CYP27B1 (25-hydroxyvitamin D 1-alpha-hydroxylase) is a mitochondrial cytochrome P450, embedded in the inner mitochondrial membrane and supplied with electrons from NADPH through adrenodoxin reductase (FDXR) and adrenodoxin (FDX1). It catalyses the rate-limiting step of vitamin D activation, 1-alpha-hydroxylation of 25-hydroxyvitamin D3 (calcidiol) to 1-alpha,25-dihydroxyvitamin D3 (calcitriol), the hormonal ligand of the vitamin D receptor; it also 1-alpha-hydroxylates 25-hydroxyvitamin D2 and 24R,25-dihydroxyvitamin D3 and other CYP24A1 pathway intermediates. Its principal site of action for circulating calcitriol is the renal proximal tubule, where expression is induced by PTH and repressed by calcitriol and FGF23, but it is also expressed in keratinocytes, macrophages/dendritic cells, osteoblasts and other extrarenal cells where locally produced calcitriol acts in an autocrine/paracrine manner. Biallelic loss-of-function variants cause vitamin D-dependent rickets type 1A (pseudovitamin D-deficiency rickets).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004497 monooxygenase activity | IEA GO_REF:0000120 | MODIFY | Summary: Generic monooxygenase parent terms of the specific 25-hydroxyvitamin D 1-alpha-hydroxylase activity. Reason: Correct but uninformative; the specific activity is calcidiol 1-monooxygenase activity (GO:0004498). Proposed replacements: calcidiol 1-monooxygenase activity Supporting Evidence: file:human/CYP27B1/CYP27B1-uniprot.txt Catalyzes the rate-limiting step in the activation of vitamin D in the kidney |
| GO:0004498 calcidiol 1-monooxygenase activity | EXP PMID:10518789 Enzymatic properties of human 25-hydroxyvitamin D3 1alpha-hy... | ACCEPT | Summary: Calcidiol 1-monooxygenase (25-hydroxyvitamin D 1-alpha-hydroxylase) activity is the defining catalytic activity of CYP27B1, producing calcitriol. Reason: Shown with cloned and recombinant human enzyme (PMID:9415400, PMID:10518789, PMID:22862690) and abolished by VDDR1A alleles; this is the core function. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. PMID:10518789 These results strongly suggest that the mutations found in the patients with PDDR completely abolished 1alpha-hydroxylase activity PMID:9415400 whereas those from a patient with VDDR-1 lacked detectable activity |
| GO:0004498 calcidiol 1-monooxygenase activity | EXP PMID:10566658 No enzyme activity of 25-hydroxyvitamin D3 1alpha-hydroxylas... | ACCEPT | Summary: Calcidiol 1-monooxygenase (25-hydroxyvitamin D 1-alpha-hydroxylase) activity is the defining catalytic activity of CYP27B1, producing calcitriol. Reason: Shown with cloned and recombinant human enzyme (PMID:9415400, PMID:10518789, PMID:22862690) and abolished by VDDR1A alleles; this is the core function. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. PMID:10518789 These results strongly suggest that the mutations found in the patients with PDDR completely abolished 1alpha-hydroxylase activity PMID:9415400 whereas those from a patient with VDDR-1 lacked detectable activity |
| GO:0004498 calcidiol 1-monooxygenase activity | EXP PMID:12050193 Novel gene mutations in patients with 1alpha-hydroxylase def... | ACCEPT | Summary: Calcidiol 1-monooxygenase (25-hydroxyvitamin D 1-alpha-hydroxylase) activity is the defining catalytic activity of CYP27B1, producing calcitriol. Reason: Shown with cloned and recombinant human enzyme (PMID:9415400, PMID:10518789, PMID:22862690) and abolished by VDDR1A alleles; this is the core function. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. PMID:10518789 These results strongly suggest that the mutations found in the patients with PDDR completely abolished 1alpha-hydroxylase activity PMID:9415400 whereas those from a patient with VDDR-1 lacked detectable activity |
| GO:0004498 calcidiol 1-monooxygenase activity | EXP PMID:9486994 Inactivating mutations in the 25-hydroxyvitamin D3 1alpha-hy... | ACCEPT | Summary: Calcidiol 1-monooxygenase (25-hydroxyvitamin D 1-alpha-hydroxylase) activity is the defining catalytic activity of CYP27B1, producing calcitriol. Reason: Shown with cloned and recombinant human enzyme (PMID:9415400, PMID:10518789, PMID:22862690) and abolished by VDDR1A alleles; this is the core function. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. PMID:10518789 These results strongly suggest that the mutations found in the patients with PDDR completely abolished 1alpha-hydroxylase activity PMID:9415400 whereas those from a patient with VDDR-1 lacked detectable activity |
