Vitamin D-binding protein

Human GC is a glycosylated alpha-globulin, ~58 kDa in size. Its 458 amino acids are coded for by 1690 nucleotides on chromosome 4 (4q11–q13). The primary structure contains 28 cysteine residues forming multiple disulfide bonds. GC contains 3 domains. Domain 1 is composed of 10 alpha helices, domain 2 of 9, and domain 3 of 4.^[8]

Vitamin D-binding protein belongs to the albumin gene family, together with human serum albumin and alpha-fetoprotein. It is a multifunctional protein found in plasma, ascitic fluid, cerebrospinal fluid and on the surface of many cell types.

It is able to bind the various forms of vitamin D including ergocalciferol (vitamin D₂) and cholecalciferol (vitamin D₃), the 25-hydroxylated forms (calcifediol), and the active hormonal product, 1,25-dihydroxyvitamin D (calcitriol). The major proportion of vitamin D in blood is bound to this protein. It transports vitamin D metabolites between skin, liver and kidney, and then on to the various target tissues.^[6][9]

Beyond acting as the carrier protein for vitamin D and its metabolites, DBP also transports free fatty acids,^[10] binds to actin^[11] and may help prevent actin polymerization during tissue injury.^[12] It also might serve as a macrophage activator, contributing to the inflammatory response by modulating T-cell activity.^[13]

As Gc protein-derived macrophage activating factor it is a Macrophage Activating Factor (MAF) that has been tested for use as a cancer treatment that would activate macrophages against cancer cells.^[14]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

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Vitamin D Synthesis Pathway (view / edit)

1. [1]

   The interactive pathway map can be edited at WikiPathways: "VitaminDSynthesis_WP1531".

It is synthesized by hepatic parenchymal cells and secreted into the blood circulation.^[9]

The transcription factors HFN1α is a positive regulator while HFN1β is a dominant negative regulator of DBP expression.^[15]

Phylogenetic analyses suggest that DBP diverged from ancestral albumin through gene duplication events that occurred after the separation of jawless fish (cyclostomes) from jawed vertebrates approximately 450 million years ago.^[16] This timeline is supported by the apparent absence of DBP-like proteins in lampreys and hagfish, though these organisms retain vitamin D transport capability through alternative lipoprotein-mediated mechanisms.^[17] DBP is found throughout jawed vertebrates, from bony fish to mammals, suggesting its evolution coincided with the development of calcified skeletons and more sophisticated calcium homeostasis requirements.^[18]

Many genetic variants of the GC gene are known. They produce 6 main haplotypes and 3 main protein variants (Gc1S, Gc1F and Gc2).^[19] The genetic variations are associated with differences in circulating 25-hydroxyvitamin D levels.^[20] They have been proposed to account for some of the differences in vitamin D status in different ethnic groups,^[21] and have been found to correlate with the response to vitamin D supplementation.^[19]