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J. Biol. Chem., Vol. 280, Issue 51, 42263-42273, December 23, 2005

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Lecithin:Retinol Acyltransferase Is Responsible for Amidation of Retinylamine, a Potent Inhibitor of the Retinoid Cycle^*

Marcin Golczak1, Yoshikazu Imanishi1, Vladimir Kuksa, Tadao Maeda1, Ryo Kubota, and Krzysztof Palczewski¶||2

From the Departments of Ophthalmology, ^¶Pharmacology, and ^||Chemistry, University of Washington and Acucela Inc., Seattle, Washington 98195

Lecithin:retinol acyltransferase (LRAT) catalyzes the transfer of an acyl group from the sn-1 position of phosphatidylcholine to all-trans-retinol (vitamin A) and plays an essential role in the regeneration of visual chromophore as well as in the metabolism of vitamin A. Here we demonstrate that retinylamine (Ret-NH₂), a potent and selective inhibitor of 11-cis-retinal biosynthesis (Golczak, M., Kuksa, V., Maeda, T., Moise, A. R., and Palczewski, K. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 8162-8167), is a substrate for LRAT. LRAT catalyzes the transfer of the acyl group onto Ret-NH₂ leading to the formation of N-retinylpalmitamide, N-retinylstearamide, and N-retinylmyristamide with a ratio of 15:6:2, respectively. The presence of N-retinylamides was detected in vivo in mice supplemented with Ret-NH₂. N-Retinylamides are thus the main metabolites of Ret-NH₂ in the liver and the eye and can be mobilized by hydrolysis/deamidation back to Ret-NH₂. Using two-photon microscopy and the intrinsic fluorescence of N-retinylamides, we showed that newly formed amides colocalize with the retinyl ester storage particles (retinosomes) in the retinal pigment epithelium. These observations provide new information concerning the substrate specificity of LRAT and explain the prolonged effect of Ret-NH₂ on the rate of 11-cis-retinal recovery in vivo.

Received for publication, August 24, 2005 , and in revised form, October 4, 2005.

^* This research was supported by National Institutes of Health Grant EY09339. The University of Washington and Acucela Inc. may commercialize some of the technology described in this work. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Dept. of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-4965.

² To whom correspondence should be addressed: Dept. of Pharmacology, School of Medicine, Case Western Reserve University, BRB Bldg., 10900 Euclid Ave., Cleveland, OH 44106-4965. E-mail: kxp65{at}case.edu.

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