| GO:0004498 calcidiol 1-monooxygenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Calcidiol 1-monooxygenase (25-hydroxyvitamin D 1-alpha-hydroxylase) activity is the defining catalytic activity of CYP27B1, producing calcitriol. Reason: Shown with cloned and recombinant human enzyme (PMID:9415400, PMID:10518789, PMID:22862690) and abolished by VDDR1A alleles; this is the core function. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. PMID:10518789 These results strongly suggest that the mutations found in the patients with PDDR completely abolished 1alpha-hydroxylase activity PMID:9415400 whereas those from a patient with VDDR-1 lacked detectable activity |
| GO:0004498 calcidiol 1-monooxygenase activity | IDA PMID:15795327 25-hydroxyvitamin D3-1alpha-hydroxylase is expressed in huma... | ACCEPT | Summary: Calcidiol 1-monooxygenase (25-hydroxyvitamin D 1-alpha-hydroxylase) activity is the defining catalytic activity of CYP27B1, producing calcitriol. Reason: Shown with cloned and recombinant human enzyme (PMID:9415400, PMID:10518789, PMID:22862690) and abolished by VDDR1A alleles; this is the core function. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. PMID:10518789 These results strongly suggest that the mutations found in the patients with PDDR completely abolished 1alpha-hydroxylase activity PMID:9415400 whereas those from a patient with VDDR-1 lacked detectable activity |
| GO:0004498 calcidiol 1-monooxygenase activity | IDA PMID:16549446 Human mammary epithelial cells express CYP27B1 and are growt... | ACCEPT | Summary: Calcidiol 1-monooxygenase (25-hydroxyvitamin D 1-alpha-hydroxylase) activity is the defining catalytic activity of CYP27B1, producing calcitriol. Reason: Shown with cloned and recombinant human enzyme (PMID:9415400, PMID:10518789, PMID:22862690) and abolished by VDDR1A alleles; this is the core function. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. PMID:10518789 These results strongly suggest that the mutations found in the patients with PDDR completely abolished 1alpha-hydroxylase activity PMID:9415400 whereas those from a patient with VDDR-1 lacked detectable activity |
| GO:0004498 calcidiol 1-monooxygenase activity | IDA PMID:17023519 Evidence for auto/paracrine actions of vitamin D in bone: 1a... | ACCEPT | Summary: Calcidiol 1-monooxygenase (25-hydroxyvitamin D 1-alpha-hydroxylase) activity is the defining catalytic activity of CYP27B1, producing calcitriol. Reason: Shown with cloned and recombinant human enzyme (PMID:9415400, PMID:10518789, PMID:22862690) and abolished by VDDR1A alleles; this is the core function. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. PMID:10518789 These results strongly suggest that the mutations found in the patients with PDDR completely abolished 1alpha-hydroxylase activity PMID:9415400 whereas those from a patient with VDDR-1 lacked detectable activity |
| GO:0004498 calcidiol 1-monooxygenase activity | IDA PMID:22862690 Expression of human CYP27B1 in Escherichia coli and characte... | ACCEPT | Summary: Calcidiol 1-monooxygenase (25-hydroxyvitamin D 1-alpha-hydroxylase) activity is the defining catalytic activity of CYP27B1, producing calcitriol. Reason: Shown with cloned and recombinant human enzyme (PMID:9415400, PMID:10518789, PMID:22862690) and abolished by VDDR1A alleles; this is the core function. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. PMID:10518789 These results strongly suggest that the mutations found in the patients with PDDR completely abolished 1alpha-hydroxylase activity PMID:9415400 whereas those from a patient with VDDR-1 lacked detectable activity |
| GO:0004498 calcidiol 1-monooxygenase activity | IDA PMID:9415400 Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and... | ACCEPT | Summary: Calcidiol 1-monooxygenase (25-hydroxyvitamin D 1-alpha-hydroxylase) activity is the defining catalytic activity of CYP27B1, producing calcitriol. Reason: Shown with cloned and recombinant human enzyme (PMID:9415400, PMID:10518789, PMID:22862690) and abolished by VDDR1A alleles; this is the core function. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. PMID:10518789 These results strongly suggest that the mutations found in the patients with PDDR completely abolished 1alpha-hydroxylase activity PMID:9415400 whereas those from a patient with VDDR-1 lacked detectable activity |
