title: RDH10 is the primary enzyme responsible for the first step of embryonic Vitamin A metabolism and retinoic acid synthesis.
abstract: Retinoic acid (atRA) signaling is essential for regulating embryonic development, and atRA levels must be tightly controlled in order to prevent congenital abnormalities and fetal death which can result from both excessive and insufficient atRA signaling. Cellular enzymes synthesize atRA from Vitamin A, which is obtained from dietary sources. Embryos express multiple enzymes that are biochemically capable of catalyzing the initial step of Vitamin A oxidation, but the precise contribution of these enzymes to embryonic atRA synthesis remains unknown. Using Rdh10(trex)-mutant embryos, dietary supplementation of retinaldehyde, and retinol dehydrogenase (RDH) activity assays, we demonstrate that RDH10 is the primary RDH responsible for the first step of embryonic Vitamin A oxidation. Moreover, we show that this initial step of atRA synthesis occurs predominantly in a membrane-bound cellular compartment, which prevents inhibition by the cytosolic cellular retinol-binding protein (RBP1). These studies reveal that widely expressed cytosolic enzymes with RDH activity play a very limited role in embryonic atRA synthesis under normal dietary conditions. This provides a breakthrough in understanding the precise cellular mechanisms that regulate Vitamin A metabolism and the synthesis of the essential embryonic regulatory molecule atRA.
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Krysten-farjo@ouhsc.edu
authors.forename: Krysten M
authors.initials: KM
authors.lastname: Farjo
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Moiseyev
authors.forename: Olga
authors.initials: O
authors.lastname: Nikolaeva
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Sandell
authors.forename: Paul A
authors.initials: PA
authors.lastname: Trainor
authors.forename: Jian-xing
authors.initials: JX
authors.lastname: Ma
mesh_terms: D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian / Q000378:metabolism*; D006801:Humans; D008081:Liposomes / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000378:metabolism; D054840:Retinol-Binding Proteins, Cellular / Q000378:metabolism; D013379:Substrate Specificity; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D008081:Liposomes; D008563:Membrane Lipids; D010743:Phospholipids; D054840:Retinol-Binding Proteins, Cellular; D014212:Tretinoin; D000429:Alcohol Oxidoreductases; C113992:trans-retinol dehydrogenase; C526911:ADH7 protein, human; D000426:Alcohol Dehydrogenase