CP27A_HUMAN
ID CP27A_HUMAN Reviewed; 531 AA.
AC Q02318; A8K303; Q6LDB4; Q86YQ6;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1993, sequence version 1.
DT 03-AUG-2022, entry version 207.
DE RecName: Full=Sterol 26-hydroxylase, mitochondrial {ECO:0000250|UniProtKB:P17177};
DE EC=1.14.15.15 {ECO:0000269|PubMed:11412116, ECO:0000269|PubMed:1708392, ECO:0000269|PubMed:2019602, ECO:0000269|PubMed:7915755, ECO:0000269|PubMed:9186905, ECO:0000269|PubMed:9790667};
DE AltName: Full=5-beta-cholestane-3-alpha,7-alpha,12-alpha-triol 26-hydroxylase {ECO:0000303|PubMed:1708392};
DE AltName: Full=Cytochrome P-450C27/25;
DE AltName: Full=Cytochrome P450 27;
DE AltName: Full=Sterol 27-hydroxylase {ECO:0000303|PubMed:1708392};
DE AltName: Full=Vitamin D(3) 25-hydroxylase {ECO:0000303|PubMed:15465040};
DE Flags: Precursor;
GN Name=CYP27A1 {ECO:0000303|PubMed:21411718, ECO:0000312|HGNC:HGNC:2605};
GN Synonyms=CYP27 {ECO:0000303|PubMed:9660774};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND CATALYTIC ACTIVITY.
RC TISSUE=Liver;
RX PubMed=1708392; DOI=10.1016/s0021-9258(20)89517-9;
RA Cali J.J., Russell D.W.;
RT "Characterization of human sterol 27-hydroxylase. A mitochondrial
RT cytochrome P-450 that catalyzes multiple oxidation reaction in bile acid
RT biosynthesis.";
RL J. Biol. Chem. 266:7774-7778(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=7690968; DOI=10.1073/pnas.90.18.8668;
RA Guo Y.-D., Strugnell S., Back D.W., Jones G.;
RT "Transfected human liver cytochrome P-450 hydroxylates vitamin D analogs at
RT different side-chain positions.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:8668-8672(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Kidney;
RA Zhang H.T., Gong Y.;
RL Submitted (NOV-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Umbilical cord blood;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Colon;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-15.
RX PubMed=8514861; DOI=10.1172/jci116484;
RA Leitersdorf E., Reshef A., Meiner V., Levitzki R., Schwartz S.P.,
RA Dann E.J., Berkman N., Cali J.J., Klapholz L., Berginer V.M.;
RT "Frameshift and splice-junction mutations in the sterol 27-hydroxylase gene
RT cause cerebrotendinous xanthomatosis in Jews or Moroccan origin.";
RL J. Clin. Invest. 91:2488-2496(1993).
RN [8]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND PATHWAY.
RX PubMed=9660774; DOI=10.1074/jbc.273.29.18153;
RA Pikuleva I.A., Babiker A., Waterman M.R., Bjoerkhem I.;
RT "Activities of recombinant human cytochrome P450c27 (CYP27) which produce
RT intermediates of alternative bile acid biosynthetic pathways.";
RL J. Biol. Chem. 273:18153-18160(1998).
RN [9]
RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF PHE-240; ILE-244; PHE-248;
RP TRP-268 AND TYR-271, AND PATHWAY.
RX PubMed=11412116; DOI=10.1021/bi010193i;
RA Pikuleva I.A., Puchkaev A., Bjoerkhem I.;
RT "Putative helix F contributes to regioselectivity of hydroxylation in
RT mitochondrial cytochrome P450 27A1.";
RL Biochemistry 40:7621-7629(2001).
RN [10]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND PATHWAY.
RX PubMed=12077124; DOI=10.1074/jbc.m201712200;
RA Bodin K., Andersson U., Rystedt E., Ellis E., Norlin M., Pikuleva I.,
RA Eggertsen G., Bjoerkhem I., Diczfalusy U.;
RT "Metabolism of 4 beta -hydroxycholesterol in humans.";
RL J. Biol. Chem. 277:31534-31540(2002).
RN [11]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND PATHWAY.
RX PubMed=15465040; DOI=10.1016/j.bbrc.2004.09.073;
RA Shinkyo R., Sakaki T., Kamakura M., Ohta M., Inouye K.;
RT "Metabolism of vitamin D by human microsomal CYP2R1.";
RL Biochem. Biophys. Res. Commun. 324:451-457(2004).