| GO:0004498 calcidiol 1-monooxygenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Calcidiol 1-monooxygenase (25-hydroxyvitamin D 1-alpha-hydroxylase) activity is the defining catalytic activity of CYP27B1, producing calcitriol. Reason: Shown with cloned and recombinant human enzyme (PMID:9415400, PMID:10518789, PMID:22862690) and abolished by VDDR1A alleles; this is the core function. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. PMID:10518789 These results strongly suggest that the mutations found in the patients with PDDR completely abolished 1alpha-hydroxylase activity PMID:9415400 whereas those from a patient with VDDR-1 lacked detectable activity |
| GO:0004498 calcidiol 1-monooxygenase activity | TAS Reactome:R-HSA-209868 | ACCEPT | Summary: Calcidiol 1-monooxygenase (25-hydroxyvitamin D 1-alpha-hydroxylase) activity is the defining catalytic activity of CYP27B1, producing calcitriol. Reason: Shown with cloned and recombinant human enzyme (PMID:9415400, PMID:10518789, PMID:22862690) and abolished by VDDR1A alleles; this is the core function. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. PMID:10518789 These results strongly suggest that the mutations found in the patients with PDDR completely abolished 1alpha-hydroxylase activity PMID:9415400 whereas those from a patient with VDDR-1 lacked detectable activity |
| GO:0004498 calcidiol 1-monooxygenase activity | TAS Reactome:R-HSA-5602186 | ACCEPT | Summary: Calcidiol 1-monooxygenase (25-hydroxyvitamin D 1-alpha-hydroxylase) activity is the defining catalytic activity of CYP27B1, producing calcitriol. Reason: Shown with cloned and recombinant human enzyme (PMID:9415400, PMID:10518789, PMID:22862690) and abolished by VDDR1A alleles; this is the core function. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. PMID:10518789 These results strongly suggest that the mutations found in the patients with PDDR completely abolished 1alpha-hydroxylase activity PMID:9415400 whereas those from a patient with VDDR-1 lacked detectable activity |
| GO:0005506 iron ion binding | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Iron ion binding reflects the heme iron of the P450 prosthetic group. Reason: The iron is bound as heme, captured by heme binding (GO:0020037); not a separate activity. Supporting Evidence: PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. |
| GO:0005737 cytoplasm | IDA PMID:15589699 Distribution of the vitamin D receptor and 1 alpha-hydroxyla... | KEEP AS NON CORE | Summary: Immunohistochemical detection of CYP27B1 in the cytoplasm of brain and endometrial cells. Reason: Consistent with a mitochondrial enzyme at light-microscope resolution; not wrong but less precise than mitochondrion. Supporting Evidence: file:human/CYP27B1/CYP27B1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion membrane. |
| GO:0005737 cytoplasm | IDA PMID:16720713 Cycling and early pregnant endometrium as a site of regulate... | KEEP AS NON CORE | Summary: Immunohistochemical detection of CYP27B1 in the cytoplasm of brain and endometrial cells. Reason: Consistent with a mitochondrial enzyme at light-microscope resolution; not wrong but less precise than mitochondrion. Supporting Evidence: file:human/CYP27B1/CYP27B1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion membrane. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: CYP27B1 is a mitochondrial P450. Reason: Mitochondrial localisation is consistent with its adrenodoxin/adrenodoxin-reductase electron supply and is supported by HTP proteomics and the reconstitution studies (PMID:22862690). Supporting Evidence: PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. file:human/CYP27B1/CYP27B1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion membrane. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: CYP27B1 is a mitochondrial P450. Reason: Mitochondrial localisation is consistent with its adrenodoxin/adrenodoxin-reductase electron supply and is supported by HTP proteomics and the reconstitution studies (PMID:22862690). Supporting Evidence: PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. file:human/CYP27B1/CYP27B1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion membrane. |
