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 10-MAY-2017, entry version 26.
DE RecName: Full=Steroid C26-monooxygenase {ECO:0000303|PubMed:20843794};
DE EC=1.14.13.221 {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
RT Mycobacterium 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.,
RA Harris D.E., Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III,
RA Tekaia F., Badcock K., Basham D., Brown D., Chillingworth T.,
RA Connor R., Davies R.M., Devlin K., Feltwell T., Gentles S., Hamlin N.,
RA Holroyd S., Hornsby T., Jagels K., Krogh A., McLean J., Moule S.,
RA Murphy L.D., Oliver S., Osborne J., Quail M.A., Rajandream M.A.,
RA Rogers J., Rutter S., Seeger K., Skelton S., Squares S., Squares R.,
RA Sulston J.E., Taylor K., Whitehead S., Barrell B.G.;
RT "Deciphering the biology of Mycobacterium tuberculosis from the
RT complete 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
RT 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.,
RA Yadav A.K., Shrivastava P., Marimuthu A., Anand S., Sundaram H.,
RA Kingsbury R., Harsha H.C., Nair B., Prasad T.S., Chauhan D.S.,
RA Katoch K., Katoch V.M., Kumar P., Chaerkady R., Ramachandran S.,
RA Dash D., Pandey A.;
RT "Proteogenomic analysis of Mycobacterium tuberculosis by high
RT resolution mass spectrometry.";
RL Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP 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, ENZYME
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.,
RA Lafite P., Rigby S.E., Leys D., Munro A.W.;
RT "Structural and biochemical characterization of Mycobacterium
RT tuberculosis CYP142: evidence for multiple cholesterol 27-hydroxylase
RT activities in a human pathogen.";
RL J. Biol. Chem. 285:38270-38282(2010).
CC -!- FUNCTION: Involved in the utilization of cholesterol as the sole
CC carbon and energy source by degrading the side chain during
CC infection (PubMed:20843794). Primarily catalyzes the sequential
CC oxidation of the terminal methyl of cholest-4-en-3-one into (25R)-
CC 26-hydroxycholest-4-en-3-one (alcohol), (25R)-26-oxocholest-4-en-
CC 3-one (aldehyde), to finally yield the carboxylic acid (25R)-3-
CC oxocholest-4-en-26-oate (PubMed:20843794, PubMed:20889498). In
CC vitro, Cyp142 catalyzes with equal preference the oxidation of
CC both (25R)- and (25S)-26-hydroxycholest-4-en-3-one diastereomers
CC to the corresponding carboxylic acid which is a prerequisite for
CC entry into the beta-oxidation pathway (PubMed:20843794). Also able
CC to sequentially oxidize cholesterol itself, not only cholest-4-en-
CC 3-one (PubMed:20843794). {ECO:0000269|PubMed:20843794,
CC ECO:0000269|PubMed:20889498, ECO:0000269|PubMed:25210044}.
CC -!- CATALYTIC ACTIVITY: Cholest-4-en-3-one + 3 NADPH + 3 O(2) = (25R)-
CC 3-oxocholest-4-en-26-oate + 3 NADP(+) + 4 H(2)O.
CC {ECO:0000269|PubMed:20843794, ECO:0000269|PubMed:20889498,
CC ECO:0000305|PubMed:25210044}.
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000269|PubMed:20843794,
CC ECO:0000269|PubMed:20889498, ECO:0000269|PubMed:25210044};
CC -!- ENZYME 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
CC substrate (PubMed:20843794). Kcat is 0.0062 min(-1) for cholest-
CC 4-en-3-one as substrate (PubMed:20889498).
CC {ECO:0000269|PubMed:20843794, 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_KK339374.1.
DR PDB; 2XKR; X-ray; 1.60 A; A=1-398.
DR PDBsum; 2XKR; -.
DR ProteinModelPortal; P9WPL5; -.
DR SMR; P9WPL5; -.
DR SwissLipids; SLP:000001011; -.
DR PaxDb; P9WPL5; -.
DR EnsemblBacteria; CCP46340; CCP46340; Rv3518c.
DR GeneID; 888282; -.
DR KEGG; mtu:Rv3518c; -.
DR TubercuList; Rv3518c; -.
DR eggNOG; ENOG4111GWC; LUCA.