RN [12]
RP FUNCTION, CATALYTIC ACTIVITY, AND TISSUE SPECIFICITY.
RX PubMed=21411718; DOI=10.1194/jlr.m014217;
RA Heo G.Y., Bederman I., Mast N., Liao W.L., Turko I.V., Pikuleva I.A.;
RT "Conversion of 7-ketocholesterol to oxysterol metabolites by recombinant
RT CYP27A1 and retinal pigment epithelial cells.";
RL J. Lipid Res. 52:1117-1127(2011).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [14]
RP FUNCTION, CATALYTIC ACTIVITY, AND TISSUE SPECIFICITY.
RX PubMed=28190002; DOI=10.1074/jbc.m116.774760;
RA Mast N., Anderson K.W., Lin J.B., Li Y., Turko I.V., Tatsuoka C.,
RA Bjorkhem I., Pikuleva I.A.;
RT "Cytochrome P450 27A1 Deficiency and Regional Differences in Brain Sterol
RT Metabolism Cause Preferential Cholestanol Accumulation in the Cerebellum.";
RL J. Biol. Chem. 292:4913-4924(2017).
RN [15]
RP VARIANTS CTX CYS-395 AND CYS-479, CHARACTERIZATION OF VARIANTS CTX CYS-395
RP AND CYS-479, CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=2019602; DOI=10.1016/s0021-9258(20)89518-0;
RA Cali J.J., Hsieh C.-L., Francke U., Russell D.W.;
RT "Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase
RT underlie cerebrotendinous xanthomatosis.";
RL J. Biol. Chem. 266:7779-7783(1991).
RN [16]
RP VARIANTS CTX GLN-474 AND TRP-474, CHARACTERIZATION OF VARIANTS CTX GLN-474
RP AND TRP-474, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=7915755;
RA Kim K.-K., Kubota S., Kuriyama M., Fujiyama J., Bjorkhem I., Eggertsen G.,
RA Seyama Y.;
RT "Identification of new mutations in sterol 27-hydroxylase gene in Japanese
RT patients with cerebrotendinous xanthomatosis (CTX).";
RL J. Lipid Res. 35:1031-1039(1994).
RN [17]
RP VARIANT CTX GLN-405, CHARACTERIZATION OF VARIANT CTX GLN-405, FUNCTION, AND
RP CATALYTIC ACTIVITY.
RX PubMed=9186905;
RA Chen W., Kubota S., Kim K.-S., Cheng J., Kuriyama M., Eggertsen G.,
RA Bjorkhem I., Seyama Y.;
RT "Novel homozygous and compound heterozygous mutations of sterol 27-
RT hydroxylase gene (CYP27) cause cerebrotendinous xanthomatosis in three
RT Japanese patients from two unrelated families.";
RL J. Lipid Res. 38:870-879(1997).
RN [18]
RP VARIANT CTX SER-395, CHARACTERIZATION OF VARIANT CTX GLN-405, FUNCTION, AND
RP CATALYTIC ACTIVITY.
RX PubMed=9790667; DOI=10.1021/bi9807660;
RA Chen W., Kubota S., Ujike H., Ishihara T., Seyama Y.;
RT "A novel arg362ser mutation in the sterol 27-hydroxylase gene (CYP27): its
RT effects on pre-mRNA splicing and enzyme activity.";
RL Biochemistry 37:15050-15056(1998).
RN [19]
RP VARIANT CTX GLU-145.
RX PubMed=12000359; DOI=10.1034/j.1399-0004.2002.610303.x;
RA Lamon-Fava S., Schaefer E.J., Garuti R., Salen G., Calandra S.;
RT "Two novel mutations in the sterol 27-hydroxylase gene causing
RT cerebrotendinous xanthomatosis.";
RL Clin. Genet. 61:185-191(2002).
CC -!- FUNCTION: Cytochrome P450 monooxygenase that catalyzes regio- and
CC stereospecific hydroxylation of cholesterol and its derivatives.
