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)

CYP24A1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCYP24A1, CP24, CYP24, HCAI, P450-CC24, cytochrome P450 family 24 subfamily A member 1, HCINF1
External IDsOMIM: 126065; MGI: 88593; HomoloGene: 68094; GeneCards: CYP24A1; OMA:CYP24A1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000782
NM_001128915

NM_009996

RefSeq (protein)

NP_000773
NP_001122387

NP_034126

Location (UCSC)Chr 20: 54.15 – 54.17 MbChr 2: 170.32 – 170.34 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

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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

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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

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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

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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

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000019186Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000038567Ensembl, 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. ^ a b "Entrez Gene: CYP24A1 cytochrome P450, family 24, subfamily A, polypeptide 1".
  6. ^ a b c d e f g h 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.
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Further reading

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