ID CP24A_HUMAN Reviewed; 514 AA. AC Q07973; Q15807; Q32ML3; Q5I2W7; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 18-OCT-2001, sequence version 2. DT 09-JUL-2014, entry version 130. DE RecName: Full=1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial; DE Short=24-OHase; DE Short=Vitamin D(3) 24-hydroxylase; DE EC=1.14.13.126; DE AltName: Full=Cytochrome P450 24A1; DE AltName: Full=Cytochrome P450-CC24; DE Flags: Precursor; GN Name=CYP24A1; Synonyms=CYP24; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=8506296; DOI=10.1073/pnas.90.10.4543; RA Chen K.-S., Prahl J.M., Deluca H.F.; RT "Isolation and expression of human 1,25-dihydroxyvitamin D3 24- RT hydroxylase cDNA."; RL Proc. Natl. Acad. Sci. U.S.A. 90:4543-4547(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3). RX PubMed=15788398; DOI=10.1074/jbc.M414522200; RA Ren S., Nguyen L., Wu S., Encinas C., Adams J.S., Hewison M.; RT "Alternative splicing of vitamin D-24-hydroxylase: a novel mechanism RT for the regulation of extrarenal 1,25-dihydroxyvitamin D synthesis."; RL J. Biol. Chem. 280:20604-20611(2005). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=11780052; DOI=10.1038/414865a; RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., RA Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 20."; RL Nature 414:865-871(2001). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-104. RX PubMed=7632726; RA Chen K.-S., DeLuca H.F.; RT "Cloning of the human 1 alpha,25-dihydroxyvitamin D-3 24-hydroxylase RT gene promoter and identification of two vitamin D-responsive RT elements."; RL Biochim. Biophys. Acta 1263:1-9(1995). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 258-514 (ISOFORM 1). RX PubMed=8266831; DOI=10.1002/jbmr.5650081114; RA Labuda M., Lemieux N., Tihy F., Prinster C., Glorieux F.H.; RT "Human 25-hydroxyvitamin D 24-hydroxylase cytochrome P450 subunit maps RT to a different chromosomal location than that of pseudovitamin D- RT deficient rickets."; RL J. Bone Miner. Res. 8:1397-1406(1993). RN [7] RP SUBSTRATE SPECIFICITY. RX PubMed=15574355; DOI=10.2741/1514; RA Sakaki T., Kagawa N., Yamamoto K., Inouye K.; RT "Metabolism of vitamin D3 by cytochromes P450."; RL Front. Biosci. 10:119-134(2005). RN [8] RP VARIANTS HCAI GLU-143 DEL; GLN-159; LYS-322; TRP-396 AND SER-409, AND RP CHARACTERIZATION OF VARIANTS HCAI GLU-143 DEL; GLN-159; LYS-322; RP TRP-396 AND SER-409. RX PubMed=21675912; DOI=10.1056/NEJMoa1103864; RA Schlingmann K.P., Kaufmann M., Weber S., Irwin A., Goos C., John U., RA Misselwitz J., Klaus G., Kuwertz-Broking E., Fehrenbach H., RA Wingen A.M., Guran T., Hoenderop J.G., Bindels R.J., Prosser D.E., RA Jones G., Konrad M.; RT "Mutations in CYP24A1 and idiopathic infantile hypercalcemia."; RL N. Engl. J. Med. 365:410-421(2011). CC -!- FUNCTION: Has a role in maintaining calcium homeostasis. Catalyzes CC the NADPH-dependent 24-hydroxylation of calcidiol (25- CC hydroxyvitamin D(3)) and calcitriol (1-alpha,25-dihydroxyvitamin CC D(3)). The enzyme can perform up to 6 rounds of hydroxylation of CC calcitriol leading to calcitroic acid. It also shows 23- CC hydroxylating activity leading to 1-alpha,25-dihydroxyvitamin CC D(3)-26,23-lactone as end product. CC -!- CATALYTIC ACTIVITY: Calcitriol + NADPH + O(2) = calcitetrol + CC NADP(+) + H(2)O. CC -!