tailieunhanh - Báo cáo khoa học: An enzymatic mechanism for generating the precursor of endogenous 13-cis retinoic acid in the brain

13-cisRetinoic acid (13cRA), a stereoisomeric form of retinoic acid, is nat-urally generated in the body and is also used clinically to treat acute prom-yelocytic 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 sui-cidal tendencies. | IFEBS Journal An enzymatic mechanism for generating the precursor of endogenous 13-cis retinoic acid in the brain Yusuke Takahashi1 Gennadiy Moiseyev2 Ying Chen2 Krysten Farjo2 Olga Nikolaeva2 and Jian-Xing Ma2 1 Department of Medicine Endocrinology Harold Hamm Oklahoma Diabetes Center University of Oklahoma Health Sciences Center OK USA 2 Department of Physiology Harold Hamm Oklahoma Diabetes Center University of Oklahoma Health Sciences Center OK USA Keywords brain isomerohydrolase retinoic acid vitamin A zebrafish Correspondence . Ma 941 Stanton L. Young Boulevard BSEB 328B Oklahoma City OK 73104 USA Fax 1 405 271 3973 Tel 1 405 271 4372 E-mail jian-xing-ma@ Received 18 August 2010 revised 26 December 2010 accepted 11 January 2011 doi 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 prom-yelocytic 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 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 Km M and kcat X 10_4-s-1. RT-PCR .