Enzymatic activation in vitamin D signaling – Past, present and future

Vitamin D signaling is important in regulating calcium homeostasis essential for bone health but also displays other functions in cells of several tissues. Disturbed vitamin D signaling is linked to a large number of diseases. The multiple cytochrome P450 (CYP) enzymes catalyzing the different hydroxylations in bioactivation of vitamin D3 are crucial for vitamin D signaling and function. This review is focused on the progress achieved in identification of the bioactivating enzymes and their genes in production of 1α,25-dihydroxyvitamin D3 and other active metabolites. Results obtained on species- and tissue-specific expression, catalytic reactions, substrate specificity, enzyme kinetics, and consequences of gene mutations are evaluated. Matters of incomplete understanding regarding the physiological roles of some vitamin D hydroxylases are critically discussed and the authors will give their view of the importance of each enzyme for vitamin D signaling. Roles of different vitamin D receptors and an alternative bioactivation pathway, leading to 20-hydroxylated vitamin D3 metabolites, are also discussed. Considerable progress has been achieved in knowledge of the vitamin D3 bioactivating enzymes. Nevertheless, several intriguing areas deserve further attention to understand the pleiotropic and diverse activities elicited by vitamin D signaling and the mechanisms of enzymatic activation necessary for vitamin D-induced responses. [Display omitted] •This review highlights the progress achieved in research on vitamin D bioactivation.•Multiple enzymes, pathways and receptors are important for vitamin D signaling.•The physiological role(s) of some vitamin D hydroxylases are a matter of controversy.•We critically discuss reported functions of vitamin D hydroxylases and pathways.•Special focus is given to the multiple enzymes catalyzing vitamin D 25-hydroxylation.