CP142_MYCTU
ID CP142_MYCTU Reviewed; 398 AA.
AC P9WPL5; D0EW73; F2GEM8; O53563;
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:20843794};
DE EC=1.14.15.28 {ECO:0000269|PubMed:20843794, ECO:0000269|PubMed:20889498, ECO:0000305|PubMed:25210044};
DE AltName: Full=Cholest-4-en-3-one C26-monooxygenase {ECO:0000303|PubMed:20843794};
DE AltName: Full=Cholest-4-en-3-one C26-monooxygenase [(25R)-3-oxocholest-4-en-26-oate forming] {ECO:0000303|PubMed:20843794};
DE AltName: Full=Cholesterol C26-monooxygenase {ECO:0000303|PubMed:20843794};
DE AltName: Full=Cholesterol C26-monooxygenase [(25R)-3beta-hydroxycholest-5-en-26-oate forming] {ECO:0000303|PubMed:20843794};
DE AltName: Full=Cytochrome P450 142 {ECO:0000303|PubMed:20889498};
DE AltName: Full=Steroid C27-monooxygenase {ECO:0000303|PubMed:20889498};
GN Name=cyp142; Synonyms=cyp142A1 {ECO:0000303|PubMed:20843794};
GN OrderedLocusNames=Rv3518c; ORFNames=MTV023.25c;
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].
RA Vasilevskaya A.V., Alyapkina Y.S., Usanov S.A.;
RT "Polymorphism of cytochrome P450 of drug resistant form of Mycobacterium
RT tuberculosis.";
RL Submitted (SEP-2009) to the EMBL/GenBank/DDBJ databases.
RN [2]
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 [3]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, COFACTOR,
RP SUBSTRATE SPECIFICITY, INDUCTION, AND PATHWAY.
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 FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND COFACTOR.
RX PubMed=25210044; DOI=10.1074/jbc.m114.602771;
RA Frank D.J., Madrona Y., Ortiz de Montellano P.R.;
RT "Cholesterol ester oxidation by mycobacterial cytochrome P450.";
RL J. Biol. Chem. 289:30417-30425(2014).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) IN COMPLEX WITH HEME, FUNCTION,
RP CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, COFACTOR, ACTIVITY
RP REGULATION, AND SUBSTRATE SPECIFICITY.
RX PubMed=20889498; DOI=10.1074/jbc.m110.164293;
RA Driscoll M.D., McLean K.J., Levy C., Mast N., Pikuleva I.A., Lafite P.,
RA Rigby S.E., Leys D., Munro A.W.;
RT "Structural and biochemical characterization of Mycobacterium tuberculosis
RT CYP142: evidence for multiple cholesterol 27-hydroxylase activities in a
RT human pathogen.";
RL J. Biol. Chem. 285:38270-38282(2010).
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). Primarily catalyzes the sequential oxidation of the
CC terminal methyl of cholest-4-en-3-one into (25R)-26-hydroxycholest-4-
CC en-3-one (alcohol), (25R)-26-oxocholest-4-en-3-one (aldehyde), to
CC finally yield the carboxylic acid (25R)-3-oxocholest-4-en-26-oate
CC (PubMed:20843794, PubMed:20889498). In vitro, Cyp142 catalyzes with
CC equal preference the oxidation of both (25R)- and (25S)-26-
CC hydroxycholest-4-en-3-one diastereomers to the corresponding carboxylic
CC acid which is a prerequisite for entry into the beta-oxidation pathway
CC (PubMed:20843794). Also able to sequentially oxidize cholesterol
CC itself, not only cholest-4-en-3-one (PubMed:20843794).