- CATALYTIC ACTIVITY: Calcidiol + NADPH + O(2) = secalciferol + CC NADP(+) + H(2)O. CC -!- COFACTOR: Heme group (By similarity). CC -!- SUBCELLULAR LOCATION: Mitochondrion. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q07973-1; Sequence=Displayed; CC Name=2; CC IsoId=Q07973-2; Sequence=VSP_043101; CC Note=No experimental confirmation available; CC Name=3; Synonyms=CYP24-SV; CC IsoId=Q07973-3; Sequence=VSP_053367, VSP_053368; CC Note=Specifically expressed in macrophages. Lacks the transit CC peptide. May be a dominant negative-acting isoform possibly by CC sequestering vitamin D metabolites; CC -!- DISEASE: Hypercalcemia infantile (HCAI) [MIM:143880]: A disorder CC characterized by abnormally high level of calcium in the blood, CC failure to thrive, vomiting, dehydration, and nephrocalcinosis. CC Note=The disease is caused by mutations affecting the gene CC represented in this entry. CC -!- SIMILARITY: Belongs to the cytochrome P450 family. 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; L13286; AAA62379.1; -; mRNA. DR EMBL; AY858838; AAW50795.1; -; mRNA. DR EMBL; AL138805; CAB91829.1; -; Genomic_DNA. DR EMBL; AL138805; CAM27343.1; -; Genomic_DNA. DR EMBL; BC109083; AAI09084.1; -; mRNA. DR EMBL; BC109084; AAI09085.1; -; mRNA. DR EMBL; U60669; AAB03776.1; ALT_SEQ; Genomic_DNA. DR EMBL; S67623; AAB29308.1; -; mRNA. DR CCDS; CCDS33491.1; -. [Q07973-1] DR CCDS; CCDS46616.1; -. [Q07973-2] DR PIR; A47436; A47436. DR PIR; I55488; I55488. DR RefSeq; NP_000773.2; NM_000782.4. [Q07973-1] DR RefSeq; NP_001122387.1; NM_001128915.1. [Q07973-2] DR RefSeq; XP_005260361.1; XM_005260304.2. [Q07973-1] DR UniGene; Hs.89663; -. DR ProteinModelPortal; Q07973; -. DR SMR; Q07973; 51-514. DR BioGrid; 107963; 2. DR IntAct; Q07973; 1. DR MINT; MINT-6773699; -. DR STRING; 9606.ENSP00000216862; -. DR BindingDB; Q07973; -. DR ChEMBL; CHEMBL4521; -. DR DrugBank; DB00146; Calcidiol. DR DrugBank; DB00136; Calcitriol. DR DrugBank; DB00169; Cholecalciferol. DR DrugBank; DB00153; Ergocalciferol. DR DrugBank; DB00910; Paricalcitol. DR PhosphoSite; Q07973; -. DR DMDM; 19862747; -. DR MaxQB; Q07973; -. DR PaxDb; Q07973; -. DR PRIDE; Q07973; -. DR Ensembl; ENST00000216862; ENSP00000216862; ENSG00000019186. [Q07973-1] DR Ensembl; ENST00000395954; ENSP00000379284; ENSG00000019186. [Q07973-3] DR Ensembl; ENST00000395955; ENSP00000379285; ENSG00000019186. [Q07973-2] DR GeneID; 1591; -. DR KEGG; hsa:1591; -. DR UCSC; uc002xwv.2; human. [Q07973-1] DR UCSC; uc002xww.2; human. [Q07973-2] DR CTD; 1591; -. DR GeneCards; GC20M052769; -. DR HGNC; HGNC:2602; CYP24A1. DR HPA; HPA022261; -. DR MIM; 126065; gene. DR MIM; 143880; phenotype. DR neXtProt; NX_Q07973; -. DR Orphanet; 300547; Autosomal recessive infantile hypercalcemia. DR PharmGKB; PA27097; -. DR eggNOG; COG2124; -. DR HOGENOM; HOG000276540; -. DR HOVERGEN; HBG099053; -. DR InParanoid; Q07973; -. DR KO; K07436; -. DR OMA; QHDTLAE; -. DR OrthoDB; EOG7ZGX4B; -. DR PhylomeDB; Q07973; -. DR TreeFam; TF105094; -. DR BioCyc; MetaCyc:HS00395-MONOMER; -. DR Reactome; REACT_111217; Metabolism. DR Reactome; REACT_15493; Steroid hormones. DR SABIO-RK; Q07973; -. DR GeneWiki; CYP24A1; -. DR GenomeRNAi; 1591; -. DR NextBio; 6538; -. DR PRO; PR:Q07973; -. DR ArrayExpress; Q07973; -. DR Bgee; Q07973; -. DR CleanEx; HS_CYP24A1; -. DR Genevestigator; Q07973; -. DR