| GO:0005739 mitochondrion | IEA GO_REF:0000117 | ACCEPT | Summary: CYP27B1 is a mitochondrial P450. Reason: Mitochondrial localisation is consistent with its adrenodoxin/adrenodoxin-reductase electron supply and is supported by HTP proteomics and the reconstitution studies (PMID:22862690). Supporting Evidence: PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. file:human/CYP27B1/CYP27B1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion membrane. |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | ACCEPT | Summary: CYP27B1 is a mitochondrial P450. Reason: Mitochondrial localisation is consistent with its adrenodoxin/adrenodoxin-reductase electron supply and is supported by HTP proteomics and the reconstitution studies (PMID:22862690). Supporting Evidence: PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. file:human/CYP27B1/CYP27B1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion membrane. |
| GO:0005739 mitochondrion | TAS PMID:9333115 The 25-hydroxyvitamin D 1-alpha-hydroxylase gene maps to the... | ACCEPT | Summary: CYP27B1 is a mitochondrial P450. Reason: Mitochondrial localisation is consistent with its adrenodoxin/adrenodoxin-reductase electron supply and is supported by HTP proteomics and the reconstitution studies (PMID:22862690). Supporting Evidence: PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. file:human/CYP27B1/CYP27B1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion membrane. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-209868 | MODIFY | Summary: Reactome places the CYP27B1 reaction at the mitochondrial outer membrane. Reason: Mitochondrial (type I) P450s that receive electrons from adrenodoxin are inner-membrane proteins facing the matrix; CYP27B1 activity is stimulated by the inner-membrane lipid cardiolipin. The outer-membrane location is not supported. Proposed replacements: mitochondrial inner membrane Supporting Evidence: file:human/CYP27B1/CYP27B1-uniprot.txt Activated by cardiolipin and dioleoyl phosphatidylethanolamine (DOPE), phospholipids found in the inner mitochondrial membrane. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-5602186 | MODIFY | Summary: Reactome places the CYP27B1 reaction at the mitochondrial outer membrane. Reason: Mitochondrial (type I) P450s that receive electrons from adrenodoxin are inner-membrane proteins facing the matrix; CYP27B1 activity is stimulated by the inner-membrane lipid cardiolipin. The outer-membrane location is not supported. Proposed replacements: mitochondrial inner membrane Supporting Evidence: file:human/CYP27B1/CYP27B1-uniprot.txt Activated by cardiolipin and dioleoyl phosphatidylethanolamine (DOPE), phospholipids found in the inner mitochondrial membrane. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. |
| GO:0006766 vitamin metabolic process | TAS Reactome:R-HSA-211916 | MODIFY | Summary: Vitamin metabolic process is a very high-level Reactome-derived term. Reason: The specific process is the formation of hormonally active vitamin D3 (vitamin D3 biosynthetic process). Proposed replacements: vitamin D3 biosynthetic process Supporting Evidence: file:human/CYP27B1/CYP27B1-uniprot.txt Catalyzes the rate-limiting step in the activation of vitamin D in the kidney |
| GO:0006816 calcium ion transport | ISS GO_REF:0000024 | REMOVE | Summary: Calcium ion transport transferred by sequence similarity. Reason: CYP27B1 is an enzyme and does not transport calcium; any effect on calcium transport is indirect, through calcitriol acting on VDR target genes in intestine and kidney. Supporting Evidence: file:human/CYP27B1/CYP27B1-uniprot.txt Catalyzes the rate-limiting step in the activation of vitamin D in the kidney |
| GO:0008285 negative regulation of cell population proliferation | IDA PMID:16549446 Human mammary epithelial cells express CYP27B1 and are growt... | KEEP AS NON CORE | Summary: Local calcitriol synthesis by CYP27B1 mediates antiproliferative and prodifferentiative effects of 25(OH)D3 in keratinocytes and mammary epithelial cells. Reason: Gene-disruption and cell studies show these effects require CYP27B1 (PMID:12496369, PMID:16549446), but they are mediated by the product acting through VDR; non-core, autocrine consequences. Supporting Evidence: PMID:12496369 It was found that 1alpha-hydroxylase inactivation blocked the antiproliferative and prodifferentiative effect of 25-OHD(3). PMID:16549446 No induction of CYP24 by 25(OH)D3 was observed in mammary cells derived from CYP27B1 null mice. |
| GO:0016705 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen | IEA GO_REF:0000120 | MODIFY | Summary: Generic monooxygenase parent terms of the specific 25-hydroxyvitamin D 1-alpha-hydroxylase activity. Reason: Correct but uninformative; the specific activity is calcidiol 1-monooxygenase activity (GO:0004498). Proposed replacements: calcidiol 1-monooxygenase activity Supporting Evidence: file:human/CYP27B1/CYP27B1-uniprot.txt Catalyzes the rate-limiting step in the activation of vitamin D in the kidney |
