CP125_MYCTU
ID CP125_MYCTU Reviewed; 433 AA.
AC P9WPP1; L0TEH2; P63709; P71856;
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=Steroid C26-monooxygenase {ECO:0000303|PubMed:19846551};
DE EC=1.14.15.29 {ECO:0000269|PubMed:20545858, ECO:0000269|PubMed:20843794, ECO:0000305|PubMed:19846551};
DE AltName: Full=Cholest-4-en-3-one 26-monooxygenase {ECO:0000303|PubMed:19846551};
DE AltName: Full=Cholest-4-en-3-one C26-monooxygenase [(25S)-3-oxocholest-4-en-26-oate forming] {ECO:0000305|PubMed:20843794};
DE AltName: Full=Cholesterol C26-monooxygenase {ECO:0000303|PubMed:19846551};
DE AltName: Full=Cholesterol C26-monooxygenase [(25S)-3beta-hydroxycholest-5-en-26-oate forming] {ECO:0000305|PubMed:20843794};
DE AltName: Full=Cytochrome P450 125 {ECO:0000303|PubMed:19846551};
DE AltName: Full=Steroid C27-monooxygenase {ECO:0000303|PubMed:19846551};
GN Name=cyp125 {ECO:0000303|PubMed:19846551};
GN Synonyms=cyp125A1 {ECO:0000303|PubMed:20545858}; OrderedLocusNames=Rv3545c;
GN ORFNames=MTCY03C7.11;
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 [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 [2]
RP FUNCTION IN CHOLESTEROL CATABOLISM, CATALYTIC ACTIVITY, SUBSTRATE
RP SPECIFICITY, DISRUPTION PHENOTYPE, AND PATHWAY.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=19846551; DOI=10.1074/jbc.m109.072132;
RA Capyk J.K., Kalscheuer R., Stewart G.R., Liu J., Kwon H., Zhao R.,
RA Okamoto S., Jacobs W.R. Jr., Eltis L.D., Mohn W.W.;
RT "Mycobacterial cytochrome p450 125 (cyp125) catalyzes the terminal
RT hydroxylation of c27 steroids.";
RL J. Biol. Chem. 284:35534-35542(2009).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, INDUCTION, PATHWAY, AND SUBSTRATE
RP SPECIFICITY.
RX PubMed=20843794; DOI=10.1074/jbc.m110.161117;
RA Johnston J.B., Ouellet H., Ortiz de Montellano P.R.;
RT "Functional redundancy of steroid C26-monooxygenase activity in
RT Mycobacterium tuberculosis revealed by biochemical and genetic analyses.";
RL J. Biol. Chem. 285:36352-36360(2010).
RN [4]
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 [5]
RP X-RAY CRYSTALLOGRAPHY (1.35 ANGSTROMS) IN COMPLEX WITH SUBSTRATE ANALOG,
RP AND COFACTOR.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=19846552; DOI=10.1074/jbc.m109.032706;
RA McLean K.J., Lafite P., Levy C., Cheesman M.R., Mast N., Pikuleva I.A.,
RA Leys D., Munro A.W.;
RT "The Structure of Mycobacterium tuberculosis CYP125: molecular basis for
RT cholesterol binding in a P450 needed for host infection.";
RL J. Biol. Chem. 284:35524-35533(2009).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (1.58 ANGSTROMS) IN COMPLEX WITH HEME, FUNCTION IN
RP CHOLESTEROL CATABOLISM, CATALYTIC ACTIVITY, COFACTOR, DISRUPTION PHENOTYPE,
RP AND SUBSTRATE SPECIFICITY.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=20545858; DOI=10.1111/j.1365-2958.2010.07243.x;
RA Ouellet H., Guan S., Johnston J.B., Chow E.D., Kells P.M., Burlingame A.L.,
RA Cox J.S., Podust L.M., de Montellano P.R.;
RT "Mycobacterium tuberculosis CYP125A1, a steroid C27 monooxygenase that
RT detoxifies intracellularly generated cholest-4-en-3-one.";
RL Mol. Microbiol. 77:730-742(2010).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (1.48 ANGSTROMS) OF 18-433.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=21109436; DOI=10.1016/j.bmcl.2010.11.007;
RA Ouellet H., Kells P.M., Ortiz de Montellano P.R., Podust L.M.;
RT "Reverse type I inhibitor of Mycobacteriumtuberculosis CYP125A1.";
RL Bioorg. Med. Chem. Lett. 21:332-337(2011).