CC {ECO:0000269|PubMed:20843794, ECO:0000269|PubMed:20889498,
CC ECO:0000269|PubMed:25210044}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cholest-4-en-3-one + 5 H(+) + 3 O2 + 6 reduced [2Fe-2S]-
CC [ferredoxin] = (25R)-3-oxocholest-4-en-26-oate + 4 H2O + 6 oxidized
CC [2Fe-2S]-[ferredoxin]; Xref=Rhea:RHEA:49996, 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:71570; EC=1.14.15.28;
CC Evidence={ECO:0000269|PubMed:20843794, ECO:0000269|PubMed:20889498,
CC ECO:0000305|PubMed:25210044};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cholest-4-en-3-one + 2 H(+) + O2 + 2 reduced [2Fe-2S]-
CC [ferredoxin] = (25R)-3-oxocholest-4-en-26-ol + H2O + 2 oxidized [2Fe-
CC 2S]-[ferredoxin]; Xref=Rhea:RHEA:43912, 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:83861;
CC Evidence={ECO:0000269|PubMed:20843794};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:43913;
CC Evidence={ECO:0000269|PubMed:20843794};
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=cholesterol + H(+) + NADPH + O2 = 26-hydroxycholesterol + H2O
CC + NADP(+); Xref=Rhea:RHEA:43836, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:16113,
CC ChEBI:CHEBI:17703, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC Evidence={ECO:0000269|PubMed:20843794};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:43837;
CC Evidence={ECO:0000269|PubMed:20843794};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=26-hydroxycholesterol + 2 H(+) + O2 + 2 reduced [2Fe-2S]-
CC [ferredoxin] = (3beta)-hydroxy-cholest-5-en-26-al + 2 H2O + 2
CC oxidized [2Fe-2S]-[ferredoxin]; Xref=Rhea:RHEA:43840, Rhea:RHEA-
CC COMP:10000, Rhea:RHEA-COMP:10001, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17703,
CC ChEBI:CHEBI:33737, ChEBI:CHEBI:33738, ChEBI:CHEBI:84145;
CC Evidence={ECO:0000269|PubMed:20843794};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:43841;
CC Evidence={ECO:0000269|PubMed:20843794};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(3beta)-hydroxy-cholest-5-en-26-al + NADPH + O2 = (3beta)-
CC hydroxy-cholest-5-en-26-oate + H2O + NADP(+); Xref=Rhea:RHEA:43844,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15379, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:84145, ChEBI:CHEBI:84146;
CC Evidence={ECO:0000269|PubMed:20843794};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:43845;
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:20843794, ECO:0000269|PubMed:20889498,
CC ECO:0000269|PubMed:25210044};
CC -!- ACTIVITY REGULATION: Inhibited by econazole, clotrimazole and
CC miconazole. {ECO:0000269|PubMed:20889498}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=3.2 uM for cholest-4-en-3-one {ECO:0000269|PubMed:20889498};
CC KM=7.7 uM for cholesterol {ECO:0000269|PubMed:20843794};
CC KM=9.2 uM for cholesteryl sulfate {ECO:0000269|PubMed:25210044};
CC KM=11.8 uM for cholest-4-en-3-one {ECO:0000269|PubMed:20843794};
CC Note=kcat is 84 min(-1) for cholest-4-en-3-one as substrate
CC (PubMed:20843794). kcat is 16.7 min(-1) for cholesterol as substrate
CC (PubMed:20843794). kcat is 0.0062 min(-1) for cholest-4-en-3-one as
CC substrate (PubMed:20889498). {ECO:0000269|PubMed:20843794,
CC ECO:0000269|PubMed:20889498};
CC -!- PATHWAY: Steroid metabolism; cholesterol degradation.
CC {ECO:0000305|PubMed:20843794}.
CC -!- INDUCTION: By cholesterol. {ECO:0000305|PubMed:20843794}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; GQ900521; ACX47920.1; -; Genomic_DNA.
DR EMBL; AL123456; CCP46340.1; -; Genomic_DNA.
DR PIR; H70807; H70807.
DR RefSeq; NP_218035.1; NC_000962.3.
DR RefSeq; WP_003900082.1; NZ_NVQJ01000014.1.
DR PDB; 2XKR; X-ray; 1.60 A; A=1-398.
DR PDBsum; 2XKR; -.
DR AlphaFoldDB; P9WPL5; -.
DR SMR; P9WPL5; -.
DR STRING; 83332.Rv3518c; -.
DR SwissLipids; SLP:000001011; -.
DR PaxDb; P9WPL5; -.
DR DNASU; 888282; -.
DR GeneID; 45427501; -.
DR GeneID; 888282; -.
DR KEGG; mtu:Rv3518c; -.