| GO:0020037 heme binding | IEA GO_REF:0000002 | ACCEPT | Summary: CYP27B1 is a heme-thiolate cytochrome P450. Reason: Heme is the catalytic cofactor of all cytochrome P450 monooxygenases, including CYP27B1 (PMID:22862690); supporting function. Supporting Evidence: PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. |
| GO:0030282 bone mineralization | IEP PMID:17023519 Evidence for auto/paracrine actions of vitamin D in bone: 1a... | KEEP AS NON CORE | Summary: Osteoblast 1-alpha-hydroxylase activity produces calcitriol that promotes mineralization in culture. Reason: Expression-based (IEP) and indirect, via locally produced calcitriol (PMID:17023519). Supporting Evidence: PMID:17023519 This study showing expression, activity, and functionality of 1alpha-hydroxylase unequivocally demonstrates that vitamin D can act in an auto/paracrine manner in bone. |
| GO:0030308 negative regulation of cell growth | IMP PMID:12496369 Targeted disruption of the 25-hydroxyvitamin D3 1alpha-hydro... | KEEP AS NON CORE | Summary: Local calcitriol synthesis by CYP27B1 mediates antiproliferative and prodifferentiative effects of 25(OH)D3 in keratinocytes and mammary epithelial cells. Reason: Gene-disruption and cell studies show these effects require CYP27B1 (PMID:12496369, PMID:16549446), but they are mediated by the product acting through VDR; non-core, autocrine consequences. Supporting Evidence: PMID:12496369 It was found that 1alpha-hydroxylase inactivation blocked the antiproliferative and prodifferentiative effect of 25-OHD(3). PMID:16549446 No induction of CYP24 by 25(OH)D3 was observed in mammary cells derived from CYP27B1 null mice. |
| GO:0030500 regulation of bone mineralization | IMP PMID:9415400 Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and... | KEEP AS NON CORE | Summary: CYP27B1 deficiency (VDDR1) disrupts calcium homeostasis and bone mineralization. Reason: Supported by the human genetics (PMID:9415400), but the effect is downstream of calcitriol production and VDR signalling; physiological, non-core consequence. Supporting Evidence: PMID:9415400 These findings establish the molecular genetic basis of VDDR-1 |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000044 | MODIFY | Summary: Generic mitochondrial membrane location. Reason: Correct but the specific membrane is the inner mitochondrial membrane, as for other adrenodoxin-dependent P450s. Proposed replacements: mitochondrial inner membrane Supporting Evidence: file:human/CYP27B1/CYP27B1-uniprot.txt Activated by cardiolipin and dioleoyl phosphatidylethanolamine (DOPE), phospholipids found in the inner mitochondrial membrane. |
| GO:0032496 response to lipopolysaccharide | IDA PMID:12855575 Regulation of 25-hydroxyvitamin D3-1 alpha-hydroxylase and p... | KEEP AS NON CORE | Summary: CYP27B1 expression/activity is induced by LPS and IFN-gamma in myeloid cells, by estrogens in vascular smooth muscle, and is feedback-regulated by vitamin D. Reason: These reflect regulation of CYP27B1 expression rather than a function of the protein; accurate as responses but not core. Supporting Evidence: PMID:12855575 which was increased after stimulation with lipopolysaccharide (LPS) PMID:9282826 p17 shares with IFN-gamma the ability to induce 1alpha-hydroxylase activity PMID:15795327 Estradiol-17beta and biochainin A also increased the generation of 1,25(OH)2D3 |
| GO:0033280 response to vitamin D | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: CYP27B1 expression/activity is induced by LPS and IFN-gamma in myeloid cells, by estrogens in vascular smooth muscle, and is feedback-regulated by vitamin D. Reason: These reflect regulation of CYP27B1 expression rather than a function of the protein; accurate as responses but not core. Supporting Evidence: PMID:12855575 which was increased after stimulation with lipopolysaccharide (LPS) PMID:9282826 p17 shares with IFN-gamma the ability to induce 1alpha-hydroxylase activity PMID:15795327 Estradiol-17beta and biochainin A also increased the generation of 1,25(OH)2D3 |
| GO:0033280 response to vitamin D | IDA PMID:16549446 Human mammary epithelial cells express CYP27B1 and are growt... | KEEP AS NON CORE | Summary: CYP27B1 expression/activity is induced by LPS and IFN-gamma in myeloid cells, by estrogens in vascular smooth muscle, and is feedback-regulated by vitamin D. Reason: These reflect regulation of CYP27B1 expression rather than a function of the protein; accurate as responses but not core. Supporting Evidence: PMID:12855575 which was increased after stimulation with lipopolysaccharide (LPS) PMID:9282826 p17 shares with IFN-gamma the ability to induce 1alpha-hydroxylase activity PMID:15795327 Estradiol-17beta and biochainin A also increased the generation of 1,25(OH)2D3 |
