CYP46A1 (cholesterol 24-hydroxylase, cholesterol 24S-hydroxylase, CH24H; EC 1.14.14.25) is a microsomal, heme-thiolate cytochrome P450 monooxygenase expressed predominantly in brain neurons. Anchored to the endoplasmic reticulum membrane by a single N-terminal transmembrane helix, it catalyzes the O2- and NADPH-cytochrome P450 reductase-dependent hydroxylation of cholesterol (with S stereochemistry) at C-24 of the side chain, producing (24S)-hydroxycholesterol. This is the principal, rate-limiting route for eliminating cholesterol from the central nervous system: unlike cholesterol, 24S-hydroxycholesterol readily crosses membranes and the blood-brain barrier, is exported to the plasma and delivered to the liver, where it can enter the alternative bile-acid pathway. 24S-hydroxycholesterol also acts as a signaling oxysterol and nuclear-receptor (LXR) ligand and helps regulate neuronal cholesterol homeostasis and cerebral cholesterol biosynthesis. As a P450 with a conformationally flexible active site, CYP46A1 has broad in vitro substrate specificity, further oxidizing sterol intermediates (7-dehydrocholesterol, desmosterol, cholestanol, 7alpha-hydroxycholesterol), C21 steroid hormones (progesterone, testosterone), and xenobiotics. It is a well-characterized drug target in Alzheimer's disease and other neurodegenerative disorders.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006707 cholesterol catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) propagation of the core biological role. CYP46A1 catalyzes the first, committed step of brain cholesterol degradation by converting cholesterol to the exportable oxysterol 24S-hydroxycholesterol. Well supported by experimental annotations. Supporting Evidence: PMID:14640697 is also the first step in enzymatic degradation of cholesterol in the brain |
| GO:0033781 cholesterol 24-hydroxylase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) support for the defining molecular function of this P450. Redundant with strong experimental (EXP/IDA) annotations to the same term; this is the core catalytic activity. Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt Primarily catalyzes the hydroxylation (with S |
| GO:0020037 heme binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) support for heme binding, a core cofactor function of this cytochrome P450. Directly confirmed by multiple crystal structures (IDA annotations below). Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt Name=heme; Xref=ChEBI:CHEBI:30413 |
| GO:0004497 monooxygenase activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based (IEA) parent molecular-function term. Correct but generic; the specific, experimentally established activity is cholesterol 24-hydroxylase activity (GO:0033781). Kept as a true but non-core generalization. Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt P450 monooxygenase that plays a major role in cholesterol |
| GO:0004508 steroid 17-alpha-monooxygenase activity | IEA GO_REF:0000116 | MARK AS OVER ANNOTATED | Summary: RHEA-mapped (IEA) activity derived from the in vitro progesterone -> 17alpha-hydroxyprogesterone reaction. This is a promiscuous secondary activity of a flexible-active-site P450, not the physiological function. Retained but marked as an over-annotation relative to the core role. Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt Reaction=progesterone + reduced [NADPH--hemoprotein reductase] + O2 = |
| GO:0005506 iron ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based (IEA) iron ion binding. Correct: CYP46A1 is a heme-thiolate P450 whose catalytic iron is the heme Fe, coordinated by the axial cysteine (Cys437). Core cofactor-related function. Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt /ligand_part="Fe" |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (IEA) subcellular location matching the UniProt annotation. CYP46A1 is a single-pass ER membrane protein; this is the core cellular location. Well supported. Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt Endoplasmic reticulum membrane |
| GO:0006707 cholesterol catabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (IEA) assignment of the core biological role, consistent with experimental IDA annotations. CYP46A1 initiates brain cholesterol degradation. Supporting Evidence: PMID:14640697 is also the first step in enzymatic degradation of cholesterol in the brain |