CC Hydroxylates (with R stereochemistry) the terminal methyl group of
CC cholesterol side-chain in a three step reaction to yield at first a C26
CC alcohol, then a C26 aldehyde and finally a C26 acid (PubMed:9660774,
CC PubMed:12077124, PubMed:21411718, PubMed:28190002). Regulates
CC cholesterol homeostasis by catalyzing the conversion of excess
CC cholesterol to bile acids via both the 'neutral' (classic) and the
CC 'acid' (alternative) pathways (PubMed:9660774, PubMed:1708392,
CC PubMed:11412116, PubMed:2019602, PubMed:7915755, PubMed:9186905,
CC PubMed:9790667). May also regulate cholesterol homeostasis via
CC generation of active oxysterols, which act as ligands for NR1H2 and
CC NR1H3 nuclear receptors, modulating the transcription of genes involved
CC in lipid metabolism (PubMed:9660774, PubMed:12077124). Plays a role in
CC cholestanol metabolism in the cerebellum. Similarly to cholesterol,
CC hydroxylates cholestanol and may facilitate sterol diffusion through
CC the blood-brain barrier to the systemic circulation for further
CC degradation (PubMed:28190002). Also hydroxylates retinal 7-
CC ketocholesterol, a noxious oxysterol with pro-inflammatory and pro-
CC apoptotic effects, and may play a role in its elimination from the
CC retinal pigment epithelium (PubMed:21411718). May play a redundant role
CC in vitamin D biosynthesis. Catalyzes 25-hydroxylation of vitamin D3
CC that is required for its conversion to a functionally active form
CC (PubMed:15465040). {ECO:0000269|PubMed:11412116,
CC ECO:0000269|PubMed:12077124, ECO:0000269|PubMed:15465040,
CC ECO:0000269|PubMed:1708392, ECO:0000269|PubMed:2019602,
CC ECO:0000269|PubMed:21411718, ECO:0000269|PubMed:28190002,
CC ECO:0000269|PubMed:7915755, ECO:0000269|PubMed:9186905,
CC ECO:0000269|PubMed:9660774, ECO:0000269|PubMed:9790667}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=5beta-cholestane-3alpha,7alpha,12alpha-triol + 5 H(+) + 3 O2 +
CC 6 reduced [adrenodoxin] = (25R)-3alpha,7alpha,12alpha-trihydroxy-
CC 5beta-cholestan-26-oate + 4 H2O + 6 oxidized [adrenodoxin];
CC Xref=Rhea:RHEA:34631, Rhea:RHEA-COMP:9998, Rhea:RHEA-COMP:9999,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16496, ChEBI:CHEBI:33737, ChEBI:CHEBI:33738,
CC ChEBI:CHEBI:58734; EC=1.14.15.15;
CC Evidence={ECO:0000269|PubMed:11412116, ECO:0000269|PubMed:1708392,
CC ECO:0000269|PubMed:2019602, ECO:0000269|PubMed:9186905,
CC ECO:0000269|PubMed:9790667};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:34632;
CC Evidence={ECO:0000269|PubMed:7915755};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cholestanol + 2 H(+) + O2 + 2 reduced [adrenodoxin] = (25R)-
CC 26-hydroxycholestanol + H2O + 2 oxidized [adrenodoxin];
CC Xref=Rhea:RHEA:53812, Rhea:RHEA-COMP:9998, Rhea:RHEA-COMP:9999,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:33737, ChEBI:CHEBI:33738, ChEBI:CHEBI:86570,
CC ChEBI:CHEBI:137688; Evidence={ECO:0000269|PubMed:28190002};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53813;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(25R)-3beta-hydroxycholest-5-en-7-one-26-al + H(+) + O2 + 2
CC reduced [adrenodoxin] = (25R)-3beta-hydroxycholest-5-en-7-one-26-oate
CC + H2O + 2 oxidized [adrenodoxin]; Xref=Rhea:RHEA:47380, Rhea:RHEA-
CC COMP:9998, Rhea:RHEA-COMP:9999, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:33737, ChEBI:CHEBI:33738,
CC ChEBI:CHEBI:87677, ChEBI:CHEBI:87678;
CC Evidence={ECO:0000269|PubMed:21411718};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:47381;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(25R)-3beta,26-dihydroxycholest-5-en-7-one + 2 H(+) + O2 + 2
CC reduced [adrenodoxin] = (25R)-3beta-hydroxycholest-5-en-7-one-26-al +
CC 2 H2O + 2 oxidized [adrenodoxin]; Xref=Rhea:RHEA:47376, Rhea:RHEA-