| GO:0034341 response to type II interferon | IDA PMID:9282826 HIV-1 p17 and IFN-gamma both induce fructose 1,6-bisphosphat... | KEEP AS NON CORE | Summary: CYP27B1 expression/activity is induced by LPS and IFN-gamma in myeloid cells, by estrogens in vascular smooth muscle, and is feedback-regulated by vitamin D. Reason: These reflect regulation of CYP27B1 expression rather than a function of the protein; accurate as responses but not core. Supporting Evidence: PMID:12855575 which was increased after stimulation with lipopolysaccharide (LPS) PMID:9282826 p17 shares with IFN-gamma the ability to induce 1alpha-hydroxylase activity PMID:15795327 Estradiol-17beta and biochainin A also increased the generation of 1,25(OH)2D3 |
| GO:0042359 vitamin D metabolic process | TAS Reactome:R-HSA-196791 | ACCEPT | Summary: CYP27B1 catalyses the final, rate-limiting activation step in the synthesis of hormonally active vitamin D (calcitriol). Reason: Direct biochemical evidence for production of 1,25(OH)2D3 from 25(OH)D3 in many systems (PMID:9415400, PMID:22862690) and loss in VDDR1A; core process. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. file:human/CYP27B1/CYP27B1-uniprot.txt Catalyzes the rate-limiting step in the activation of vitamin D in the kidney |
| GO:0042368 vitamin D biosynthetic process | IEA GO_REF:0000041 | ACCEPT | Summary: CYP27B1 catalyses the final, rate-limiting activation step in the synthesis of hormonally active vitamin D (calcitriol). Reason: Direct biochemical evidence for production of 1,25(OH)2D3 from 25(OH)D3 in many systems (PMID:9415400, PMID:22862690) and loss in VDDR1A; core process. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. file:human/CYP27B1/CYP27B1-uniprot.txt Catalyzes the rate-limiting step in the activation of vitamin D in the kidney |
| GO:0042369 vitamin D catabolic process | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Vitamin D catabolic process inferred from family members (CYP24A1-type activity). Reason: CYP27B1 can 1-alpha-hydroxylate intermediates of the CYP24A1 inactivation pathway (PMID:22862690), but the product 1,24,25(OH)3D3 is an active VDR ligand; CYP27B1's role is activation, and catabolism is performed by CYP24A1. Supporting Evidence: PMID:22862690 Human CYP27B1 was also active on 25-hydroxyvitamin D(2) and on intermediates of the CYP24A1-mediated inactivation pathway, 24R,25-dihydroxyvitamin D3 file:human/CYP27B1/CYP27B1-uniprot.txt Catalyzes the rate-limiting step in the activation of vitamin D in the kidney |
| GO:0042369 vitamin D catabolic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Vitamin D catabolic process inferred from family members (CYP24A1-type activity). Reason: CYP27B1 can 1-alpha-hydroxylate intermediates of the CYP24A1 inactivation pathway (PMID:22862690), but the product 1,24,25(OH)3D3 is an active VDR ligand; CYP27B1's role is activation, and catabolism is performed by CYP24A1. Supporting Evidence: PMID:22862690 Human CYP27B1 was also active on 25-hydroxyvitamin D(2) and on intermediates of the CYP24A1-mediated inactivation pathway, 24R,25-dihydroxyvitamin D3 file:human/CYP27B1/CYP27B1-uniprot.txt Catalyzes the rate-limiting step in the activation of vitamin D in the kidney |
| GO:0043627 response to estrogen | IDA PMID:15795327 25-hydroxyvitamin D3-1alpha-hydroxylase is expressed in huma... | KEEP AS NON CORE | Summary: CYP27B1 expression/activity is induced by LPS and IFN-gamma in myeloid cells, by estrogens in vascular smooth muscle, and is feedback-regulated by vitamin D. Reason: These reflect regulation of CYP27B1 expression rather than a function of the protein; accurate as responses but not core. Supporting Evidence: PMID:12855575 which was increased after stimulation with lipopolysaccharide (LPS) PMID:9282826 p17 shares with IFN-gamma the ability to induce 1alpha-hydroxylase activity PMID:15795327 Estradiol-17beta and biochainin A also increased the generation of 1,25(OH)2D3 |
