Biology:CYP24A1

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).

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.

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.

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.

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

The structure of CYP24A1 is highly conserved between different species although the balance of functions can differ. 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.

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|{{{bSize}}}px|alt=Vitamin D Synthesis Pathway (view / edit)]]

Vitamin D Synthesis Pathway (view / edit)

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. 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.

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

Clinical relevance

Abnormal functioning CYP24A1 is thought to be one of the causes of severe infantile hypercalcemia. However, increasingly patients are also being diagnosed in adulthood, often when they present with hypercalcaemia. 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.

See also

• Vitamin D
• CYP27B1
• Calcium in biology

External links

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

Further reading

• "Recent progress in enzymology and molecular biology of enzymes involved in vitamin D metabolism". Journal of Lipid Research 36 (8): 1641–52. August 1995. doi:10.1016/S0022-2275(20)41484-1. PMID 7595086. 
• "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. July 1995. doi:10.1016/0167-4781(95)00060-t. PMID 7632726. 
• "Isolation of novel and known genes from a human fetal cochlear cDNA library using subtractive hybridization and differential screening". Genomics 23 (1): 42–50. September 1994. doi:10.1006/geno.1994.1457. PMID 7829101. 
• "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. October 1994. doi:10.3181/00379727-207-43791. PMID 7938037. 
• "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. November 1993. doi:10.1002/jbmr.5650081114. PMID 8266831. 
• "Localization of the human vitamin D 24-hydroxylase gene (CYP24) to chromosome 20q13.2→q13.3". Cytogenetics and Cell Genetics 62 (4): 192–3. 1993. doi:10.1159/000133473. PMID 8440135. 
• "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. May 1993. doi:10.1073/pnas.90.10.4543. PMID 8506296. Bibcode: 1993PNAS...90.4543C. 
• "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. May 1999. doi:10.1210/endo.140.5.6683. PMID 10218951. 
• "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. January 2001. doi:10.1359/jbmr.2001.16.1.57. PMID 11149490. 
• "Transcriptional inhibition of CYP24 by genistein". Annals of the New York Academy of Sciences 973 (1): 459–62. November 2002. doi:10.1111/j.1749-6632.2002.tb04683.x. PMID 12485911. Bibcode: 2002NYASA.973..459F. 
• "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. April 2003. doi:10.1046/j.1365-2265.2003.01743.x. PMID 12641633. 
• "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. November 2003. doi:10.1182/blood-2002-11-3521. PMID 12855575. 
• "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. February 2004. doi:10.1074/jbc.M309517200. PMID 14665637. 
• "Clinical significance of the overexpression of the candidate oncogene CYP24 in esophageal cancer". Annals of Oncology 15 (2): 236–41. February 2004. doi:10.1093/annonc/mdh056. PMID 14760115. 
• "Novel metabolism of 1 alpha,25-dihydroxyvitamin D3 with C24-C25 bond cleavage catalyzed by human CYP24A1". Biochemistry 43 (15): 4530–7. April 2004. doi:10.1021/bi030207f. PMID 15078099. 
• "Metabolism of A-ring diastereomers of 1alpha,25-dihydroxyvitamin D3 by CYP24A1". Biochemical and Biophysical Research Communications 321 (4): 774–82. September 2004. doi:10.1016/j.bbrc.2004.07.040. PMID 15358094. 
• "Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia". The Journal of Clinical Investigation 115 (1): 177–86. January 2005. doi:10.1172/JCI21867. PMID 15630458. PMC 539191. http://www.hal.inserm.fr/inserm-00086875/document.