| GO:0016705 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based (IEA) high-level parent of monooxygenase activity. Correct but generic; the specific term cholesterol 24-hydroxylase activity is preferred. Kept as a true but non-core generalization. Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt P450 monooxygenase that plays a major role in cholesterol |
| GO:0020037 heme binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based (IEA) heme binding, redundant with experimental IDA annotations. Core cofactor function of this P450. Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt Name=heme; Xref=ChEBI:CHEBI:30413 |
| GO:0030425 dendrite | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Automated (IEA) location transferred from the mouse ortholog (Q9WVK8). A plausible neuronal cell-projection location but not directly demonstrated for the human protein; the primary location is the ER membrane. Kept as non-core. Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt Cell projection, dendrite |
| GO:0033781 cholesterol 24-hydroxylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (IEA) assignment of the core catalytic activity (EC 1.14.14.25, RHEA:22716), redundant with strong experimental annotations. Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt Primarily catalyzes the hydroxylation (with S |
| GO:0050649 testosterone 6-beta-hydroxylase activity | IEA GO_REF:0000116 | MARK AS OVER ANNOTATED | Summary: RHEA-mapped (IEA) promiscuous activity (testosterone -> 6beta,17beta-dihydroxyandrost-4-en-3-one), observed in vitro. Not the physiological function of this brain cholesterol hydroxylase; retained as an over-annotation. Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt 6beta,17beta-dihydroxyandrost-4-en-3-one |
| GO:0062184 testosterone 16-beta-hydroxylase activity | IEA GO_REF:0000116 | MARK AS OVER ANNOTATED | Summary: RHEA-mapped (IEA) promiscuous activity (testosterone -> 16beta,17beta-dihydroxyandrost-4-en-3-one), observed in vitro. Secondary to the core cholesterol-hydroxylase role; retained as an over-annotation. Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt 16beta,17beta-dihydroxyandrost-4-en-3-one |
| GO:0098793 presynapse | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Automated (IEA) location transferred from the mouse ortholog (Q9WVK8). Plausible for a neuronal protein but not demonstrated for the human protein; the core location is the ER membrane. Kept as non-core. Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt Presynapse |
| GO:0098794 postsynapse | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Automated (IEA) location transferred from the mouse ortholog (Q9WVK8). Plausible neuronal location but not demonstrated for the human protein; the core location is the ER membrane. Kept as non-core. Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt Postsynapse |
| GO:1900271 regulation of long-term synaptic potentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-based (IEA) transfer from the mouse ortholog. Cyp46a1 loss in mice reduces cerebral cholesterol turnover and geranylgeraniol production needed for hippocampal plasticity/learning. A downstream physiological consequence of altered cholesterol turnover rather than a direct molecular role; kept as non-core. Supporting Evidence: PMID:20667828 necessary for normal learning and hippocampal plasticity |
| GO:0006699 bile acid biosynthetic process | TAS Reactome:R-HSA-193775 | KEEP AS NON CORE | Summary: Reactome (TAS) pathway annotation. CYP46A1's product 24S-hydroxycholesterol is exported from the brain to the liver where it feeds an alternative, minor bile-acid biosynthetic pathway. This is a downstream, whole-body pathway role rather than the enzyme's core neuronal cholesterol-elimination function; kept as non-core. Supporting Evidence: Reactome:R-HSA-193775 24-hydroxycholesterol is synthesized in the brain, exported to the liver, and converted there to bile acids and bile salts |
| GO:0016125 sterol metabolic process | TAS Reactome:R-HSA-211976 | KEEP AS NON CORE | Summary: Reactome (TAS) high-level biological process. Correct but generic parent of the specific cholesterol catabolic process; kept as a true but non-core generalization. Supporting Evidence: Reactome:R-HSA-211976 take part in cholesterol biosynthesis and elimination |