| GO:0045618 positive regulation of keratinocyte differentiation | IMP PMID:12496369 Targeted disruption of the 25-hydroxyvitamin D3 1alpha-hydro... | KEEP AS NON CORE | Summary: Local calcitriol synthesis by CYP27B1 mediates antiproliferative and prodifferentiative effects of 25(OH)D3 in keratinocytes and mammary epithelial cells. Reason: Gene-disruption and cell studies show these effects require CYP27B1 (PMID:12496369, PMID:16549446), but they are mediated by the product acting through VDR; non-core, autocrine consequences. Supporting Evidence: PMID:12496369 It was found that 1alpha-hydroxylase inactivation blocked the antiproliferative and prodifferentiative effect of 25-OHD(3). PMID:16549446 No induction of CYP24 by 25(OH)D3 was observed in mammary cells derived from CYP27B1 null mice. |
| GO:0055074 calcium ion homeostasis | IMP PMID:9415400 Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and... | KEEP AS NON CORE | Summary: CYP27B1 deficiency (VDDR1) disrupts calcium homeostasis and bone mineralization. Reason: Supported by the human genetics (PMID:9415400), but the effect is downstream of calcitriol production and VDR signalling; physiological, non-core consequence. Supporting Evidence: PMID:9415400 These findings establish the molecular genetic basis of VDDR-1 |
| GO:0062185 secalciferol 1-monooxygenase activity | IDA PMID:10518789 Enzymatic properties of human 25-hydroxyvitamin D3 1alpha-hy... | ACCEPT | Summary: CYP27B1 1-alpha-hydroxylates 24R,25-dihydroxyvitamin D3 (secalciferol) to 1,24,25-trihydroxyvitamin D3. Reason: Direct kinetic evidence with recombinant human enzyme shows 24R,25(OH)2D3 is an efficient substrate (PMID:10518789, PMID:22862690). Real but secondary to calcidiol 1-hydroxylation. Supporting Evidence: PMID:10518789 The lower Km value and higher Vmax/Km value for (24R),25(OH)2D3 indicated that it is a better substrate than 25(OH)D3 for 1alpha-hydroxylase. PMID:22862690 Human CYP27B1 was also active on 25-hydroxyvitamin D(2) and on intermediates of the CYP24A1-mediated inactivation pathway, 24R,25-dihydroxyvitamin D3 |
| GO:0062185 secalciferol 1-monooxygenase activity | IEA GO_REF:0000116 | ACCEPT | Summary: CYP27B1 1-alpha-hydroxylates 24R,25-dihydroxyvitamin D3 (secalciferol) to 1,24,25-trihydroxyvitamin D3. Reason: Direct kinetic evidence with recombinant human enzyme shows 24R,25(OH)2D3 is an efficient substrate (PMID:10518789, PMID:22862690). Real but secondary to calcidiol 1-hydroxylation. Supporting Evidence: PMID:10518789 The lower Km value and higher Vmax/Km value for (24R),25(OH)2D3 indicated that it is a better substrate than 25(OH)D3 for 1alpha-hydroxylase. PMID:22862690 Human CYP27B1 was also active on 25-hydroxyvitamin D(2) and on intermediates of the CYP24A1-mediated inactivation pathway, 24R,25-dihydroxyvitamin D3 |
| GO:0070314 G1 to G0 transition | IMP PMID:12496369 Targeted disruption of the 25-hydroxyvitamin D3 1alpha-hydro... | KEEP AS NON CORE | Summary: Local calcitriol synthesis by CYP27B1 mediates antiproliferative and prodifferentiative effects of 25(OH)D3 in keratinocytes and mammary epithelial cells. Reason: Gene-disruption and cell studies show these effects require CYP27B1 (PMID:12496369, PMID:16549446), but they are mediated by the product acting through VDR; non-core, autocrine consequences. Supporting Evidence: PMID:12496369 It was found that 1alpha-hydroxylase inactivation blocked the antiproliferative and prodifferentiative effect of 25-OHD(3). PMID:16549446 No induction of CYP24 by 25(OH)D3 was observed in mammary cells derived from CYP27B1 null mice. |
| GO:0070564 positive regulation of vitamin D receptor signaling pathway | IDA PMID:16549446 Human mammary epithelial cells express CYP27B1 and are growt... | KEEP AS NON CORE | Summary: CYP27B1 produces the VDR ligand and so enables VDR signalling from 25(OH)D3. Reason: Supported (PMID:16549446) and biologically sensible, but it describes the downstream consequence of ligand production. Supporting Evidence: PMID:16549446 No induction of CYP24 by 25(OH)D3 was observed in mammary cells derived from CYP27B1 null mice. |
| GO:0071305 cellular response to vitamin D | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CYP27B1 expression/activity is induced by LPS and IFN-gamma in myeloid cells, by estrogens in vascular smooth muscle, and is feedback-regulated by vitamin D. Reason: These reflect regulation of CYP27B1 expression rather than a function of the protein; accurate as responses but not core. Supporting Evidence: PMID:12855575 which was increased after stimulation with lipopolysaccharide (LPS) PMID:9282826 p17 shares with IFN-gamma the ability to induce 1alpha-hydroxylase activity PMID:15795327 Estradiol-17beta and biochainin A also increased the generation of 1,25(OH)2D3 |
