The printable version is no longer supported and may have rendering errors. Please update your browser bookmarks and please use the default browser print function instead.
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).[1] It has also been identified as vitamin D3 24-hydroxylase.(EC1.14.15.16)
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.[1][2]
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.[2]
CYP24A1 also is able to catalyse another pathway which starts with 23-hydroxylation of 1,25-(OH)2D3 and culminates in 1,25-(OH)2D3-26,23-lactone.[2]
The side chains of the ergocalciferol (vitamin D2) derivatives, 25-OH-D2 and 1,25-(OH)2D2, are also hydroxylated by CYP24A1.[2]
The structure of CYP24A1 is highly conserved between different species although the balance of functions can differ.[2] 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]
[[File:
<imagemap>
Image:VitaminDSynthesis WP1531.png
[[]]
[[]]
[[]]
[[]]
[[]]
[[]]
[[]]
[[]]
[[]]
[[]]
[[]]
[[]]
[[]]
[[]]
[[]]
[[]]
[[]]
[[]]
[[]]
[[]]
[[]]
[[]]
<imagemap>
Image:VitaminDSynthesis WP1531.png
|{{{bSize}}}px|alt=Vitamin D Synthesis Pathway (view / edit)]]
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.[2] 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.[2]
PTH and FGF23 also regulate CYP24A1 gene expression.[2] Additionally, it is translationally regulated via IRES within the 5'UTR, which is responsive to an inflammatory environment.[3]
Clinical relevance
Abnormal functioning CYP24A1 is thought to be one of the causes of severe infantile hypercalcemia.[4] 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.[5]
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. PMID7595086.
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. 1263 (1): 1–9. doi:10.1016/0167-4781(95)00060-t. PMID7632726.
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. PMID7829101.
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. Society for Experimental Biology and Medicine. 207 (1): 57–61. doi:10.3181/00379727-207-43791. PMID7938037.
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. PMID8266831.
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. PMID8440135.
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/en.140.5.2027. PMID10218951.
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. PMID11149490.
Farhan H, Cross HS (November 2002). "Transcriptional inhibition of CYP24 by genistein". Annals of the New York Academy of Sciences. 973: 459–62. doi:10.1111/j.1749-6632.2002.tb04683.x. PMID12485911.
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. PMID12641633.
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. PMID12855575.
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. PMID14665637.
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. PMID14760115.
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. PMID15078099.
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. PMID15358094.