DR TubercuList; Rv3518c; -.
DR eggNOG; COG2124; Bacteria.
DR OMA; AGIHFCI; -.
DR PhylomeDB; P9WPL5; -.
DR BioCyc; MetaCyc:G185E-7795-MON; -.
DR BRENDA; 1.14.15.28; 3445.
DR UniPathway; UPA01058; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0009274; C:peptidoglycan-based cell wall; HDA:MTBBASE.
DR GO; GO:0036199; F:cholest-4-en-3-one 26-monooxygenase activity; IDA:MTBBASE.
DR GO; GO:0031073; F:cholesterol 26-hydroxylase 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; IBA:GO_Central.
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; IPR017972; Cyt_P450_CS.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00359; BP450.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cholesterol metabolism; Heme; Iron; Lipid degradation;
KW Lipid metabolism; Metal-binding; Monooxygenase; NADP; Oxidoreductase;
KW Reference proteome; Steroid metabolism; Sterol metabolism; Virulence.
FT CHAIN 1..398
FT /note="Steroid C26-monooxygenase"
FT /id="PRO_0000052304"
FT BINDING 340
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:20889498,
FT ECO:0007744|PDB:2XKR"
FT HELIX 12..15
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 20..30
FT /evidence="ECO:0007829|PDB:2XKR"
FT STRAND 32..35
FT /evidence="ECO:0007829|PDB:2XKR"
FT STRAND 41..43
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 46..53
FT /evidence="ECO:0007829|PDB:2XKR"
FT TURN 56..58
FT /evidence="ECO:0007829|PDB:2XKR"
FT STRAND 59..61
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 75..77
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 82..90
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 91..93
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 96..100
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 103..115
FT /evidence="ECO:0007829|PDB:2XKR"
FT TURN 116..120
FT /evidence="ECO:0007829|PDB:2XKR"
FT STRAND 121..124
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 125..128
FT /evidence="ECO:0007829|PDB:2XKR"
FT TURN 129..131
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 132..142
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 146..148
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 149..163
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 169..195
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 201..207
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 217..231
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 233..248
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 250..258
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 260..262
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 263..274
FT /evidence="ECO:0007829|PDB:2XKR"
FT STRAND 279..286
FT /evidence="ECO:0007829|PDB:2XKR"
FT STRAND 288..290
FT /evidence="ECO:0007829|PDB:2XKR"
FT STRAND 293..295
FT /evidence="ECO:0007829|PDB:2XKR"
FT STRAND 300..304
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 305..309
FT /evidence="ECO:0007829|PDB:2XKR"
FT TURN 312..314
FT /evidence="ECO:0007829|PDB:2XKR"
FT STRAND 315..317
FT /evidence="ECO:0007829|PDB:2XKR"
FT HELIX 343..360
FT /evidence="ECO:0007829|PDB:2XKR"
FT STRAND 365..367
FT /evidence="ECO:0007829|PDB:2XKR"
FT STRAND 379..381
FT /evidence="ECO:0007829|PDB:2XKR"
FT STRAND 388..390
FT /evidence="ECO:0007829|PDB:2XKR"
SQ SEQUENCE 398 AA; 44399 MW; BCFF3C23ECB5767F CRC64;
MTEAPDVDLA DGNFYASREA RAAYRWMRAN QPVFRDRNGL AAASTYQAVI DAERQPELFS
NAGGIRPDQP ALPMMIDMDD PAHLLRRKLV NAGFTRKRVK DKEASIAALC DTLIDAVCER
GECDFVRDLA APLPMAVIGD MLGVRPEQRD MFLRWSDDLV TFLSSHVSQE DFQITMDAFA
AYNDFTRATI AARRADPTDD LVSVLVSSEV DGERLSDDEL VMETLLILIG GDETTRHTLS
GGTEQLLRNR DQWDLLQRDP SLLPGAIEEM LRWTAPVKNM CRVLTADTEF HGTALCAGEK
MMLLFESANF DEAVFCEPEK FDVQRNPNSH LAFGFGTHFC LGNQLARLEL SLMTERVLRR
LPDLRLVADD SVLPLRPANF VSGLESMPVV FTPSPPLG