CC -!- FUNCTION: Involved in the utilization of cholesterol as the sole carbon
CC and energy source by degrading the side chain during infection
CC (PubMed:20843794, PubMed:20545858). Primarily catalyzes the sequential
CC oxidation of the terminal methyl of cholest-4-en-3-one into (25S)-26-
CC hydroxycholest-4-en-3-one (alcohol), (25S)-26-oxocholest-4-en-3-one
CC (aldehyde), to finally yield the carboxylic acid (25S)-3-oxocholest-4-
CC en-26-oate (PubMed:19846551, PubMed:20843794, PubMed:20545858). Also
CC able to sequentially oxidize cholesterol itself, not only cholest-4-en-
CC 3-one (PubMed:19846551, PubMed:20843794, PubMed:20545858).
CC {ECO:0000269|PubMed:19846551, ECO:0000269|PubMed:20545858,
CC ECO:0000269|PubMed:20843794}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cholest-4-en-3-one + 5 H(+) + 3 O2 + 6 reduced [2Fe-2S]-
CC [ferredoxin] = (25S)-3-oxocholest-4-en-26-oate + 4 H2O + 6 oxidized
CC [2Fe-2S]-[ferredoxin]; Xref=Rhea:RHEA:51564, Rhea:RHEA-COMP:10000,
CC Rhea:RHEA-COMP:10001, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16175, ChEBI:CHEBI:33737,
CC ChEBI:CHEBI:33738, ChEBI:CHEBI:71541; EC=1.14.15.29;
CC Evidence={ECO:0000269|PubMed:20545858, ECO:0000269|PubMed:20843794,
CC ECO:0000305|PubMed:19846551};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(25R)-3-oxocholest-4-en-26-ol + 2 H(+) + O2 + 2 reduced [2Fe-
CC 2S]-[ferredoxin] = (25R)-3-oxocholest-4-en-26-al + 2 H2O + 2 oxidized
CC [2Fe-2S]-[ferredoxin]; Xref=Rhea:RHEA:43916, Rhea:RHEA-COMP:10000,
CC Rhea:RHEA-COMP:10001, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:33737, ChEBI:CHEBI:33738,
CC ChEBI:CHEBI:83861, ChEBI:CHEBI:83862;
CC Evidence={ECO:0000269|PubMed:20843794};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:43917;
CC Evidence={ECO:0000269|PubMed:20843794};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(25R)-3-oxocholest-4-en-26-al + H(+) + O2 + 2 reduced [2Fe-
CC 2S]-[ferredoxin] = (25R)-3-oxocholest-4-en-26-oate + H2O + 2 oxidized
CC [2Fe-2S]-[ferredoxin]; Xref=Rhea:RHEA:43920, Rhea:RHEA-COMP:10000,
CC Rhea:RHEA-COMP:10001, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:33737, ChEBI:CHEBI:33738,
CC ChEBI:CHEBI:71570, ChEBI:CHEBI:83862;
CC Evidence={ECO:0000269|PubMed:20843794};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:43921;
CC Evidence={ECO:0000269|PubMed:20843794};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cholest-4-en-3-one + 2 H(+) + O2 + 2 reduced [2Fe-2S]-
CC [ferredoxin] = (25S)-3-oxocholest-4-en-26-ol + H2O + 2 oxidized [2Fe-
CC 2S]-[ferredoxin]; Xref=Rhea:RHEA:31943, Rhea:RHEA-COMP:10000,
CC Rhea:RHEA-COMP:10001, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:16175, ChEBI:CHEBI:33737,
CC ChEBI:CHEBI:33738, ChEBI:CHEBI:83860;
CC Evidence={ECO:0000269|PubMed:20843794};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:31944;
CC Evidence={ECO:0000269|PubMed:20843794};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(25S)-3-oxocholest-4-en-26-ol + 2 H(+) + O2 + 2 reduced [2Fe-
CC 2S]-[ferredoxin] = (25S)-3-oxocholest-4-en-26-al + 2 H2O + 2 oxidized
CC [2Fe-2S]-[ferredoxin]; Xref=Rhea:RHEA:51568, Rhea:RHEA-COMP:10000,
CC Rhea:RHEA-COMP:10001, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:33737, ChEBI:CHEBI:33738,
CC ChEBI:CHEBI:83860, ChEBI:CHEBI:83863;
CC Evidence={ECO:0000269|PubMed:20843794};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:51569;
CC Evidence={ECO:0000269|PubMed:20843794};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(25S)-3-oxocholest-4-en-26-al + H(+) + O2 + 2 reduced [2Fe-
CC 2S]-[ferredoxin] = (25S)-3-oxocholest-4-en-26-oate + H2O + 2 oxidized
CC [2Fe-2S]-[ferredoxin]; Xref=Rhea:RHEA:51572, Rhea:RHEA-COMP:10000,
CC Rhea:RHEA-COMP:10001, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:33737, ChEBI:CHEBI:33738,
CC ChEBI:CHEBI:71541, ChEBI:CHEBI:83863;
CC Evidence={ECO:0000269|PubMed:20843794};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:51573;
CC Evidence={ECO:0000269|PubMed:20843794};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000269|PubMed:19846552, ECO:0000269|PubMed:20545858};
CC -!- PATHWAY: Steroid metabolism; cholesterol degradation.
