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.(
EC1.14.15.16)
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]
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]
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.
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. 207 (1): 57–61.
doi:
10.3181/00379727-207-43791.
PMID7938037.
S2CID22566441.
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.
S2CID32582996.
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.
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.
S2CID44330630.
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.