UniProt functional annotation for Q9Y6A2

UniProt code: Q9Y6A2.

Organism: Homo sapiens (Human).
Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.
 
Function: P450 monooxygenase that plays a major role in cholesterol homeostasis in the brain. Primarily catalyzes the hydroxylation (with S stereochemistry) at C-24 of cholesterol side chain, triggering cholesterol diffusion out of neurons and its further degradation (PubMed:10377398, PubMed:14640697, PubMed:25017465, PubMed:18621681). By promoting constant cholesterol elimination in neurons, may activate the mevalonate pathway and coordinate the synthesis of new cholesterol and nonsterol isoprenoids involved in synaptic activity and learning (By similarity). Further hydroxylates cholesterol derivatives and hormone steroids on both the ring and side chain of these molecules, converting them into active oxysterols involved in lipid signaling and biosynthesis (PubMed:12077124, PubMed:14640697, PubMed:28190002). Acts as an epoxidase converting cholesta-5,24-dien-3beta-ol/desmosterol into (24S),25-epoxycholesterol, an abundant lipid ligand of nuclear NR1H2 and NR1H3 receptors shown to promote neurogenesis in developing brain (PubMed:25017465). May also catalyze the oxidative metabolism of xenobiotics, such as clotrimazole (PubMed:20667828). {ECO:0000250|UniProtKB:Q9WVK8, ECO:0000269|PubMed:10377398, ECO:0000269|PubMed:12077124, ECO:0000269|PubMed:14640697, ECO:0000269|PubMed:18621681, ECO:0000269|PubMed:20667828, ECO:0000269|PubMed:25017465, ECO:0000269|PubMed:28190002}.
 
