Journal
JOURNAL OF LIPID RESEARCH
Volume 55, Issue 1, Pages 13-31Publisher
ELSEVIER
DOI: 10.1194/jlr.R031534
Keywords
1,25-(OH)(2)D-3; CYP2R1; CYP27A1; CYP27B1; CYP24A1; vitamin D-dependent rickets; chronic kidney disease; idiopathic infantile hypercalcemia; vitamin D analog; regioselectivity
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The vitamin D signal transduction system involves a series of cytochrome P450-containing sterol hydroxylases to generate and degrade the active hormone, 1 alpha,25-dihydroxyvitamin D-3, which serves as a ligand for the vitamin D receptor-mediated transcriptional gene expression described in companion articles in this review series. This review updates our current knowledge of the specific anabolic cytochrome P450s involved in 25- and 1 alpha-hydroxylation, as well as the catabolic cytochrome P450 involved in 24- and 23-hydroxylation steps, which are believed to initiate inactivation of the vitamin D molecule. We focus on the biochemical properties of these enzymes; key residues in their active sites derived from crystal structures and mutagenesis studies; the physiological roles of these enzymes as determined by animal knockout studies and human genetic diseases; and the regulation of these different cytochrome P450s by extracellular ions and peptide modulators. We highlight the importance of these cytochrome P450s in the pathogenesis of kidney disease, metabolic bone disease, and hyperproliferative diseases, such as psoriasis and cancer; as well as explore potential future developments in the field.
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