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.
Highlights
All-trans-retinoic acid is a biologically active derivative of vitamin A that regulates numerous physiological processes
Because RDH12 is localized in the inner segments rather than outer segments of photoreceptors, its primary function would be to protect the cells from excessive all-trans-retinaldehyde that diffuses into the inner segments from illuminated rhodopsin and can reach as high as 3 mM concentration [70, 76]
The current state of knowledge suggests that there is a certain redundancy in the enzymes and proteins associated with each step in the conversion of retinol to retinaldehyde and further to All-trans-retinoic acid (atRA)
Summary
The precursors of atRA have to be obtained from the diet, either as retinyl esters from animal sources or provitamin A carotenoids from plants, mainly as -carotene (reviewed in Refs. 15 and 16, and in this thematic series by Harrison and colleagues). Retinol is released from storage by retinyl ester hydrolases and is delivered to peripheral tissues in the form bound to plasma retinol-binding protein (RBP4) [16]. This form of all-trans-retinol (holoRBP4) is the main source of vitamin A for most extrahepatic tissues. The first step, the oxidation of retinol to retinaldehyde, is generally considered to be rate-limiting [17], but as discussed later, in some cells, an increase in the rate of the second step appears to raise the steady-state levels of atRA [18, 19], suggesting that the second step may be rate-limiting under certain conditions. Retinaldehyde can be converted back to retinol, but the oxidation of retinaldehyde to atRA is irreversible
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