Enzymology of retinoic acid biosynthesis and degradation

Abstract

All-trans-retinoic acid is a biologically active derivative of vitamin A that regulates numerous physiological processes. The concentration of retinoic acid in the cells is tightly regulated, but the exact mechanisms responsible for this regulation are not completely understood, largely because the enzymes involved in the biosynthesis of retinoic acid have not been fully defined. Recent studies using in vitro and in vivo models suggest that several members of the short-chain dehydrogenase/reductase superfamily of proteins are essential for retinoic acid biosynthesis and the maintenance of retinoic acid homeostasis. However, the exact roles of some of these recently identified enzymes are yet to be characterized. The properties of the known contributors to retinoid metabolism have now been better defined and allow for more detailed understanding of their interactions with retinoid-binding proteins and other retinoid enzymes. At the same time, further studies are needed to clarify the interactions between the cytoplasmic and membrane-bound proteins involved in the processing of hydrophobic retinoid metabolites. This review summarizes current knowledge about the roles of various biosynthetic and catabolic enzymes in the regulation of retinoic acid homeostasis and outlines the remaining questions in the field.

Keywords: dehydrogenase; reductase; retinol; vitamin A.

Fig. 1.

Retinoic acid biosynthesis. Retinol (ROL, depicted as yellow pyramids) is delivered to extrahepatic cells bound to plasma RBP4. holoRBP4 binds to RBP4 receptor STRA6. CRBPI accepts retinol from STRA6 in the cytoplasm and delivers retinol to membranes, where retinol is either esterified by LRAT to REs (depicted as purple rhombuses) or oxidized by RDH10 to RAL (depicted as orange pyramids). RAL is oxidized further to RA (depicted as brown pyramids) by ALDH in the cytoplasm or is reduced back to retinol by retinaldehyde reductases (RalRD) in the membranes. RA binds to CRABP type I or type II and is transferred by holoCRABPII to the nucleus for binding to heterodimers of RAR and RXR or delivered to CYP enzymes by holoCRABPI for degradation. In addition, β-carotene (βCAR, depicted as duplicate of olive pyramids) is taken up by the cells through SR-B1 and cleaved into two molecules of retinaldehyde by BCMO1. Retinaldehyde derived from β-carotene may be oxidized to RA or converted to retinol as described above. LD, lipid droplet; MT, mitochondria; NUC, nucleus; RE, retinyl ester; RXR, retinoid X receptor.

Fig. 2.

Neighbor-joining phylogenetic tree of retinoid-active SDRs. Three branches of SDRs that include human and rodent retinoid-active enzymes implicated in retinoic acid biosynthesis are shown. SDR9C group is comprised of enzymes with preference for NAD(H) as cofactor. SDR7C group is composed of enzymes with preference for NADP(H) as cofactor. SDR16C group includes both NAD(H)- and NADP(H)-preferring enzymes. Murine enzymes are prefixed with Mm, and rat enzymes are prefixed with Rn. Scale bar, 0.2 amino acid substitutions per site.