| GO:1901755 vitamin D3 biosynthetic process | IDA PMID:15795327 25-hydroxyvitamin D3-1alpha-hydroxylase is expressed in huma... | ACCEPT | Summary: CYP27B1 catalyses the final, rate-limiting activation step in the synthesis of hormonally active vitamin D (calcitriol). Reason: Direct biochemical evidence for production of 1,25(OH)2D3 from 25(OH)D3 in many systems (PMID:9415400, PMID:22862690) and loss in VDDR1A; core process. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. file:human/CYP27B1/CYP27B1-uniprot.txt Catalyzes the rate-limiting step in the activation of vitamin D in the kidney |
| GO:1901755 vitamin D3 biosynthetic process | IDA PMID:16549446 Human mammary epithelial cells express CYP27B1 and are growt... | ACCEPT | Summary: CYP27B1 catalyses the final, rate-limiting activation step in the synthesis of hormonally active vitamin D (calcitriol). Reason: Direct biochemical evidence for production of 1,25(OH)2D3 from 25(OH)D3 in many systems (PMID:9415400, PMID:22862690) and loss in VDDR1A; core process. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. file:human/CYP27B1/CYP27B1-uniprot.txt Catalyzes the rate-limiting step in the activation of vitamin D in the kidney |
| GO:1901755 vitamin D3 biosynthetic process | IDA PMID:17023519 Evidence for auto/paracrine actions of vitamin D in bone: 1a... | ACCEPT | Summary: CYP27B1 catalyses the final, rate-limiting activation step in the synthesis of hormonally active vitamin D (calcitriol). Reason: Direct biochemical evidence for production of 1,25(OH)2D3 from 25(OH)D3 in many systems (PMID:9415400, PMID:22862690) and loss in VDDR1A; core process. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. file:human/CYP27B1/CYP27B1-uniprot.txt Catalyzes the rate-limiting step in the activation of vitamin D in the kidney |
| GO:1901755 vitamin D3 biosynthetic process | IDA PMID:22862690 Expression of human CYP27B1 in Escherichia coli and characte... | ACCEPT | Summary: CYP27B1 catalyses the final, rate-limiting activation step in the synthesis of hormonally active vitamin D (calcitriol). Reason: Direct biochemical evidence for production of 1,25(OH)2D3 from 25(OH)D3 in many systems (PMID:9415400, PMID:22862690) and loss in VDDR1A; core process. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. file:human/CYP27B1/CYP27B1-uniprot.txt Catalyzes the rate-limiting step in the activation of vitamin D in the kidney |
| GO:1901755 vitamin D3 biosynthetic process | IDA PMID:9415400 Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and... | ACCEPT | Summary: CYP27B1 catalyses the final, rate-limiting activation step in the synthesis of hormonally active vitamin D (calcitriol). Reason: Direct biochemical evidence for production of 1,25(OH)2D3 from 25(OH)D3 in many systems (PMID:9415400, PMID:22862690) and loss in VDDR1A; core process. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. file:human/CYP27B1/CYP27B1-uniprot.txt Catalyzes the rate-limiting step in the activation of vitamin D in the kidney |
| GO:1901755 vitamin D3 biosynthetic process | IEA GO_REF:0000107 | ACCEPT | Summary: CYP27B1 catalyses the final, rate-limiting activation step in the synthesis of hormonally active vitamin D (calcitriol). Reason: Direct biochemical evidence for production of 1,25(OH)2D3 from 25(OH)D3 in many systems (PMID:9415400, PMID:22862690) and loss in VDDR1A; core process. Supporting Evidence: PMID:9415400 Mammalian cells transfected with the cloned P450c1 alpha cDNA exhibit robust 1 alpha-hydroxylase activity. PMID:22862690 CYP27B1 is a mitochondrial cytochrome P450 that catalyses the hydroxylation of 25-hydroxyvitamin D3 at the C1Ξ±-position to give the hormonally active form of vitamin D3, 1Ξ±,25-dihydroxyvitamin D3. file:human/CYP27B1/CYP27B1-uniprot.txt Catalyzes the rate-limiting step in the activation of vitamin D in the kidney |
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Download this section (compressed HTML)Q: How much of circulating 1,24,25(OH)3D3 is produced by CYP27B1 acting on CYP24A1 products, and does it have a distinct physiological role?
Q: What is the relative contribution of extrarenal CYP27B1 (macrophage, keratinocyte, bone) to systemic calcitriol in granulomatous disease versus health?
Experiment: Cell-type-specific Cyp27b1 deletion (renal proximal tubule versus myeloid versus osteoblast) with measurement of serum and tissue calcitriol to partition endocrine versus local contributions.
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