Английская Википедия:CYP24A1

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Шаблон:Use dmy datesШаблон:Cs1 configШаблон:Use American English Шаблон:Infobox gene 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.(Шаблон:EC number)

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.[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 catalyze 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

Шаблон: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.[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] However, increasingly patients are also being diagnosed in adulthood, often when they present with hypercalcaemia.[5] 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.[6]

References

Шаблон:Reflist

External links

Further reading

Шаблон:Refbegin

Шаблон:Refend

Шаблон:Cytochrome P450 Шаблон:Metabolism of vitamins, coenzymes, and cofactors

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  1. ↑ 1,0 1,1 Шаблон:Cite web
  2. ↑ 2,0 2,1 2,2 2,3 2,4 2,5 2,6 2,7 Шаблон:Cite journal
  3. ↑ Шаблон:Cite journal
  4. ↑ Шаблон:Cite journal
  5. ↑ Шаблон:Cite book
  6. ↑ Шаблон:Cite journal
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