CC COMP:9998, Rhea:RHEA-COMP:9999, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:33737, ChEBI:CHEBI:33738,
CC ChEBI:CHEBI:87653, ChEBI:CHEBI:87677;
CC Evidence={ECO:0000269|PubMed:21411718};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:47377;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=7-oxocholesterol + 2 H(+) + O2 + 2 reduced [adrenodoxin] =
CC (25R)-3beta,26-dihydroxycholest-5-en-7-one + H2O + 2 oxidized
CC [adrenodoxin]; Xref=Rhea:RHEA:47344, Rhea:RHEA-COMP:9998, Rhea:RHEA-
CC COMP:9999, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:33737, ChEBI:CHEBI:33738, ChEBI:CHEBI:64294,
CC ChEBI:CHEBI:87653; Evidence={ECO:0000269|PubMed:21411718};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:47345;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=calciol + 2 H(+) + O2 + 2 reduced [adrenodoxin] = calcidiol +
CC H2O + 2 oxidized [adrenodoxin]; Xref=Rhea:RHEA:46588, Rhea:RHEA-
CC COMP:9998, Rhea:RHEA-COMP:9999, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:17933, ChEBI:CHEBI:28940,
CC ChEBI:CHEBI:33737, ChEBI:CHEBI:33738;
CC Evidence={ECO:0000269|PubMed:15465040};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46589;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(25R)-5beta-cholestane-3alpha,7alpha,12alpha,26-tetrol + 2
CC H(+) + O2 + 2 reduced [adrenodoxin] = (25R)-3alpha,7alpha,12alpha-
CC trihydroxy-5beta-cholestan-26-al + 2 H2O + 2 oxidized [adrenodoxin];
CC Xref=Rhea:RHEA:40231, Rhea:RHEA-COMP:9998, Rhea:RHEA-COMP:9999,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:33737, ChEBI:CHEBI:33738, ChEBI:CHEBI:48939,
CC ChEBI:CHEBI:48940; Evidence={ECO:0000269|PubMed:11412116,
CC ECO:0000269|PubMed:1708392};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:40232;
CC Evidence={ECO:0000269|PubMed:7915755};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cholesterol + 2 H(+) + O2 + 2 reduced [adrenodoxin] = (25R)-
CC cholest-5-ene-3beta,26-diol + H2O + 2 oxidized [adrenodoxin];
CC Xref=Rhea:RHEA:46400, Rhea:RHEA-COMP:9998, Rhea:RHEA-COMP:9999,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16113, ChEBI:CHEBI:33737, ChEBI:CHEBI:33738,
CC ChEBI:CHEBI:76591; Evidence={ECO:0000269|PubMed:12077124,
CC ECO:0000269|PubMed:21411718, ECO:0000269|PubMed:9660774};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46401;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(25R)-3beta,4beta-dihydroxycholest-5-en-26-al + H(+) + O2 + 2
CC reduced [adrenodoxin] = (25R)-3beta,4beta-dihydroxycholest-5-en-26-
CC oate + H2O + 2 oxidized [adrenodoxin]; Xref=Rhea:RHEA:46436,
CC Rhea:RHEA-COMP:9998, Rhea:RHEA-COMP:9999, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:33737,
CC ChEBI:CHEBI:33738, ChEBI:CHEBI:86115, ChEBI:CHEBI:86116;
CC Evidence={ECO:0000269|PubMed:12077124};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46437;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(25R)-4beta,26-dihydroxycholesterol + 2 H(+) + O2 + 2 reduced
CC [adrenodoxin] = (25R)-3beta,4beta-dihydroxycholest-5-en-26-al + 2 H2O
CC + 2 oxidized [adrenodoxin]; Xref=Rhea:RHEA:46432, Rhea:RHEA-
CC COMP:9998, Rhea:RHEA-COMP:9999, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:33737, ChEBI:CHEBI:33738,
CC ChEBI:CHEBI:86113, ChEBI:CHEBI:86115;
CC Evidence={ECO:0000269|PubMed:12077124};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46433;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4beta-hydroxycholesterol + 2 H(+) + O2 + 2 reduced
CC [adrenodoxin] = (25R)-4beta,26-dihydroxycholesterol + H2O + 2
CC oxidized [adrenodoxin]; Xref=Rhea:RHEA:46428, Rhea:RHEA-COMP:9998,
CC Rhea:RHEA-COMP:9999, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:33737, ChEBI:CHEBI:33738,
CC ChEBI:CHEBI:85778, ChEBI:CHEBI:86113;
