:0007829|PDB:2BMX"
FT STRAND 110..112
FT /evidence="ECO:0007829|PDB:2BMX"
FT HELIX 117..121
FT /evidence="ECO:0007829|PDB:2BMX"
FT STRAND 129..131
FT /evidence="ECO:0007829|PDB:2BMX"
FT STRAND 133..138
FT /evidence="ECO:0007829|PDB:2BMX"
FT STRAND 142..150
FT /evidence="ECO:0007829|PDB:2BMX"
FT HELIX 158..169
FT /evidence="ECO:0007829|PDB:2BMX"
FT HELIX 175..177
FT /evidence="ECO:0007829|PDB:2BMX"
SQ SEQUENCE 195 AA; 21566 MW; 011C1014F07C7095 CRC64;
MPLLTIGDQF PAYQLTALIG GDLSKVDAKQ PGDYFTTITS DEHPGKWRVV FFWPKDFTFV
CPTEIAAFSK LNDEFEDRDA QILGVSIDSE FAHFQWRAQH NDLKTLPFPM LSDIKRELSQ
AAGVLNADGV ADRVTFIVDP NNEIQFVSAT AGSVGRNVDE VLRVLDALQS DELCACNWRK
GDPTLDAGEL LKASA