CC {ECO:0000305|PubMed:19846551, ECO:0000305|PubMed:20843794}.
CC -!- INDUCTION: By cholesterol. {ECO:0000269|PubMed:20843794}.
CC -!- DISRUPTION PHENOTYPE: Cells lacking this gene appear to metabolize
CC cholesterol normally, probably due to the ability of Cyp142 to
CC compensate for loss of Cyp125. {ECO:0000269|PubMed:19846551,
CC ECO:0000269|PubMed:20545858}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; AL123456; CCP46367.1; -; Genomic_DNA.
DR PIR; B70677; B70677.
DR RefSeq; NP_218062.1; NC_000962.3.
DR RefSeq; WP_003419304.1; NC_000962.3.
DR PDB; 2X5L; X-ray; 1.48 A; A=18-433.
DR PDB; 2X5W; X-ray; 1.58 A; A=1-433.
DR PDB; 2XC3; X-ray; 1.50 A; A=18-433.
DR PDB; 2XN8; X-ray; 1.64 A; A=18-433.
DR PDB; 3IVY; X-ray; 1.35 A; A=1-433.
DR PDB; 3IW0; X-ray; 1.70 A; A=1-433.
DR PDB; 3IW1; X-ray; 2.00 A; A=1-433.
DR PDB; 3IW2; X-ray; 2.19 A; A=1-433.
DR PDBsum; 2X5L; -.
DR PDBsum; 2X5W; -.
DR PDBsum; 2XC3; -.
DR PDBsum; 2XN8; -.
DR PDBsum; 3IVY; -.
DR PDBsum; 3IW0; -.
DR PDBsum; 3IW1; -.
DR PDBsum; 3IW2; -.
DR AlphaFoldDB; P9WPP1; -.
DR SMR; P9WPP1; -.
DR STRING; 83332.Rv3545c; -.
DR ChEMBL; CHEMBL5629; -.
DR SwissLipids; SLP:000000994; -.
DR PaxDb; P9WPP1; -.
DR PRIDE; P9WPP1; -.
DR DNASU; 887782; -.
DR GeneID; 887782; -.
DR KEGG; mtu:Rv3545c; -.
DR PATRIC; fig|83332.111.peg.3950; -.
DR TubercuList; Rv3545c; -.
DR eggNOG; COG2124; Bacteria.
DR OMA; FQRTATQ; -.
DR PhylomeDB; P9WPP1; -.
DR BioCyc; MetaCyc:G185E-7822-MON; -.
DR BRENDA; 1.14.15.29; 3445.
DR UniPathway; UPA01058; -.
DR PRO; PR:P9WPP1; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0036199; F:cholest-4-en-3-one 26-monooxygenase activity; IDA:MTBBASE.
DR GO; GO:0020037; F:heme binding; IDA:MTBBASE.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0008395; F:steroid hydroxylase activity; IDA:MTBBASE.
DR GO; GO:0051701; P:biological process involved in interaction with host; IMP:MTBBASE.
DR GO; GO:0006707; P:cholesterol catabolic process; IDA:MTBBASE.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR002397; Cyt_P450_B.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00359; BP450.