CC Evidence={ECO:0000269|PubMed:12077124};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46429;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(25R)-3beta-hydroxy-5-cholesten-26-al + H(+) + O2 + 2 reduced
CC [adrenodoxin] = (25R)-3beta-hydroxy-5-cholestenoate + H2O + 2
CC oxidized [adrenodoxin]; Xref=Rhea:RHEA:45236, Rhea:RHEA-COMP:9998,
CC Rhea:RHEA-COMP:9999, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:33737, ChEBI:CHEBI:33738,
CC ChEBI:CHEBI:86096, ChEBI:CHEBI:86098;
CC Evidence={ECO:0000269|PubMed:12077124, ECO:0000269|PubMed:9660774};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45237;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(25R)-cholest-5-ene-3beta,26-diol + 2 H(+) + O2 + 2 reduced
CC [adrenodoxin] = (25R)-3beta-hydroxy-5-cholesten-26-al + 2 H2O + 2
CC oxidized [adrenodoxin]; Xref=Rhea:RHEA:46092, Rhea:RHEA-COMP:9998,
CC Rhea:RHEA-COMP:9999, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:33737, ChEBI:CHEBI:33738,
CC ChEBI:CHEBI:76591, ChEBI:CHEBI:86096;
CC Evidence={ECO:0000269|PubMed:12077124, ECO:0000269|PubMed:9660774};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46093;
CC Evidence={ECO:0000305};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(25R)-3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-26-al +
CC H(+) + O2 + 2 reduced [adrenodoxin] = (25R)-3alpha,7alpha,12alpha-
CC trihydroxy-5beta-cholestan-26-oate + H2O + 2 oxidized [adrenodoxin];
CC Xref=Rhea:RHEA:34627, Rhea:RHEA-COMP:9998, Rhea:RHEA-COMP:9999,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:33737, ChEBI:CHEBI:33738, ChEBI:CHEBI:48940,
CC ChEBI:CHEBI:58734; Evidence={ECO:0000269|PubMed:11412116,
CC ECO:0000269|PubMed:1708392};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:34628;
CC Evidence={ECO:0000269|PubMed:7915755};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=5beta-cholestane-3alpha,7alpha,12alpha-triol + 2 H(+) + O2 + 2
CC reduced [adrenodoxin] = (25R)-5beta-cholestane-
CC 3alpha,7alpha,12alpha,26-tetrol + H2O + 2 oxidized [adrenodoxin];
CC Xref=Rhea:RHEA:14373, Rhea:RHEA-COMP:9998, Rhea:RHEA-COMP:9999,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16496, ChEBI:CHEBI:33737, ChEBI:CHEBI:33738,
CC ChEBI:CHEBI:48939; Evidence={ECO:0000269|PubMed:11412116,
CC ECO:0000269|PubMed:1708392};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14374;
CC Evidence={ECO:0000269|PubMed:7915755};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P17177};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC Vmax=0.22 nmol/min/nmol enzyme toward cholesterol
CC {ECO:0000269|PubMed:12077124};
CC Vmax=0.41 nmol/min/nmol enzyme toward 4beta-hydroxycholesterol
CC {ECO:0000269|PubMed:12077124};
CC Vmax=0.20 mol/min/mol enzyme toward calciol
CC {ECO:0000269|PubMed:15465040};
CC Note=kcat/KM=0.005 umol/min for cholesterol and kcat/KM=0.018
CC umol/min for (25R)-cholest-5-ene-3beta,26-diol.
CC {ECO:0000269|PubMed:9660774};
CC -!- PATHWAY: Hormone biosynthesis; cholecalciferol biosynthesis.
CC {ECO:0000305|PubMed:15465040}.
CC -!- PATHWAY: Steroid metabolism; cholesterol degradation.
CC {ECO:0000305|PubMed:12077124, ECO:0000305|PubMed:9660774}.
CC -!- PATHWAY: Lipid metabolism; bile acid biosynthesis.
CC {ECO:0000305|PubMed:11412116}.
CC -!- SUBUNIT: Interacts with HSP70; this interaction is required for initial
CC targeting to mitochondria. {ECO:0000250|UniProtKB:P17178}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC {ECO:0000250|UniProtKB:P17178}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:P17178}. Note=Post-translationally targeted to
CC mitochondria. All three of the receptor proteins in the TOM complex,
CC TOMM70, TOMM20 and TOMM22 are required for the translocation across the
CC mitochondrial outer membrane. After translocation into the matrix,
CC associates with the inner membrane as a membrane extrinsic protein.