| GO:0008207 C21-steroid hormone metabolic process | IEA GO_REF:0000041 | MARK AS OVER ANNOTATED | Summary: UniPathway-based (IEA) process reflecting the in vitro hydroxylation of C21 steroid hormones (progesterone, testosterone). This is a promiscuous secondary activity, not a demonstrated physiological role of this brain enzyme; retained as an over-annotation. Supporting Evidence: PMID:14640697 introduce a hydroxyl group on the steroid nucleus of the C21-steroid hormones with the C4-C5 double bond (progesterone and testosterone) |
| GO:0033781 cholesterol 24-hydroxylase activity | TAS Reactome:R-HSA-192061 | ACCEPT | Summary: Reactome (TAS) assertion of the core catalytic activity (CYP46A1 24-hydroxylates cholesterol). Redundant with experimental annotations; the defining molecular function. Supporting Evidence: Reactome:R-HSA-192061 catalyses the 24-hydroxylation of cholesterol (CHOL) to 24-hydroxycholesterol |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity (ISS) transfer of the core ER-membrane location from the mouse ortholog. Consistent with the original cloning study localizing the enzyme to the ER and with its single N-terminal transmembrane helix. Supporting Evidence: PMID:10377398 both proteins are localized to the endoplasmic reticulum |
| GO:0033781 cholesterol 24-hydroxylase activity | EXP PMID:10377398 cDNA cloning of cholesterol 24-hydroxylase, a mediator of ch... | ACCEPT | Summary: Direct experimental evidence: expression cloning of CYP46A1 produced an enzymatic activity converting cholesterol to 24S-hydroxycholesterol. This is the defining, core molecular function of the gene. Supporting Evidence: PMID:10377398 the cDNAs produce an enzymatic activity that converts cholesterol into 24S-hydroxycholesterol |
| GO:0050649 testosterone 6-beta-hydroxylase activity | EXP PMID:14640697 Broad substrate specificity of human cytochrome P450 46A1 wh... | MARK AS OVER ANNOTATED | Summary: Experimentally observed in vitro promiscuous activity: recombinant CYP46A1 hydroxylates the C21 steroid hormone testosterone on the steroid nucleus. A real but secondary activity of this flexible-active-site P450, not its physiological cholesterol-hydroxylase role; treated as an over-annotation. Not removed per experimental-annotation policy. Supporting Evidence: PMID:14640697 introduce a hydroxyl group on the steroid nucleus of the C21-steroid hormones with the C4-C5 double bond (progesterone and testosterone) |
| GO:0062184 testosterone 16-beta-hydroxylase activity | EXP PMID:14640697 Broad substrate specificity of human cytochrome P450 46A1 wh... | MARK AS OVER ANNOTATED | Summary: Experimentally observed in vitro promiscuous testosterone hydroxylation. Real but secondary to the core cholesterol-hydroxylase function; treated as an over-annotation. Not removed per experimental-annotation policy. Supporting Evidence: PMID:14640697 introduce a hydroxyl group on the steroid nucleus of the C21-steroid hormones with the C4-C5 double bond (progesterone and testosterone) |
| GO:0098793 presynapse | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity (ISS) transfer from the mouse ortholog (Q9WVK8). Plausible neuronal location but not directly demonstrated for the human protein; the core location is the ER membrane. Kept as non-core. Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt Presynapse |
| GO:0098794 postsynapse | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity (ISS) transfer from the mouse ortholog (Q9WVK8). Plausible neuronal location but not directly demonstrated for the human protein; the core location is the ER membrane. Kept as non-core. Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt Postsynapse |
| GO:0006707 cholesterol catabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity (ISS) transfer of the core biological role from the mouse ortholog, consistent with human experimental IDA annotations. Supporting Evidence: PMID:14640697 is also the first step in enzymatic degradation of cholesterol in the brain |
| GO:1903044 protein localization to membrane raft | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity (ISS) transfer from the mouse ortholog with an acts_upstream_of_negative_effect qualifier. Represents an indirect, downstream regulatory consequence of CYP46A1-driven changes in membrane cholesterol content rather than a direct molecular activity. Kept as non-core. Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt triggering cholesterol diffusion out of neurons |
