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1,25-dihydroxyvitamin D3 biosynthesis

General Background Vitamin D occurs in two forms, : VITAMIN_D3 (cholecalciferol) produced in animal skin after exposure to : UV-Light and : Heat, and : VITAMIN_D2 (ergocalciferol) produced in plants, or plant material after exposure to : UV-Light. In its activated form, : VITAMIN_D3 is necessary for optimal absorption and regulation of dietary : CA+2 and : Pi. This nutrient is essential for the prevention of rickets, a bone-softening disease. Reviewed in . There is controversy in the literature as to whether supplemental : VITAMIN_D2 is as effective as : VITAMIN_D3 in maintaining circulating levels of the 25-hydroxyvitamin D metabolite . The production of vitamin D analogs is also an active area of research (reviewed in . About This Pathway : VITAMIN_D3, a secosteroid pro-hormone, is produced in the skin by the action of : UV-Light and : Heat on : CPD-4187 (pro-vitamin D3), a : CHOLESTEROL biosynthetic intermediate (as shown in the pathway link). The initial product of photolysis is : CPD-10570, which is converted by thermal equilibration to the thermodynamically favored 5,6-isomer, : VITAMIN_D3 . Under normal conditions, : VITAMIN_D3 is transported to the liver via the plasma vitamin D binding protein where it is hydroxylated to : CALCIDIOL (25-hydroxy vitamin D3). This compound is transported to the kidney where it is further hydroxylated to the active metabolite : CALCITRIOL (1,25-dihydroxyvitamin D3). This metabolite is considered to be a hormone. Its binding to the nuclear vitamin D receptor is followed by a complex series of events that regulate gene expression. It also has non-genomic effects mediated by a membrane receptor and second messengers. Evidence is accumulating that : CALCITRIOL has many other functions, including cancer prevention, immune system modulation and endocrine system regulation. Reviewed in . The identity of the liver enzyme catalyzing the hydroxylation of vitamin D3 at carbon 25 to form : CALCIDIOL has not been firmly established, although current evidence suggests that microsomal : HS17721-MONOMER is the most likely candidate for this function (in and in ). However, studies in pig suggest that both liver microsomal CYP2D25 and mitochondrial : MONOMER-14308 (EC 1.14.13.15, see : PWY-6061) can hydroxylate vitamin D3 to calcidiol . The key, rate-limiting enzyme in the pathway appears to be kidney mitochondrial : MONOMER-14354 (P450C1) (EC 1.14.13.13), based on studies in mouse, human and rat. It is negatively regulated by : CALCITRIOL at the transcriptional level (reviewed in . However, based on pig studies it has been suggested that 1alpha hydroxylation of calcidiol in kidney can be accomplished by mitochondrial : MONOMER-14308, or a microsomal enzyme, as well as : MONOMER-14354 (reviewed in ). Catabolism (inactivation) of excess hormone : CALCITRIOL is an important regulatory point. It is catabolized in the kidney by pathways involving species-dependent side chain C24, or C23 hydroxylation. The C24 pathway is initiated by : MONOMER-14357 which catalyzes initial side chain hydroxylation (: CPLX-7690). In the C24 pathway the final metabolite : CPD-10578 is excreted. The C23 pathway produces a side chain lactone end product (in ). The expression of both : MONOMER-14354 and : MONOMER-14357 is modulated by : CALCITRIOL and a variety of cellular regulatory agents including parathyroid hormone, calcitonin, and : CA+2 and : Pi levels (reviewed in ). An additional pathway involving a C3 epimerization of the A-ring has been described . Although the intermediate metabolites in the C24 and C23 pathways have been determined ( and in ) and : MONOMER-14357 has been suggested to catalyze successive oxidations in these pathways, the complete reaction equations and the identity of any other enzymes that may participate in these pathways remain to be determined.

from BIOCYC source record: HUMAN_PWY-6076
Type: pathway
Taxonomic scope
:
organism-specific biosystem
Organism
:
Homo sapiens
BSID:
545291

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