CC {ECO:0000250|UniProtKB:P17178}.
CC -!- TISSUE SPECIFICITY: Expressed in the neural retina and underlying
CC retinal pigment epithelium (at protein level) (PubMed:21411718).
CC Expressed in the gray and white matter of cerebellum (at protein level)
CC (PubMed:28190002). {ECO:0000269|PubMed:21411718,
CC ECO:0000269|PubMed:28190002}.
CC -!- DISEASE: Cerebrotendinous xanthomatosis (CTX) [MIM:213700]: Rare sterol
CC storage disorder characterized clinically by progressive neurologic
CC dysfunction, premature atherosclerosis, and cataracts.
CC {ECO:0000269|PubMed:12000359, ECO:0000269|PubMed:2019602,
CC ECO:0000269|PubMed:7915755, ECO:0000269|PubMed:9186905,
CC ECO:0000269|PubMed:9790667}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; M62401; AAA52142.1; -; mRNA.
DR EMBL; X59812; CAA42481.1; -; mRNA.
DR EMBL; AY178622; AAO21126.1; -; mRNA.
DR EMBL; AK290418; BAF83107.1; -; mRNA.
DR EMBL; CH471063; EAW70654.1; -; Genomic_DNA.
DR EMBL; BC040430; AAH40430.1; -; mRNA.
DR EMBL; BC051851; AAH51851.1; -; mRNA.
DR EMBL; S62709; AAB27199.1; -; Genomic_DNA.
DR CCDS; CCDS2423.1; -.
DR PIR; A39740; A39740.
DR RefSeq; NP_000775.1; NM_000784.3.
DR AlphaFoldDB; Q02318; -.
DR SMR; Q02318; -.
DR BioGRID; 107965; 8.
DR IntAct; Q02318; 6.
DR STRING; 9606.ENSP00000258415; -.
DR BindingDB; Q02318; -.
DR ChEMBL; CHEMBL5992; -.
DR DrugBank; DB06777; Chenodeoxycholic acid.
DR DrugBank; DB00169; Cholecalciferol.
DR DrugBank; DB06410; Doxercalciferol.
DR DrugBank; DB00153; Ergocalciferol.
DR DrugBank; DB00082; Pegvisomant.
DR DrugCentral; Q02318; -.
DR GuidetoPHARMACOLOGY; 1369; -.
DR SwissLipids; SLP:000000142; -.
DR iPTMnet; Q02318; -.
DR PhosphoSitePlus; Q02318; -.
DR BioMuta; CYP27A1; -.
DR DMDM; 399288; -.
DR EPD; Q02318; -.
DR jPOST; Q02318; -.
DR MassIVE; Q02318; -.
DR MaxQB; Q02318; -.
DR PaxDb; Q02318; -.
DR PeptideAtlas; Q02318; -.
DR PRIDE; Q02318; -.
DR ProteomicsDB; 58080; -.
DR Antibodypedia; 34289; 304 antibodies from 34 providers.
DR DNASU; 1593; -.
DR Ensembl; ENST00000258415.9; ENSP00000258415.4; ENSG00000135929.9.
DR GeneID; 1593; -.
DR KEGG; hsa:1593; -.
DR MANE-Select; ENST00000258415.9; ENSP00000258415.4; NM_000784.4; NP_000775.1.
DR UCSC; uc002viz.5; human.
DR CTD; 1593; -.
DR DisGeNET; 1593; -.
DR GeneCards; CYP27A1; -.
DR GeneReviews; CYP27A1; -.
DR HGNC; HGNC:2605; CYP27A1.
DR HPA; ENSG00000135929; Tissue enriched (liver).
DR MalaCards; CYP27A1; -.
DR MIM; 213700; phenotype.
DR MIM; 606530; gene.
DR neXtProt; NX_Q02318; -.
DR OpenTargets; ENSG00000135929; -.
DR Orphanet; 909; Cerebrotendinous xanthomatosis.
DR PharmGKB; PA135; -.
DR VEuPathDB; HostDB:ENSG00000135929; -.
DR eggNOG; KOG0159; Eukaryota.
DR GeneTree; ENSGT00950000182905; -.
DR HOGENOM; CLU_001570_28_3_1; -.
DR InParanoid; Q02318; -.
DR OMA; QVSDMAH; -.
DR OrthoDB; 871849at2759; -.
DR PhylomeDB; Q02318; -.
DR TreeFam; TF105094; -.
