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      Lecithin:Retinol Acyltransferase: A Key Enzyme Involved in the Retinoid (visual) Cycle

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      Biochemistry

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          Abstract

          Lecithin:retinol acyltransferase (LRAT) catalyzes the acyl transfer from the sn-1 position of phosphatidylcholine (PC) to all- trans-retinol, creating fatty acid retinyl esters (palmitoyl, stearoyl, and some unsaturated derivatives). In the eye, these retinyl esters are substrates for the 65 kDa retinoid isomerase (RPE65). LRAT is well characterized biochemically, and recent structural data from closely related family members of the NlpC/P60 superfamily and a chimeric protein have established its catalytic mechanism. Mutations in the LRAT gene are responsible for approximately 1% of reported cases of Leber congenital amaurosis (LCA). Lack of functional LRAT, expressed in the retinal pigmented epithelium (RPE), results in loss of the visual chromophore and photoreceptor degeneration. LCA is a rare hereditary retinal dystrophy with an early onset associated with mutations in one of 21 known genes. Protocols have been devised to identify therapeutics that compensate for mutations in RPE65, also associated with LCA. The same protocols can be adapted to combat dystrophies associated with LRAT. Improvement in the visual function of clinical recipients of therapy with recombinant adeno-associated virus (rAAV) vectors incorporating the RPE65 gene provides a proof of concept for LRAT, which functions in the same cell type and metabolic pathway as RPE65. In parallel, a clinical trial that employs oral 9- cis-retinyl acetate to replace the missing chromophore in RPE65 and LRAT causative disease has proven to be effective and free of adverse effects. This article summarizes the biochemistry of LRAT and examines chromophore replacement as a treatment for LCA caused by LRAT mutations.

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          Author and article information

          Journal
          0370623
          1028
          Biochemistry
          Biochemistry
          Biochemistry
          0006-2960
          1520-4995
          11 July 2017
          23 May 2016
          07 June 2016
          14 August 2017
          : 55
          : 22
          : 3082-3091
          Affiliations
          Cleveland Center for Membrane and Structural Biology, Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, United States
          Author notes
          [* ] Corresponding Author: Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106. kxp65@ 123456case.edu
          Article
          PMC5555363 PMC5555363 5555363 nihpa891255
          10.1021/acs.biochem.6b00319
          5555363
          27183166
          fb2adc84-f0ee-4ad4-8a5b-ee14c2264084
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