CYP24A1

CYP24A1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3K9V, 3K9Y
Identifiers
Aliases	CYP24A1 , CP24, CYP24, HCAI, P450-CC24, cytochrome P450 family 24 subfamily A member 1, HCINF1
External IDs	OMIM: 126065; MGI: 88593; HomoloGene: 68094; GeneCards: CYP24A1; OMA:CYP24A1 - orthologs
Gene location (Human) Chr. Chromosome 20 (human) [1] Band 20q13.2 Start 54,153,446 bp [1] End 54,173,986 bp [1]
Gene location (Mouse) Chr. Chromosome 2 (mouse) [2] Band 2 H3|2 91.91 cM Start 170,324,628 bp [2] End 170,339,065 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in olfactory zone of nasal mucosa secondary oocyte testicle mucosa of urinary bladder human kidney epithelium of nasopharynx gonad gingival epithelium palpebral conjunctiva tonsil Top expressed in right kidney human kidney renal cortex proximal tubule corneal stroma embryo epiblast axial skeleton efferent ductule lactiferous gland More reference expression data BioGPS More reference expression data
Gene ontology Molecular function iron ion binding 25-hydroxycholecalciferol-24-hydroxylase activity metal ion binding monooxygenase activity heme binding oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen oxidoreductase activity 1-alpha,25-dihydroxyvitamin D3 24-hydroxylase activity Cellular component plasma membrane nucleoplasm mitochondrion nucleus mitochondrial outer membrane Biological process response to vitamin D vitamin D metabolic process vitamin metabolic process osteoblast differentiation vitamin D catabolic process vitamin D receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1591 13081 Ensembl ENSG00000019186 ENSMUSG00000038567 UniProt Q07973 Q64441 RefSeq (mRNA) NM_000782 NM_001128915 NM_009996 RefSeq (protein) NP_000773 NP_001122387 NP_034126 Location (UCSC) Chr 20: 54.15 – 54.17 Mb Chr 2: 170.32 – 170.34 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Cytochrome P450 family 24 subfamily A member 1 (abbreviated CYP24A1) is a member of the cytochrome P450 superfamily of enzymes encoded by the CYP24A1 gene. It is a mitochondrial monooxygenase which catalyzes reactions including 24-hydroxylation of calcitriol (1,25-dihydroxyvitamin D₃). ^[5] It has also been identified as vitamin D3 24-hydroxylase.(EC 1.14.15.16)

Function

CYP24A1 is an enzyme expressed in the mitochondrion of humans and other species. It catalyzes hydroxylation reactions which lead to the degradation of 1,25-dihydroxyvitamin D₃, the physiologically active form of vitamin D. Hydroxylation of the side chain produces calcitroic acid and other metabolites which are excreted in bile. ^{[5] [6]}

CYP24A1 was identified in the early 1970s and was first thought to be involved in vitamin D metabolism as the renal 25-hydroxyvitamin D3-24-hydroxylase, modifying calcifediol (25-hydroxyvitamin D) to produce 24,25-dihydroxycholecalciferol (24,25-dihydroxyvitamin D). Subsequent studies using recombinant CYP24A1 showed that it could also catalyze multiple other hydroxylation reactions at the side chain carbons known as C-24 and C-23 in both 25-OH-D₃ and the active hormonal form, 1,25-(OH)₂D₃. It is now considered responsible for the entire five-step, 24-oxidation pathway from 1,25-(OH)₂D₃ producing calcitroic acid. ^[6]

CYP24A1 also is able to catalyze another pathway which starts with 23-hydroxylation of 1,25-(OH)₂D₃ and culminates in 1,25-(OH)₂D₃-26,23-lactone. ^[6]

The side chains of the ergocalciferol (vitamin D₂) derivatives, 25-OH-D₂ and 1,25-(OH)₂D₂, are also hydroxylated by CYP24A1. ^[6]

The structure of CYP24A1 is highly conserved between different species although the balance of functions can differ. ^[6] Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

This enzyme plays an important role in calcium homeostasis and the vitamin D endocrine system through its regulation of the level of vitamin D₃.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

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|alt=Vitamin D Synthesis Pathway (view / edit)]]

Vitamin D Synthesis Pathway (view / edit)

1. The interactive pathway map can be edited at WikiPathways: "VitaminDSynthesis_WP1531".

Regulation

CYP24A1 is expressed in tissues which are considered targets for vitamin D, including kidney, intestine and bone. Transcription of the CYP24A1 gene is markedly inducible by 1,25-(OH)₂D₃ binding to the vitamin D receptor. ^[6] The gene has a strong, positive vitamin D response element in the promoter. Through regulation of CYP24A1 expression, a negative feedback control system is created to limit the effects of 1,25-(OH)₂D₃. ^[6]

