Essential Genes in Vitamin D Metabolism

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.

Major Metabolic Enzymes

CYP2R1 (Vitamin D 25-Hydroxylase)

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).

CYP27B1 (25(OH)D-1-α Hydroxylase)

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).

CYP24A1 (Vitamin D 24-Hydroxylase)

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).

CYP27A1 (Sterol 27-Hydroxylase)

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).

CYP3A4, CYP2J3, and CYP2J2

These enzymes exhibit 25-hydroxylase activity and are particularly important in extrahepatic vitamin D production (R1).

CYP11A1 (Cholesterol Side-Chain Cleavage Enzyme)

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).

Transport Proteins

GC (Group-Specific Component)

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.

Nuclear Receptors and Signaling

VDR (Vitamin D Receptor)

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).

RXR (Retinoid X Receptor)

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).

Additional Related Genes

DHCR7 (7-Dehydrocholesterol Reductase)

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).

Regulatory Elements

FGF23 (Fibroblast Growth Factor 23)

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).

Conclusion

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.