Cytochrome P450 family 24 subfamily A member 1 (abbreviated CYP24A1) is a member of the
cytochrome P450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various comp ...
superfamily of enzymes encoded by the ''CYP24A1'' gene. It is a mitochondrial
monooxygenase
Monooxygenases are enzymes that incorporate one hydroxyl group (−OH) into substrates in many metabolic pathways. In this reaction, the two atoms of dioxygen are reduced to one hydroxyl group and one H2O molecule by the concomitant oxidation of ...
which catalyzes reactions including 24-hydroxylation of
calcitriol
Calcitriol is the active form of vitamin D, normally made in the kidney. It is also known as 1,25-dihydroxycholecalciferol. It is a hormone which binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the ...
(1,25-dihydroxyvitamin D
3).
It has also been identified as
vitamin D3 24-hydroxylase.()
Function
CYP24A1 is an enzyme expressed in the
mitochondrion
A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...
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
Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 ( ...
. Hydroxylation of the side chain produces
calcitroic acid and other metabolites which are excreted in
bile
Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver 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
Calcifediol, also known as calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D3 (abbreviated 25(OH)D3), is a form of vitamin D produced in the liver by hydroxylation of vitamin D3 (cholecalciferol) by the enzyme vitamin D 25-hydroxylas ...
(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-D
3 and the active hormonal form, 1,25-(OH)
2D
3. It is now considered responsible for the entire five-step, 24-oxidation pathway from 1,25-(OH)
2D
3 producing calcitroic acid.
CYP24A1 also is able to catalyse another pathway which starts with 23-hydroxylation of 1,25-(OH)
2D
3 and culminates in 1,25-(OH)
2D
3-26,23-lactone.
The side chains of the
ergocalciferol
Ergocalciferol, also known as vitamin D2 and nonspecifically calciferol, is a type of vitamin D found in food and used as a dietary supplement. As a supplement it is used to prevent and treat vitamin D deficiency. This includes vitamin D defici ...
(vitamin D
2) derivatives, 25-OH-D
2 and 1,25-(OH)
2D
2, 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
Calcium metabolism is the movement and regulation of calcium ions (Ca2+) ''in'' (via the gut) and ''out'' (via the gut and kidneys) of the body, and ''between'' body compartments: the blood plasma, the extracellular and intracellular fluids, and ...
and the vitamin D endocrine system through its regulation of the level of vitamin D
3.
Interactive pathway map
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)
2D
3 binding to the
vitamin D receptor
The vitamin D receptor (VDR also known as the calcitriol receptor) is a member of the nuclear receptor family of transcription factors. Calcitriol (the active form of vitamin D, 1,25-(OH)2vitamin D3) binds to VDR, which then forms a heterodimer ...
.
The gene has a strong, positive
vitamin D response element in the
promoter. Through regulation of CYP24A1 expression, a
negative feedback
Negative feedback (or balancing feedback) occurs when some function of the output of a system, process, or mechanism is fed back in a manner that tends to reduce the fluctuations in the output, whether caused by changes in the input or by othe ...
control system is created to limit the effects of 1,25-(OH)
2D
3.
PTH and
FGF23
Fibroblast growth factor 23 (FGF23) is a protein and member of the fibroblast growth factor (FGF) family which participates in the regulation of phosphate in plasma and vitamin D metabolism. In humans it is encoded by the gene. FGF23 decreases re ...
also regulate CYP24A1 gene expression.
Additionally, it is translationally regulated via
IRES within the
5'UTR
The 5′ untranslated region (also known as 5′ UTR, leader sequence, transcript leader, or leader RNA) is the region of a messenger RNA (mRNA) that is directly upstream from the initiation codon. This region is important for the regulation of ...
, which is responsive to an inflammatory environment.
Clinical relevance
Abnormal functioning CYP24A1 is thought to be one of the causes of severe infantile
hypercalcemia
Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as 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.
References
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{{Metabolism of vitamins, coenzymes, and cofactors