PTH and FGF23 also regulate CYP24A1 gene expression. ^[6] Additionally, it is translationally regulated via IRES within the 5'UTR, which is responsive to an inflammatory environment. ^[7]

Clinical relevance

Abnormal functioning CYP24A1 is thought to be one of the causes of severe infantile hypercalcemia. ^[8] However, increasingly patients are also being diagnosed in adulthood, often when they present with hypercalcaemia. ^[9] Patients with mutations of the CYP24A1 gene have elevated serum calcium concentrations, elevated serum 1,25-(OH)₂D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and sometimes reduced bone density. Variations in the gene may also be found in people with renal stones. ^[10]

References

1. GRCh38: Ensembl release 89: ENSG00000019186 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000038567 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: CYP24A1 cytochrome P450, family 24, subfamily A, polypeptide 1".
6. Jones G, Prosser DE, Kaufmann M (January 2014). "Cytochrome P450-mediated metabolism of vitamin D". Journal of Lipid Research. 55 (1): 13–31. doi: 10.1194/jlr.R031534 . PMC   3927478 . PMID   23564710.
7. Rübsamen D, Kunze MM, Buderus V, Brauß TF, Bajer MM, Brüne B, Schmid T (1 January 2014). "Inflammatory conditions induce IRES-dependent translation of cyp24a1". PLOS ONE. 9 (1) e85314. Bibcode:2014PLoSO...985314R. doi: 10.1371/journal.pone.0085314 . PMC   3885688 . PMID   24416388.
8. Dauber A, Nguyen TT, Sochett E, Cole DE, Horst R, Abrams SA, Carpenter TO, Hirschhorn JN (February 2012). "Genetic defect in CYP24A1, the vitamin D 24-hydroxylase gene, in a patient with severe infantile hypercalcemia". The Journal of Clinical Endocrinology and Metabolism. 97 (2): E268-74. doi:10.1210/jc.2011-1972. PMC   3275367 . PMID   22112808.
9. Hill FJ, Sayer JA (2017). "Clinical and Biochemical Features of Patients with CYP24A1 Mutations". A Critical Evaluation of Vitamin D - Basic Overview. IntechOpen. doi:10.5772/64503. ISBN   978-953-51-3083-3. S2CID   54572220.
10. Tebben PJ, Singh RJ, Kumar R (October 2016). "Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment". Endocrine Reviews. 37 (5): 521–547. doi:10.1210/er.2016-1070. PMC   5045493 . PMID   27588937.

External links

• Human CYP24A1 genome location and CYP24A1 gene details page in the UCSC Genome Browser .

