Vitamin D metabolism represents a complex network of enzymatic reactions and regulatory pathways. The following is a comprehensive list of the key genes involved in human vitamin D metabolism, from initial synthesis to biological function and regulation.
CYP2R1 encodes the main hepatic 25-hydroxylase enzyme that catalyzes the first activation step of vitamin D metabolism by converting cholecalciferol (vitamin D3) to 25-hydroxyvitamin D (25(OH)D) in the liver (R1, R2, R3).
This is the rate-limiting step in producing the major circulating form of vitamin D. Mutations in this gene can cause selective 25-hydroxyvitamin D deficiency (R3).
This gene encodes the enzyme that performs the second hydroxylation step, converting 25(OH)D to the biologically active 1,25-dihydroxyvitamin D (1,25(OH)2D or calcitriol) primarily in the kidneys (R1, R2).
Expression of CYP27B1 is upregulated by parathyroid hormone (PTH) and downregulated by fibroblast growth factor 23 (FGF23) and 1,25(OH)2D itself (R1).
Located on chromosome 20, CYP24A1 encodes a mitochondrial enzyme expressed in VDR-containing target cells that catalyzes the catabolism of both 25(OH)D and 1,25(OH)2D to inactive metabolites (R1, R2).
This enzyme prevents accumulation of potentially toxic levels of vitamin D metabolites and is induced by 1,25(OH)2D as part of a negative feedback mechanism (R2).
This enzyme has 25-hydroxylase activity similar to CYP2R1 but is distributed throughout the body. Unlike CYP2R1, it can only 25-hydroxylate vitamin D3 (not vitamin D2) (R1).
These enzymes exhibit 25-hydroxylase activity and are particularly important in extrahepatic vitamin D production (R1).
This enzyme initiates a non-canonical vitamin D metabolic pathway by hydroxylating vitamin D3 at several positions (C-20, C-22, and C-23) without cleaving the side chain, producing metabolites that act as inverse agonists for certain receptors (R2, R6).
This gene encodes vitamin D binding protein (VDBP), which transports vitamin D metabolites in the bloodstream to various sites of action, facilitating their activity(R1, R2, R7). VDBP binds to vitamin D and its metabolites, enabling their circulation throughout the body.
Located on chromosome 12, VDR encodes the vitamin D receptor, a member of the nuclear receptor superfamily of steroid hormone receptors (R1, R2, R4). When activated by binding to 1,25(OH)2D, VDR forms a heterodimer with RXR that acts as a transcription factor, regulating the expression of numerous target genes.
VDR contains a DNA-binding domain (exons 2-4) that interacts with vitamin D response elements (VDREs) and a ligand-binding domain (exons 6-9) that binds 1,25(OH)2D (R1).
This gene encodes a receptor that forms a heterodimer with VDR, which is essential for vitamin D signaling (R1, R4, R9). The VDR/RXR complex is considered the major active transcription unit in regulating vitamin D target gene transcription. RXR is critically important for both ligand-independent and ligand-dependent functions of VDR (R4).
This gene is involved in cholesterol biosynthesis and affects the amount of 7-dehydrocholesterol available in the skin for vitamin D synthesis upon UVB exposure (R1).
While not directly involved in vitamin D metabolism, FGF23 is a significant regulator of vitamin D homeostasis. It suppresses the expression of CYP27B1 and increases CYP24A1 production in the kidneys, thereby reducing 1,25(OH)2D secretion (R1).
These genes form the molecular framework for vitamin D metabolism, from its initial synthesis in the skin to its activation, transport, signaling, and eventual degradation. Polymorphisms in these genes can significantly affect vitamin D status and response to supplementation, with implications for bone health, immune function, and various disease risks.