DR BRENDA; 1.14.15.15; 2681.
DR BRENDA; 1.14.99.38; 2681.
DR PathwayCommons; Q02318; -.
DR Reactome; R-HSA-193368; Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol.
DR Reactome; R-HSA-193775; Synthesis of bile acids and bile salts via 24-hydroxycholesterol.
DR Reactome; R-HSA-193807; Synthesis of bile acids and bile salts via 27-hydroxycholesterol.
DR Reactome; R-HSA-211976; Endogenous sterols.
DR Reactome; R-HSA-5578996; Defective CYP27A1 causes CTX.
DR SignaLink; Q02318; -.
DR SIGNOR; Q02318; -.
DR UniPathway; UPA00221; -.
DR UniPathway; UPA00955; -.
DR UniPathway; UPA01058; -.
DR BioGRID-ORCS; 1593; 7 hits in 1072 CRISPR screens.
DR ChiTaRS; CYP27A1; human.
DR GeneWiki; CYP27A1; -.
DR GenomeRNAi; 1593; -.
DR Pharos; Q02318; Tchem.
DR PRO; PR:Q02318; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q02318; protein.
DR Bgee; ENSG00000135929; Expressed in right lobe of liver and 184 other tissues.
DR ExpressionAtlas; Q02318; baseline and differential.
DR Genevisible; Q02318; HS.
DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR GO; GO:0047103; F:3-alpha,7-alpha,12-alpha-trihydroxycholestan-26-al 26-oxidoreductase activity; IEA:UniProtKB-EC.
DR GO; GO:0047748; F:cholestanetetraol 26-dehydrogenase activity; IEA:RHEA.
DR GO; GO:0047749; F:cholestanetriol 26-monooxygenase activity; IDA:UniProtKB.
DR GO; GO:0031073; F:cholesterol 26-hydroxylase activity; IDA:UniProtKB.
DR GO; GO:0020037; F:heme binding; IDA:UniProtKB.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0008395; F:steroid hydroxylase activity; TAS:Reactome.
DR GO; GO:0030343; F:vitamin D3 25-hydroxylase activity; IDA:UniProtKB.
DR GO; GO:0006699; P:bile acid biosynthetic process; IDA:UniProtKB.
DR GO; GO:0036378; P:calcitriol biosynthetic process from calciol; IDA:UniProtKB.
DR GO; GO:0006707; P:cholesterol catabolic process; IDA:UniProtKB.
DR GO; GO:0008203; P:cholesterol metabolic process; IBA:GO_Central.
DR GO; GO:0016125; P:sterol metabolic process; TAS:Reactome.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR017972; Cyt_P450_CS.
DR InterPro; IPR002401; Cyt_P450_E_grp-I.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00463; EP450I.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 1: Evidence at protein level;
KW Acetylation; Cataract; Cholesterol metabolism; Disease variant; Heme; Iron;
KW Lipid biosynthesis; Lipid metabolism; Membrane; Metal-binding;
KW Mitochondrion; Mitochondrion inner membrane; Monooxygenase; Oxidoreductase;
KW Reference proteome; Steroid biosynthesis; Steroid metabolism;
KW Sterol metabolism; Transit peptide.