| GO:0006707 cholesterol catabolic process | IDA PMID:14640697 Broad substrate specificity of human cytochrome P450 46A1 wh... | ACCEPT | Summary: Direct experimental support for the core biological role: the 24(S)- hydroxylation of cholesterol is the first step in enzymatic degradation of cholesterol in the brain. Supporting Evidence: PMID:14640697 is also the first step in enzymatic degradation of cholesterol in the brain |
| GO:0006707 cholesterol catabolic process | IDA PMID:25017465 Oxidation of 7-dehydrocholesterol and desmosterol by human c... | ACCEPT | Summary: Experimental support (IDA); CYP46A1 oxidizes cholesterol to 24S-hydroxycholesterol, initiating its catabolism. Core biological role. Supporting Evidence: PMID:25017465 its ability to oxidize cholesterol to 24S-hydroxycholesterol |
| GO:0008395 steroid hydroxylase activity | IDA PMID:14640697 Broad substrate specificity of human cytochrome P450 46A1 wh... | KEEP AS NON CORE | Summary: Experimentally supported (IDA) parent molecular function. CYP46A1 hydroxylates a range of steroids/sterols. This is the correct broad class, but the specific, physiologically relevant activity is cholesterol 24-hydroxylase activity (GO:0033781). Retained as a true but non-core generalization. Supporting Evidence: PMID:14640697 P450 46A1 was able to carry out side chain hydroxylations of two endogenous C27-steroids |
| GO:0020037 heme binding | IDA PMID:20667828 Structural basis of drug binding to CYP46A1, an enzyme that ... | ACCEPT | Summary: Direct experimental (crystallographic) evidence of heme binding; the drug co-complex structures show ligands coordinating the CYP46A1 heme iron. Core cofactor function. Supporting Evidence: PMID:20667828 coordinating the heme iron via their nitrogen atoms |
| GO:0020037 heme binding | IDA PMID:23288837 Binding of a cyano- and fluoro-containing drug bicalutamide ... | ACCEPT | Summary: Direct experimental (crystallographic) evidence of heme binding; a water molecule coordinated to the CYP46A1 heme iron is described in the bicalutamide co-complex. Core cofactor function. Supporting Evidence: PMID:23288837 a water molecule that is coordinated to the P450 |
| GO:0030425 dendrite | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity (ISS) transfer of a neuronal cell-projection location from the mouse ortholog. Not directly demonstrated for the human protein; the core location is the ER membrane. Kept as non-core. Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt Cell projection, dendrite |
| GO:0033781 cholesterol 24-hydroxylase activity | IDA PMID:14640697 Broad substrate specificity of human cytochrome P450 46A1 wh... | ACCEPT | Summary: Direct experimental evidence for the defining molecular function; recombinant P450 46A1 24(S)-hydroxylates cholesterol. Core function. Supporting Evidence: PMID:14640697 The known activity of cytochrome P450 46A1 (P450 46A1) is 24(S)-hydroxylation of cholesterol |
| GO:0033781 cholesterol 24-hydroxylase activity | IDA PMID:25017465 Oxidation of 7-dehydrocholesterol and desmosterol by human c... | ACCEPT | Summary: Direct experimental evidence for the core catalytic activity; CYP46A1 oxidizes cholesterol to 24S-hydroxycholesterol. Core function. Supporting Evidence: PMID:25017465 its ability to oxidize cholesterol to 24S-hydroxycholesterol |
| GO:0042448 progesterone metabolic process | IDA PMID:14640697 Broad substrate specificity of human cytochrome P450 46A1 wh... | MARK AS OVER ANNOTATED | Summary: Experimentally observed in vitro: CYP46A1 hydroxylates the C21 steroid hormone progesterone on the steroid nucleus (progesterone -> 17alpha-hydroxyprogesterone). A promiscuous secondary activity of this flexible-active-site P450, not its physiological function; treated as an over-annotation. Not removed per experimental-annotation policy. Supporting Evidence: PMID:14640697 introduce a hydroxyl group on the steroid nucleus of the C21-steroid hormones with the C4-C5 double bond (progesterone and testosterone) |
| GO:1900271 regulation of long-term synaptic potentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity (ISS) transfer from the mouse ortholog. Reflects the indirect effect of CYP46A1-mediated cholesterol turnover on hippocampal plasticity/learning rather than a direct molecular role; kept as non-core. Supporting Evidence: PMID:20667828 necessary for normal learning and hippocampal plasticity |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-192061 | ACCEPT | Summary: Reactome (TAS) ER-membrane location, consistent with the UniProt annotation and original cloning study. Core cellular location. Supporting Evidence: Reactome:R-HSA-192061 an enzyme associated with the ER membrane |
