All ETDs from UAB

Advisory Committee Chair

Natalia Y Kedishvili

Advisory Committee Members

Louise T Chow

Thomas M Ryan

Robert A Kesterson

Chenbei Chang

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Bioactive vitamin A takes form as several molecules, among them all-trans-retinoic acid (RA) is the major form and influences a wide range of biological processes. RA must be synthesized through a two-step mechanism, where all-trans-retinol is first oxidized to all-trans-retinaldehyde by retinol dehydrogenases (RDHs) and retinaldehyde is further oxidized to RA by retinaldehyde dehydrogenases (RALDHs). The first step, retinol to retinaldehyde conversion is the rate limiting step and therefore a likely target of mechanisms that modulate RA synthesis. Despite this, many of the enzymes that are involved in retinol and retinaldehyde interconversion have yet to be identified and thus many questions remain regarding the mechanisms of RA synthesis regulation. The described work was performed to shed light on these unaddressed issues. Our findings suggest that multiple RDH enzymes exist that possess unique activities and modes of regulation. Further, we conclude that a retinaldehyde reductase (dehydrogenase reductase 3, DHRS3) is essential for the maintenance of retinoid homeostasis in vivo and that it likely functions as part of a feedback regulatory mechanism whereby RA synthesis is influenced by RA concentrations. In summary, this work greatly enhances our understanding of the mechanisms involved in the maintenance of retinoid homeostasis and further illuminates the importance of retinol-retinaldehyde interconversion in this process

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