Catalytic activity: Reaction=cholesterol + O2 + reduced [NADPH--hemoprotein reductase] = (24S)-hydroxycholesterol + H(+) + H2O + oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:22716, Rhea:RHEA-COMP:11964, Rhea:RHEA- COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:16113, ChEBI:CHEBI:34310, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210; EC=1.14.14.25; Evidence={ECO:0000269|PubMed:10377398, ECO:0000269|PubMed:14640697, ECO:0000269|PubMed:18621681, ECO:0000269|PubMed:25017465}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22717; Evidence={ECO:0000250|UniProtKB:Q9WVK8};
Catalytic activity: Reaction=cholestanol + O2 + reduced [NADPH--hemoprotein reductase] = (24S)-hydroxycholestanol + H(+) + H2O + oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:53808, Rhea:RHEA-COMP:11964, Rhea:RHEA- COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:86570, ChEBI:CHEBI:137687; Evidence={ECO:0000269|PubMed:28190002}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53809; Evidence={ECO:0000250|UniProtKB:Q9WVK8};
Catalytic activity: Reaction=cholesta-5,7-dien-3beta-ol + O2 + reduced [NADPH--hemoprotein reductase] = cholesta-5,7-dien-3beta,24S-diol + H(+) + H2O + oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:53244, Rhea:RHEA- COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17759, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:137061; Evidence={ECO:0000269|PubMed:25017465}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53245; Evidence={ECO:0000305};
Catalytic activity: Reaction=cholesta-5,7-dien-3beta-ol + O2 + reduced [NADPH--hemoprotein reductase] = cholesta-5,7-dien-3beta,25-diol + H(+) + H2O + oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:53240, Rhea:RHEA- COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17759, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:137057; Evidence={ECO:0000269|PubMed:25017465}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53241; Evidence={ECO:0000305};
Catalytic activity: Reaction=cholesta-5,24-dien-3beta-ol + O2 + reduced [NADPH--hemoprotein reductase] = cholesta-5,24Z-dien-3beta,27-diol + H(+) + H2O + oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:53236, Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17737, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:137053; Evidence={ECO:0000269|PubMed:25017465}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53237; Evidence={ECO:0000305};
Catalytic activity: Reaction=cholesta-5,24-dien-3beta-ol + O2 + reduced [NADPH--hemoprotein reductase] = (24S)-25-epoxycholesterol + H(+) + H2O + oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:53232, Rhea:RHEA- COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17737, ChEBI:CHEBI:41633, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210; Evidence={ECO:0000269|PubMed:25017465}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53233; Evidence={ECO:0000305};
Catalytic activity: Reaction=4beta-hydroxycholesterol + O2 + reduced [NADPH--hemoprotein reductase] = 4beta,24S-dihydroxycholesterol + H(+) + H2O + oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:46392, Rhea:RHEA- COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:85778, ChEBI:CHEBI:86087; Evidence={ECO:0000269|PubMed:12077124}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46393; Evidence={ECO:0000305};
Catalytic activity: Reaction=(24S)-hydroxycholesterol + O2 + reduced [NADPH--hemoprotein reductase] = (24S,25R)-24,26-dihydroxycholesterol + H(+) + H2O + oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:46388, Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:34310, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:86165; Evidence={ECO:0000269|PubMed:14640697}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46389; Evidence={ECO:0000305};
Catalytic activity: Reaction=(24S)-hydroxycholesterol + O2 + reduced [NADPH--hemoprotein reductase] = 24S,25-dihydroxycholesterol + H(+) + H2O + oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:46384, Rhea:RHEA- COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:34310, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:86074; Evidence={ECO:0000269|PubMed:14640697, ECO:0000269|PubMed:18621681}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46385; Evidence={ECO:0000305};
Catalytic activity: Reaction=7alpha-hydroxycholesterol + O2 + reduced [NADPH--hemoprotein reductase] = (24S)-7alpha-dihydroxycholesterol + H(+) + H2O + oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:46380, Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17500, ChEBI:CHEBI:37640, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210; Evidence={ECO:0000269|PubMed:14640697}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46381; Evidence={ECO:0000305};
Catalytic activity: Reaction=O2 + progesterone + reduced [NADPH--hemoprotein reductase] = 17alpha-hydroxyprogesterone + H(+) + H2O + oxidized [NADPH-- hemoprotein reductase]; Xref=Rhea:RHEA:46308, Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17026, ChEBI:CHEBI:17252, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210; Evidence={ECO:0000269|PubMed:14640697}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46309; Evidence={ECO:0000305};
Catalytic activity: Reaction=O2 + reduced [NADPH--hemoprotein reductase] + testosterone = 16beta,17beta-dihydroxyandrost-4-en-3-one + H(+) + H2O + oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:46304, Rhea:RHEA- COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17347, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:83027; Evidence={ECO:0000269|PubMed:14640697}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46305; Evidence={ECO:0000305};
Catalytic activity: Reaction=O2 + reduced [NADPH--hemoprotein reductase] + testosterone = 2-hydroxytestosterone + H(+) + H2O + oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:46300, Rhea:RHEA-COMP:11964, Rhea:RHEA- COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17347, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:86013; Evidence={ECO:0000269|PubMed:14640697}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46301; Evidence={ECO:0000305};
Catalytic activity: Reaction=O2 + reduced [NADPH--hemoprotein reductase] + testosterone = 6beta,17beta-dihydroxyandrost-4-en-3-one + H(+) + H2O + oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:46296, Rhea:RHEA- COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17347, ChEBI:CHEBI:34477, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210; Evidence={ECO:0000269|PubMed:14640697}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46297; Evidence={ECO:0000305};
Cofactor: Name=heme; Xref=ChEBI:CHEBI:30413; Evidence={ECO:0000269|PubMed:18621681, ECO:0000269|PubMed:20667828, ECO:0000269|PubMed:23288837};
Biophysicochemical properties: Kinetic parameters: KM=2.2 uM for 24(S)-hydroxycholesterol {ECO:0000269|PubMed:14640697}; KM=7 uM for cholesterol {ECO:0000269|PubMed:25017465}; KM=2.8 uM for cholesta-5,7-dien-3beta-ol/7-dehydrocholesterol {ECO:0000269|PubMed:25017465}; KM=9.4 uM for cholesta-5,24-dien-3beta-ol/desmosterol {ECO:0000269|PubMed:25017465}; Note=kcat/KM=8.4 mM/min for cholesterol, kcat/KM=8.5 mM/min for cholesta-5,7-dien-3beta-ol/7-dehydrocholesterol and kcat/KM=3.5 mM/min for cholesta-5,24-dien-3beta-ol/desmosterol. {ECO:0000269|PubMed:25017465};
Pathway: Steroid metabolism; cholesterol degradation. {ECO:0000305|PubMed:14640697}.
Pathway: Lipid metabolism; C21-steroid hormone metabolism. {ECO:0000305|PubMed:14640697}.
Subcellular location: Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:Q9WVK8}; Single-pass membrane protein {ECO:0000250|UniProtKB:Q9WVK8}. Microsome membrane {ECO:0000250|UniProtKB:Q9WVK8}; Single-pass membrane protein {ECO:0000250|UniProtKB:Q9WVK8}. Cell junction, synapse, postsynapse {ECO:0000250|UniProtKB:Q9WVK8}. Cell junction, synapse, presynapse {ECO:0000250|UniProtKB:Q9WVK8}. Cell projection, dendrite {ECO:0000250|UniProtKB:Q9WVK8}.
Tissue specificity: Expressed in brain. The mRNA was broadly distributed with higher levels in gray matter zones and lower levels in regions rich in white matter. Not detected in fetal sample but its expression increases linearly with age. {ECO:0000269|PubMed:10377398}.
Similarity: Belongs to the cytochrome P450 family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.