| GO:0006707 cholesterol catabolic process | IDA PMID:18621681 Crystal structures of substrate-bound and substrate-free cyt... | ACCEPT | Summary: Experimental support (IDA); the structural study confirms CYP46A1 initiates the major pathway for cholesterol removal from the brain by converting cholesterol to 24S-hydroxycholesterol. Core biological role. Supporting Evidence: PMID:18621681 cytochrome P450 46A1 (CYP46A1) initiates the major pathway for cholesterol removal from the brain |
| GO:0006805 xenobiotic metabolic process | IDA PMID:20667828 Structural basis of drug binding to CYP46A1, an enzyme that ... | KEEP AS NON CORE | Summary: Experimentally supported (IDA); CYP46A1 metabolizes the xenobiotic clotrimazole (and, in vitro, dextromethorphan, diclofenac, phenacetin). A promiscuous secondary activity of this P450, not its core physiological role; kept as non-core. Not removed per experimental-annotation policy. Supporting Evidence: PMID:20667828 clotrimazole is also a substrate for CYP46A1 |
| GO:0020037 heme binding | IDA PMID:18621681 Crystal structures of substrate-bound and substrate-free cyt... | ACCEPT | Summary: Direct experimental (crystallographic) evidence of heme binding; the substrate-bound and substrate-free CYP46A1 structures resolve the heme. Core cofactor function. Supporting Evidence: file:human/CYP46A1/CYP46A1-uniprot.txt Name=heme; Xref=ChEBI:CHEBI:30413 |
| GO:0033781 cholesterol 24-hydroxylase activity | IDA PMID:18621681 Crystal structures of substrate-bound and substrate-free cyt... | ACCEPT | Summary: Direct experimental/structural evidence for the core catalytic activity; the CYP46A1-cholesterol 3-sulfate structure captures the substrate in the productive orientation for 24-hydroxylation. Core function. Supporting Evidence: PMID:18621681 By converting cholesterol to 24S-hydroxycholesterol, cytochrome P450 46A1 |
| GO:0005783 endoplasmic reticulum | TAS PMID:10377398 cDNA cloning of cholesterol 24-hydroxylase, a mediator of ch... | KEEP AS NON CORE | Summary: Author statement (TAS) that the enzyme localizes to the endoplasmic reticulum. Correct but a less specific parent of endoplasmic reticulum membrane (GO:0005789), which better captures the single-pass membrane topology. Kept as a true but non-core generalization. Supporting Evidence: PMID:10377398 both proteins are localized to the endoplasmic reticulum |
| GO:0006707 cholesterol catabolic process | TAS PMID:10377398 cDNA cloning of cholesterol 24-hydroxylase, a mediator of ch... | ACCEPT | Summary: Author statement (TAS) of the core biological role: brain cholesterol turnover via conversion of excess cholesterol to 24S-hydroxycholesterol. Supporting Evidence: PMID:10377398 The turnover of cholesterol in the brain is thought to occur via conversion of excess cholesterol into 24S-hydroxycholesterol |
| GO:0007399 nervous system development | TAS PMID:10377398 cDNA cloning of cholesterol 24-hydroxylase, a mediator of ch... | KEEP AS NON CORE | Summary: Author statement (TAS) capturing the neuronal/CNS context of CYP46A1. This is a very broad developmental process; CYP46A1's role is metabolic (cholesterol elimination in neurons) rather than a developmental function per se. Kept as non-core. Supporting Evidence: PMID:10377398 this P450 to neurons in multiple subregions of the brain |
| GO:0008395 steroid hydroxylase activity | TAS PMID:10377398 cDNA cloning of cholesterol 24-hydroxylase, a mediator of ch... | KEEP AS NON CORE | Summary: Author statement (TAS) of the broad steroid/sterol hydroxylase class. Correct but generic; the specific activity is cholesterol 24-hydroxylase activity. Retained as a true but non-core generalization. Supporting Evidence: PMID:10377398 cholesterol 24-hydroxylases that synthesize oxysterols in neurons |
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Download this section (compressed HTML)Q: Are the synaptic (pre-/postsynapse) and dendrite localizations, currently transferred by similarity from the mouse ortholog, directly demonstrable for the human protein, or is CYP46A1 essentially confined to the neuronal ER?
Experiment: Determine the subcellular distribution of endogenous human CYP46A1 in neurons (e.g. by subcellular fractionation combined with high-resolution/expansion imaging) to test whether it localizes beyond the ER membrane to synaptic compartments and dendrites.
Type: subcellular localization
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