FT TRANSIT 1..33
FT /note="Mitochondrion"
FT CHAIN 34..531
FT /note="Sterol 26-hydroxylase, mitochondrial"
FT /id="PRO_0000003618"
FT REGION 384..398
FT /note="Sterol-binding"
FT /evidence="ECO:0000255"
FT BINDING 476
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 MOD_RES 283
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9DBG1"
FT MOD_RES 509
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9DBG1"
FT MOD_RES 520
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9DBG1"
FT VARIANT 145
FT /note="G -> E (in CTX; dbSNP:rs72551313)"
FT /evidence="ECO:0000269|PubMed:12000359"
FT /id="VAR_016966"
FT VARIANT 169
FT /note="A -> V (in dbSNP:rs59443548)"
FT /id="VAR_061046"
FT VARIANT 175
FT /note="T -> M (in dbSNP:rs2229381)"
FT /id="VAR_048467"
FT VARIANT 395
FT /note="R -> C (in CTX; impairs sterol 26-hydroxylase
FT activity; dbSNP:rs121908096)"
FT /evidence="ECO:0000269|PubMed:2019602"
FT /id="VAR_001303"
FT VARIANT 395
FT /note="R -> S (in CTX; impairs sterol 26-hydroxylase
FT activity; dbSNP:rs121908096)"
FT /evidence="ECO:0000269|PubMed:9790667"
FT /id="VAR_012285"
FT VARIANT 405
FT /note="R -> Q (in CTX; impairs sterol 26-hydroxylase
FT activity; dbSNP:rs121908099)"
FT /evidence="ECO:0000269|PubMed:9186905"
FT /id="VAR_012286"
FT VARIANT 474
FT /note="R -> Q (in CTX; impairs sterol 26-hydroxylase
FT activity; dbSNP:rs121908097)"
FT /evidence="ECO:0000269|PubMed:7915755"
FT /id="VAR_012287"
FT VARIANT 474
FT /note="R -> W (in CTX; impairs sterol 26-hydroxylase
FT activity; dbSNP:rs121908098)"
FT /evidence="ECO:0000269|PubMed:7915755"
FT /id="VAR_012288"
FT VARIANT 479
FT /note="R -> C (in CTX; impairs sterol 26-hydroxylase
FT activity; dbSNP:rs72551322)"
FT /evidence="ECO:0000269|PubMed:2019602"
FT /id="VAR_001304"
FT MUTAGEN 240
FT /note="F->A: Impairs sterol 26-hydroxylase activity; when
FT associated with A-244 and A-248."
FT /evidence="ECO:0000269|PubMed:11412116"
FT MUTAGEN 240
FT /note="F->K: Impairs sterol 26-hydroxylase activity."
FT /evidence="ECO:0000269|PubMed:11412116"
FT MUTAGEN 244
FT /note="I->A: Impairs sterol 26-hydroxylase activity; when
FT associated with A-240 and A-248."
FT /evidence="ECO:0000269|PubMed:11412116"
FT MUTAGEN 244
FT /note="I->K: Impairs sterol 26-hydroxylase activity."
FT /evidence="ECO:0000269|PubMed:11412116"
FT MUTAGEN 248
FT /note="F->A: Impairs sterol 26-hydroxylase activity; when
FT associated with A-240 and A-244."
FT /evidence="ECO:0000269|PubMed:11412116"
FT MUTAGEN 248
FT /note="F->K: Impairs sterol 26-hydroxylase activity;
FT confers demethylase activity."
FT /evidence="ECO:0000269|PubMed:11412116"
FT MUTAGEN 268
FT /note="W->A: Reduces sterol 26-hydroxylase activity."
FT /evidence="ECO:0000269|PubMed:11412116"
FT MUTAGEN 271
FT /note="Y->A: Reduces sterol 26-hydroxylase activity."
FT /evidence="ECO:0000269|PubMed:11412116"
FT CONFLICT 20..25
FT /note="LCPHGA -> SAPTG (in Ref. 2; CAA42481)"
FT /evidence="ECO:0000305"
FT CONFLICT 171
FT /note="A -> R (in Ref. 2; CAA42481)"
FT /evidence="ECO:0000305"
FT CONFLICT 359
FT /note="E -> K (in Ref. 3; AAO21126)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 531 AA; 60235 MW; 62025EB670DBD8E9 CRC64;
MAALGCARLR WALRGAGRGL CPHGARAKAA IPAALPSDKA TGAPGAGPGV RRRQRSLEEI
PRLGQLRFFF QLFVQGYALQ LHQLQVLYKA KYGPMWMSYL GPQMHVNLAS APLLEQVMRQ
EGKYPVRNDM ELWKEHRDQH DLTYGPFTTE GHHWYQLRQA LNQRLLKPAE AALYTDAFNE
VIDDFMTRLD QLRAESASGN QVSDMAQLFY YFALEAICYI LFEKRIGCLQ RSIPEDTVTF
VRSIGLMFQN SLYATFLPKW TRPVLPFWKR YLDGWNAIFS FGKKLIDEKL EDMEAQLQAA
GPDGIQVSGY LHFLLASGQL SPREAMGSLP ELLMAGVDTT SNTLTWALYH LSKDPEIQEA
LHEEVVGVVP AGQVPQHKDF AHMPLLKAVL KETLRLYPVV PTNSRIIEKE IEVDGFLFPK
NTQFVFCHYV VSRDPTAFSE PESFQPHRWL RNSQPATPRI QHPFGSVPFG YGVRACLGRR
IAELEMQLLL ARLIQKYKVV LAPETGELKS VARIVLVPNK KVGLQFLQRQ C