DR SUPFAM; SSF48264; SSF48264; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cholesterol metabolism; Heme; Iron; Lipid degradation;
KW Lipid metabolism; Metal-binding; Monooxygenase; NAD; Oxidoreductase;
KW Reference proteome; Steroid metabolism; Sterol metabolism; Virulence.
FT CHAIN 1..433
FT /note="Steroid C26-monooxygenase"
FT /id="PRO_0000052280"
FT BINDING 202
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:19846552,
FT ECO:0007744|PDB:3IW1"
FT BINDING 377
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000269|PubMed:20545858,
FT ECO:0007744|PDB:2X5L, ECO:0007744|PDB:2X5W,
FT ECO:0007744|PDB:2XC3, ECO:0007744|PDB:2XN8,
FT ECO:0007744|PDB:3IVY, ECO:0007744|PDB:3IW0,
FT ECO:0007744|PDB:3IW1, ECO:0007744|PDB:3IW2"
FT HELIX 31..34
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 40..49
FT /evidence="ECO:0007829|PDB:3IVY"
FT STRAND 51..56
FT /evidence="ECO:0007829|PDB:3IVY"
FT STRAND 67..73
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 76..84
FT /evidence="ECO:0007829|PDB:3IVY"
FT TURN 86..88
FT /evidence="ECO:0007829|PDB:3IVY"
FT STRAND 89..91
FT /evidence="ECO:0007829|PDB:3IVY"
FT TURN 92..94
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 106..110
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 111..114
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 116..118
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 123..131
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 132..134
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 137..141
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 144..161
FT /evidence="ECO:0007829|PDB:3IVY"
FT STRAND 163..165
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 166..169
FT /evidence="ECO:0007829|PDB:3IVY"
FT TURN 170..172
FT /evidence="ECO:0007829|PDB:2X5W"
FT HELIX 173..183
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 187..189
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 190..197
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 206..208
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 213..230
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 240..244
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 255..268
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 271..286
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 288..297
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 302..310
FT /evidence="ECO:0007829|PDB:3IVY"
FT STRAND 315..322
FT /evidence="ECO:0007829|PDB:3IVY"
FT STRAND 324..326
FT /evidence="ECO:0007829|PDB:3IVY"
FT STRAND 329..331
FT /evidence="ECO:0007829|PDB:3IVY"
FT STRAND 336..340
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 341..344
FT /evidence="ECO:0007829|PDB:3IVY"
FT TURN 348..350
FT /evidence="ECO:0007829|PDB:3IVY"
FT STRAND 351..353
FT /evidence="ECO:0007829|PDB:3IVY"
FT STRAND 371..373
FT /evidence="ECO:0007829|PDB:3IVY"
FT HELIX 380..397
FT /evidence="ECO:0007829|PDB:3IVY"
FT STRAND 402..405
FT /evidence="ECO:0007829|PDB:3IVY"
FT STRAND 413..415
FT /evidence="ECO:0007829|PDB:3IVY"
FT STRAND 418..420
FT /evidence="ECO:0007829|PDB:3IVY"
FT STRAND 422..425
FT /evidence="ECO:0007829|PDB:3IVY"
SQ SEQUENCE 433 AA; 48433 MW; FCBE0594D92171F4 CRC64;
MSWNHQSVEI AVRRTTVPSP NLPPGFDFTD PAIYAERLPV AEFAELRSAA PIWWNGQDPG
KGGGFHDGGF WAITKLNDVK EISRHSDVFS SYENGVIPRF KNDIAREDIE VQRFVMLNMD
APHHTRLRKI ISRGFTPRAV GRLHDELQER AQKIAAEAAA AGSGDFVEQV SCELPLQAIA
GLLGVPQEDR GKLFHWSNEM TGNEDPEYAH IDPKASSAEL IGYAMKMAEE KAKNPADDIV
TQLIQADIDG EKLSDDEFGF FVVMLAVAGN ETTRNSITQG MMAFAEHPDQ WELYKKVRPE
TAADEIVRWA TPVTAFQRTA LRDYELSGVQ IKKGQRVVMF YRSANFDEEV FQDPFTFNIL
RNPNPHVGFG GTGAHYCIGA NLARMTINLI FNAVADHMPD LKPISAPERL RSGWLNGIKH
WQVDYTGRCP VAH
