Retinoic acid biosynthesis and metabolism

Metabolic activation of retinol into the hormone retinoic acid and metabolism of retinoic acid entail essential aspects of retinoid biology that seem interdependent with functions of retinoid binding-proteins. Cellular retinol binding protein and cellular retinoic acid binding protein enjoy widespread expression and, where expressed, their liganded forms represent the major physiological forms of retinol and retinoic acid, respectively. These retinoid binding proteins may protect cells from the amphipathic properties of retinoids and protect the structurally sensitive retinoids from the cellular milieu. Starting from the perspective that the enzymes most likely to metabolize retinoids in vivo might recognize the major forms of retinoids that occur in vivo, several laboratories have produced results that support a model of retinoid metabolism with prominent roles for the cellular retinoid binding proteins. In this model, liganded cellular retinoid binding proteins serve as substrates for the metabolism of some retinoids (retinol, retinoic acid), restricting access to those enzymes that recognize both the binding protein and the retinoid. Other retinoids (3,4-didehydroretinol, 4-oxo-retinoic acid) liganded to binding-proteins have their metabolism arrested. In its unliganded form, at least one retinoid binding protein (cellular retinol binding protein) serves as a retinoid concentration-sensitive modulator of enzymes that catalyze retinol metabolism. This review will describe the model and the intrinsic relationships among retinoid-specific enzymes and retinoid binding proteins.