Further reading

• Okuda K, Usui E, Ohyama Y (August 1995). "Recent progress in enzymology and molecular biology of enzymes involved in vitamin D metabolism". Journal of Lipid Research. 36 (8): 1641–52. doi: 10.1016/S0022-2275(20)41484-1 . PMID   7595086.
• Chen KS, DeLuca HF (July 1995). "Cloning of the human 1 alpha,25-dihydroxyvitamin D-3 24-hydroxylase gene promoter and identification of two vitamin D-responsive elements". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1263 (1): 1–9. doi:10.1016/0167-4781(95)00060-t. PMID   7632726.
• Robertson NG, Khetarpal U, Gutiérrez-Espeleta GA, Bieber FR, Morton CC (September 1994). "Isolation of novel and known genes from a human fetal cochlear cDNA library using subtractive hybridization and differential screening". Genomics. 23 (1): 42–50. doi:10.1006/geno.1994.1457. hdl: 10669/15162 . PMID   7829101.
• Chen ML, Heinrich G, Ohyama YI, Okuda K, Omdahl JL, Chen TC, Holick MF (October 1994). "Expression of 25-hydroxyvitamin D3-24-hydroxylase mRNA in cultured human keratinocytes". Proceedings of the Society for Experimental Biology and Medicine. 207 (1): 57–61. doi:10.3181/00379727-207-43791. PMID   7938037. S2CID   22566441.
• Labuda M, Lemieux N, Tihy F, Prinster C, Glorieux FH (November 1993). "Human 25-hydroxyvitamin D 24-hydroxylase cytochrome P450 subunit maps to a different chromosomal location than that of pseudovitamin D-deficient rickets". Journal of Bone and Mineral Research. 8 (11): 1397–406. doi:10.1002/jbmr.5650081114. PMID   8266831. S2CID   32582996.
• Hahn CN, Baker E, Laslo P, May BK, Omdahl JL, Sutherland GR (1993). "Localization of the human vitamin D 24-hydroxylase gene (CYP24) to chromosome 20q13.2→q13.3". Cytogenetics and Cell Genetics. 62 (4): 192–3. doi:10.1159/000133473. PMID   8440135.
• Chen KS, Prahl JM, DeLuca HF (May 1993). "Isolation and expression of human 1,25-dihydroxyvitamin D3 24-hydroxylase cDNA". Proceedings of the National Academy of Sciences of the United States of America. 90 (10): 4543–7. Bibcode:1993PNAS...90.4543C. doi: 10.1073/pnas.90.10.4543 . PMC   46548 . PMID   8506296.
• Bland R, Walker EA, Hughes SV, Stewart PM, Hewison M (May 1999). "Constitutive expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in a transformed human proximal tubule cell line: evidence for direct regulation of vitamin D metabolism by calcium". Endocrinology. 140 (5): 2027–34. doi: 10.1210/endo.140.5.6683 . PMID   10218951.
• Taniguchi T, Eto TA, Shiotsuki H, Sueta H, Higashi S, Iwamura T, Okuda KI, Setoguchi T (January 2001). "Newly established assay method for 25-hydroxyvitamin D3 24-hydroxylase revealed much lower Km for 25-hydroxyvitamin D3 than for 1alpha,25-dihydroxyvitamin D3". Journal of Bone and Mineral Research. 16 (1): 57–62. doi: 10.1359/jbmr.2001.16.1.57 . PMID   11149490. S2CID   23117091.
• Farhan H, Cross HS (November 2002). "Transcriptional inhibition of CYP24 by genistein". Annals of the New York Academy of Sciences. 973 (1): 459–62. Bibcode:2002NYASA.973..459F. doi:10.1111/j.1749-6632.2002.tb04683.x. PMID   12485911. S2CID   30861453.
• Theodoropoulos C, Demers C, Delvin E, Ménard D, Gascon-Barré M (April 2003). "Calcitriol regulates the expression of the genes encoding the three key vitamin D3 hydroxylases and the drug-metabolizing enzyme CYP3A4 in the human fetal intestine". Clinical Endocrinology. 58 (4): 489–99. doi:10.1046/j.1365-2265.2003.01743.x. PMID   12641633. S2CID   44330630.
• Fritsche J, Mondal K, Ehrnsperger A, Andreesen R, Kreutz M (November 2003). "Regulation of 25-hydroxyvitamin D3-1 alpha-hydroxylase and production of 1 alpha,25-dihydroxyvitamin D3 by human dendritic cells". Blood. 102 (9): 3314–6. doi: 10.1182/blood-2002-11-3521 . PMID   12855575.
• Nguyen TM, Lieberherr M, Fritsch J, Guillozo H, Alvarez ML, Fitouri Z, Jehan F, Garabédian M (February 2004). "The rapid effects of 1,25-dihydroxyvitamin D3 require the vitamin D receptor and influence 24-hydroxylase activity: studies in human skin fibroblasts bearing vitamin D receptor mutations". The Journal of Biological Chemistry. 279 (9): 7591–7. doi: 10.1074/jbc.M309517200 . PMID   14665637.
• Mimori K, Tanaka Y, Yoshinaga K, Masuda T, Yamashita K, Okamoto M, Inoue H, Mori M (February 2004). "Clinical significance of the overexpression of the candidate oncogene CYP24 in esophageal cancer". Annals of Oncology. 15 (2): 236–41. doi: 10.1093/annonc/mdh056 . PMID   14760115.
• Sawada N, Kusudo T, Sakaki T, Hatakeyama S, Hanada M, Abe D, Kamao M, Okano T, Ohta M, Inouye K (April 2004). "Novel metabolism of 1 alpha,25-dihydroxyvitamin D3 with C24-C25 bond cleavage catalyzed by human CYP24A1". Biochemistry. 43 (15): 4530–7. doi:10.1021/bi030207f. PMID   15078099.
• Kusudo T, Sakaki T, Abe D, Fujishima T, Kittaka A, Takayama H, Hatakeyama S, Ohta M, Inouye K (September 2004). "Metabolism of A-ring diastereomers of 1alpha,25-dihydroxyvitamin D3 by CYP24A1". Biochemical and Biophysical Research Communications. 321 (4): 774–82. doi:10.1016/j.bbrc.2004.07.040. PMID   15358094.
• Pascussi JM, Robert A, Nguyen M, Walrant-Debray O, Garabedian M, Martin P, Pineau T, Saric J, Navarro F, Maurel P, Vilarem MJ (January 2005). "Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia". The Journal of Clinical Investigation. 115 (1): 177–86. doi:10.1172/JCI21867. PMC   539191 . PMID   15630458.