DR KO; K16046; -.
DR OMA; AYAWMRA; -.
DR PhylomeDB; P9WPL5; -.
DR BioCyc; MetaCyc:G185E-7795-MONOMER; -.
DR UniPathway; UPA01058; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005618; C:cell wall; IDA: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:0006707; P:cholesterol catabolic process; IDA:MTBBASE.
DR GO; GO:0009405; P:pathogenesis; IEA:UniProtKB-KW.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR002397; Cyt_P450_B.
DR InterPro; IPR017972; Cyt_P450_CS.
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; Complete proteome; Heme; Iron;
KW Lipid degradation; Lipid metabolism; Metal-binding; Monooxygenase;
KW NADP; Oxidoreductase; Reference proteome; Steroid metabolism;
KW Sterol metabolism; Virulence.
FT CHAIN 1 398 Steroid C26-monooxygenase.
FT /FTId=PRO_0000052304.
FT METAL 340 340 Iron (heme axial ligand).
FT {ECO:0000244|PDB:2XKR,
FT ECO:0000269|PubMed:20889498}.
FT HELIX 12 15 {ECO:0000244|PDB:2XKR}.
FT HELIX 20 30 {ECO:0000244|PDB:2XKR}.
FT STRAND 32 35 {ECO:0000244|PDB:2XKR}.
FT STRAND 41 43 {ECO:0000244|PDB:2XKR}.
FT HELIX 46 53 {ECO:0000244|PDB:2XKR}.
FT TURN 56 58 {ECO:0000244|PDB:2XKR}.
FT STRAND 59 61 {ECO:0000244|PDB:2XKR}.
FT HELIX 75 77 {ECO:0000244|PDB:2XKR}.
FT HELIX 82 90 {ECO:0000244|PDB:2XKR}.
FT HELIX 91 93 {ECO:0000244|PDB:2XKR}.
FT HELIX 96 100 {ECO:0000244|PDB:2XKR}.
FT HELIX 103 115 {ECO:0000244|PDB:2XKR}.
FT TURN 116 120 {ECO:0000244|PDB:2XKR}.
FT STRAND 121 124 {ECO:0000244|PDB:2XKR}.
FT HELIX 125 128 {ECO:0000244|PDB:2XKR}.
FT TURN 129 131 {ECO:0000244|PDB:2XKR}.
FT HELIX 132 142 {ECO:0000244|PDB:2XKR}.
FT HELIX 146 148 {ECO:0000244|PDB:2XKR}.
FT HELIX 149 163 {ECO:0000244|PDB:2XKR}.
FT HELIX 169 195 {ECO:0000244|PDB:2XKR}.
FT HELIX 201 207 {ECO:0000244|PDB:2XKR}.
FT HELIX 217 231 {ECO:0000244|PDB:2XKR}.
FT HELIX 233 248 {ECO:0000244|PDB:2XKR}.
FT HELIX 250 258 {ECO:0000244|PDB:2XKR}.
FT HELIX 260 262 {ECO:0000244|PDB:2XKR}.
FT HELIX 263 274 {ECO:0000244|PDB:2XKR}.
FT STRAND 279 286 {ECO:0000244|PDB:2XKR}.
FT STRAND 288 290 {ECO:0000244|PDB:2XKR}.
FT STRAND 293 295 {ECO:0000244|PDB:2XKR}.
FT STRAND 300 304 {ECO:0000244|PDB:2XKR}.
FT HELIX 305 309 {ECO:0000244|PDB:2XKR}.
FT TURN 312 314 {ECO:0000244|PDB:2XKR}.
FT STRAND 315 317 {ECO:0000244|PDB:2XKR}.
FT HELIX 343 360 {ECO:0000244|PDB:2XKR}.
FT STRAND 365 367 {ECO:0000244|PDB:2XKR}.
FT STRAND 379 381 {ECO:0000244|PDB:2XKR}.
FT STRAND 388 390 {ECO:0000244|PDB:2XKR}.
CC --------------------------------------------------------------------------
CC The following FT lines are automated annotations from the MyHits database.
CC --------------------------------------------------------------------------
FT MYHIT 163 360 ipfam:p450 [T]
FT MYHIT 333 342 ipat:CYTOCHROME_P450 [T]
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
//
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