GO; GO:0005743; C:mitochondrial inner membrane; TAS:Reactome. DR GO; GO:0030342; F:1-alpha,25-dihydroxyvitamin D3 24-hydroxylase activity; IDA:UniProtKB. DR GO; GO:0008403; F:25-hydroxycholecalciferol-24-hydroxylase activity; IEA:Ensembl. DR GO; GO:0020037; F:heme binding; TAS:UniProtKB. DR GO; GO:0005506; F:iron ion binding; IEA:InterPro. DR GO; GO:0016491; F:oxidoreductase activity; NAS:UniProtKB. DR GO; GO:0001649; P:osteoblast differentiation; IEP:BHF-UCL. DR GO; GO:0055114; P:oxidation-reduction process; IDA:UniProtKB. DR GO; GO:0033280; P:response to vitamin D; IDA:BHF-UCL. DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome. DR GO; GO:0008202; P:steroid metabolic process; TAS:Reactome. DR GO; GO:0042369; P:vitamin D catabolic process; NAS:BHF-UCL. DR GO; GO:0042359; P:vitamin D metabolic process; TAS:Reactome. DR GO; GO:0070561; P:vitamin D receptor signaling pathway; NAS:BHF-UCL. DR GO; GO:0006766; P:vitamin metabolic process; TAS:Reactome. DR GO; GO:0006805; P:xenobiotic 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 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 Alternative splicing; Complete proteome; Disease mutation; Heme; Iron; KW Metal-binding; Mitochondrion; Monooxygenase; NADP; Oxidoreductase; KW Polymorphism; Reference proteome; Transit peptide. FT TRANSIT 1 35 Mitochondrion (By similarity). FT CHAIN 36 514 1,25-dihydroxyvitamin D(3) 24- FT hydroxylase, mitochondrial. FT /FTId=PRO_0000003615. FT METAL 462 462 Iron (heme axial ligand) (By similarity). FT VAR_SEQ 1 8 MSSPISKS -> MYSCFSHR (in isoform 3). FT /FTId=VSP_053367. FT VAR_SEQ 9 150 Missing (in isoform 3). FT /FTId=VSP_053368. FT VAR_SEQ 413 478 Missing (in isoform 2). FT /FTId=VSP_043101. FT VARIANT 143 143 Missing (in HCAI; complete loss of FT function). FT /FTId=VAR_066408. FT VARIANT 157 157 R -> Q (in dbSNP:rs35051736). FT /FTId=VAR_048464. FT VARIANT 159 159 R -> Q (in HCAI; complete loss of FT function). FT /FTId=VAR_066409. FT VARIANT 322 322 E -> K (in HCAI; complete loss of FT function). FT /FTId=VAR_066410. FT VARIANT 374 374 M -> T (in dbSNP:rs6022990). FT /FTId=VAR_048465. FT VARIANT 396 396 R -> W (in HCAI; complete loss of FT function; dbSNP:rs114368325). FT /FTId=VAR_066411. FT VARIANT 409 409 L -> S (in HCAI; retains small but FT measurable levels of activity; FT dbSNP:rs6068812). FT /FTId=VAR_048466. FT CONFLICT 68 68 G -> A (in Ref. 1; AAA62379/AAB03776). FT CONFLICT 124 125 AY -> V (in Ref. 1; AAA62379). FT CONFLICT 270 270 D -> G (in Ref. 1; AAA62379). FT CONFLICT 365 365 V -> R (in Ref. 1; AAA62379). FT CONFLICT 368 368 A -> E (in Ref. 1; AAA62379). FT CONFLICT 390 390 S -> G (in Ref. 1; AAA62379). FT CONFLICT 511 511 F -> S (in Ref. 6; AAB29308). SQ SEQUENCE 514 AA; 58875 MW; 8862F63771981195 CRC64; MSSPISKSRS LAAFLQQLRS PRQPPRLVTS TAYTSPQPRE VPVCPLTAGG ETQNAAALPG PTSWPLLGSL LQILWKGGLK KQHDTLVEYH KKYGKIFRMK LGSFESVHLG SPCLLEALYR TESAYPQRLE IKPWKAYRDY RKEGYGLLIL EGEDWQRVRS AFQKKLMKPG EVMKLDNKIN EVLADFMGRI DELCDERGHV EDLYSELNKW SFESICLVLY EKRFGLLQKN AGDEAVNFIM AIKTMMSTFG RMMVTPVELH KSLNTKVWQD HTLAWDTIFK SVKACIDNRL EKYSQQPSAD FLCDIYHQNR LSKKELYAAV TELQLAAVET TANSLMWILY NLSRNPQVQQ KLLKEIQSVL PENQVPRAED LRNMPYLKAC LKESMRLTPS VPFTTRTLDK ATVLGEYALP KGTVLMLNTQ VLGSSEDNFE DSSQFRPERW LQEKEKINPF AHLPFGVGKR MCIGRRLAEL QLHLALCWIV RKYDIQATDN EPVEMLHSGT LVPSRELPIA FCQR //