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

Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109-0606

Corresponding Author: akhajra{at}umich.edu

In this study, we report novel and simple chemical syntheses of acyl dihydroxyacetone phosphate (acyl DHAP) and 1-acyl glycero-3-phosphate (lysophosphatidate or LPA), key intermediaries in the formation of glycerolipids containing ester and ether bonds. Synthesis of acyl DHAPs involved acylating the dimethylketal 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 was generated in the reaction mixture from the corresponding fatty acid using dicyclohexylcarbodiimide as the condensing agent. Employing these methods, a number of acyl DHAPs having short, medium and long chain saturated and unsaturated acyl groups were synthesized with the 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 1-acyl-rac-glycero-3-phosphates (lysophosphatidates or LPAs) were synthesized by chemical reduction of the ketone group. Biological activities of these LPAs were determined by measuring their relative ability to release intracellular Ca2+ via the LPA receptor. A combined chemical-enzymatic method is also described to prepare the natural LPA (1-acyl-sn-glycero-3-phosphate) from the racemic mixture.

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