title: An enzymatic mechanism for generating the precursor of endogenous 13-cis retinoic acid in the brain.
abstract: 13-cis Retinoic acid (13cRA), a stereoisomeric form of retinoic acid, is naturally generated in the body and is also used clinically to treat acute promyelocytic leukemia, some skin diseases and cancer. Furthermore, it has been suggested that 13cRA modulates brain neurochemical systems because increased 13cRA levels are correlated with depression and increased suicidal tendencies. However, the mechanism for the generation of endogenous 13cRA is not well understood. The present study identified and characterized a novel enzyme in zebrafish brain, 13-cis isomerohydrolase (13cIMH) (EC 5.2.1.7), which exclusively generated 13-cis retinol and can be oxidized to 13cRA. 13cIMH shares 74% amino acid sequence identity with human retinal pigment epithelium specific 65 kDa protein (RPE65), an 11-cis isomerohydrolase in the visual cycle, and retains the key residues essential for the isomerohydrolase activity of RPE65. Similar to RPE65, 13cIMH is a membrane-associated protein, requires all-trans retinyl ester as its intrinsic substrate, and its enzymatic activity is dependent on iron. The purified 13cIMH converted all-trans retinyl ester exclusively to 13-cis retinol with K(m)  = 2.6 μm and k(cat) = 4.4 × 10(-4) ·s(-1) . RT-PCR, western blot analysis and immunohistochemistry detected 13cIMH expression in the brain. These results suggest that 13cIMH may play a key role in the generation of 13cRA, as well as in the modulation of neuronal functions in the brain.
authors.affiliation: Department of Medicine Endocrinology, Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, OK, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Moiseyev
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Krysten
authors.initials: K
authors.lastname: Farjo
authors.forename: Olga
authors.initials: O
authors.lastname: Nikolaeva
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: Ma
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002352:Carrier Proteins / Q000737:chemistry; D003001:Cloning, Molecular; D005136:Eye Proteins / Q000737:chemistry; D006801:Humans; D015474:Isotretinoin / Q000378:metabolism*; D007700:Kinetics; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D015027:Zebrafish; D019745:cis-trans-Isomerases / Q000378:metabolism*; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; D015474:Isotretinoin; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase