Abstract
Generation of the autacoid all-trans-retinoic acid (ATRA) from retinol (vitamin A) relies on a complex metabolon that includes retinol binding-proteins and enzymes from the short-chain dehydrogenase/reductase and aldehyde dehydrogenase gene families. Serum retinol binding-protein delivers all-trans-retinol (vitamin A) from blood to cells through two membrane receptors, Stra6 and Rbpr2. Stra6 and Rbpr2 convey retinol to cellular retinol binding-protein type 1 (Crbp1). Holo-Crbp1 delivers retinol to lecithin: retinol acyl transferase (Lrat) for esterification and storage. Lrat channels retinol directly into its active site from holo-Crbp1 by protein-protein interaction. The ratio apo-Crbp1/holo-Crbp1 directs flux of retinol into and out of retinyl esters, through regulating esterification vs ester hydrolysis. Multiple retinol dehydrogenases (Rdh1, Rdh10, Dhrs9, Rdhe2, Rdhe2s) channel retinol from holo-Crbp1 to generate retinal for ATRA biosynthesis. β-Carotene oxidase type 1 generates retinal from carotenoids, delivered by the scavenger receptor-B1. Retinal reductases (Dhrs3, Dhrs4, Rdh11) reduce retinal into retinol, thereby restraining ATRA biosynthesis. Retinal dehydrogenases (Raldh1, 2, 3) dehydrogenate retinal irreversibly into ATRA. ATRA regulates its own concentrations by inducing Lrat and ATRA degradative enzymes. ATRA exhibits hormesis. Its effects relate to its concentration as an inverted J-shaped curve, transitioning from beneficial in the "goldilocks" zone to toxicity, as concentrations increase. Hormesis has distorted understanding physiological effects of ATRA post-nataly using chow-diet fed, ATRA-dosed animal models. Cancer, immune deficiency and metabolic abnormalities result from mutations and/or insufficiency in Crbp1 and retinoid metabolizing enzymes.