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Journal of Lipid Research, Vol. 47, 1874-1880, August 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Methods

Facile syntheses of acyl dihydroxyacetone phosphates and lysophosphatidic acids having different acyl groups

Arun K. Das^*,, Jami E. Milam, Raju C. Reddy and Amiya K. Hajra^*,,1

^* Molecular and Behavioral Neuroscience Research Institute, University of Michigan, Ann Arbor, MI 48109
Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109

Published, JLR Papers in Press, May 22, 2006.

¹ To whom correspondence should be addressed. e-mail: akhajra{at}umich.edu

In this study, we report novel and simple chemical syntheses of acyl dihydroxyacetone phosphate (DHAP) and 1-acyl glycero-3-phosphate [lysophosphatidic acid (LPA)], key intermediaries in the formation of glycerolipids containing ester and ether bonds. The synthesis of acyl DHAPs involved acylating the dimethyl ketal of DHAP by acid anhydride using 4-pyrrolidinopyridine as the catalyst, and the resulting product was deketalized by HClO₄ in acetone to produce acyl DHAP. The acid anhydride was either added directly or generated in the reaction mixture from the corresponding fatty acid using dicyclohexylcarbodiimide as the condensing agent. Using these methods, a number of acyl DHAPs having short-, medium-, and long-chain saturated and unsaturated acyl groups were synthesized, with overall yields from 37% to 75%. The activities of these acyl DHAPs as substrates for guinea pig liver peroxisomal acyl DHAP:NADPH reductase and alkyl DHAP synthase were then determined. Next, starting from these acyl DHAPs, a variety of LPAs were synthesized by chemical reduction of the ketone group. Biological activities of these LPAs were determined by measuring their relative abilities to release intracellular Ca²⁺ via the LPA receptor. A combined chemical-enzymatic method is also described to prepare the natural LPA from the racemic mixture.

Supplementary key words acylation • dihydroxyacetone phosphate dimethyl ketal • acyl dihydroxyacetone phosphate reductase • alkyl dihydroxyacetone phosphate synthase • sodium cyanoborohydride reduction

Abbreviations: DCC, dicyclohexylcarbodiimide; DHAP, dihydroxyacetone phosphate; DHAP-DMK, dimethyl ketal of dihydroxyacetone phosphate; LPA, lysophosphatidic acid; PA, phosphatidic acid; PMR, proton magnetic resonance; 4-PrPy, 4-pyrrolidinopyridine

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