Retinoid metabolism

University Of California Berkeley, Berkeley CA

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Abstract

DESCRIPTION (provided by applicant): In the long-term, this project will characterize biosynthesis of atRA (all-trans-retinoic acid) at the molecular, biochemical and endocrine levels. Data from previous project periods are consistent with a model of atRA biosynthesis that involves interactions between CRBP (cellular retinol-binding protein, type I) and an RDH (all-trans-retinol dehydrogenase), which belongs to the short-chain dehydrogenase/reductase gene family. The proposed work will continue to evaluate the hypotheses that mouse RDH1 serves as a major enzyme in the physiological pathway of atRA biosynthesis, and that CRBP serves as a physiological substrate for retinol metabolism. The specific aims are to: 1) generate RDH1 null mice by homologous recombination and evaluate the impact of the knockout on retinoid function and metabolism; 2) establish cellular expression of RDH1 mRNA and protein in the embryonic and adult mouse; 3) determine the mechanism(s) of the CRBP sparing effect on retinoids by examining in detail the metabolism of retinol and atRA in wild-type and CRBP null mice; 4) determine RDH1 membrane topology and identify amino acid residues that establish topology; 5) identify RDH1 gene regions with regulatory elements active in vivo. Much is already known about the structures, forms and loci of retinoid receptors and retinoid binding-proteins during embryogenesis and in the adult. Less has been revealed about the enzymes that catalyze the physiological paths of retinoid metabolism, even though retinoid function depends on the integrated relationship among binding proteins, receptors and atRA generating enzymes. The work proposed here will provide insight into atRA biosynthesis by identifying and characterizing the major physiological enzyme(s) that catalyzes the first and rate-limiting reaction, and by providing insight into their ontology and regulation. This work will contribute to revealing pathology caused or exacerbated by impaired atRA biosynthesis during carcinogenesis, skin disease, birth defects, or diseases of intermediary metabolism.