713|Int. J. of Multidisciplinary and Current research, Vol.3 (July/Aug 2015) International Journal of Multidisciplinary and Current Research Research Article ISSN: 2321-3124 Available at: http://ijmcr.com In silico Study on the Active Site Conformation and Structural Modulation of Glycerol-3-Phosphate Acyltransferase in Relevance to Medicinal Significance Sweta Sharma, Swapna K Srivastava and Sanjay Mishra School of Biotechnology, IFTM University, Lodhipur Rajput, Delhi Road (NH - 24), Moradabad 244102, U.P., India Accepted 30 June 2015, Available online 05 July 2015, Vol.3 (July/Aug 2015 issue) Abstract Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the first step in the synthesis of glycerolipid and glycerophospholipids.Overexpression of GPAT can lead to certain diseases like atherosclerosis and by extension, the risk of heart disease, stroke, obesity and hypertension. The present study was designed to develop specific analogues having high binding affinity for the receptor, probably helping in controlling the overexpression of triacylglycerol (TG) by molecular docking using Vlife MDS. To study the molecular interaction the receptor was docked with GPAT isomers 1IUQ &1K30 after energy minimization. The results obtained after docking indicated formation of a stable complex with strong binding affinity. It was also observed that the amino acid residues involved in this interaction and the predicted residues responsible for binding are GLU124, TYR158, ILE159, ALA160, ASP162, THR163, LEU177 & LEU226 and PRO238, GLY243, TRY245, LYS246, HIS279, ASP280, PRO283, GLU294, ARG296 & ALN299.The molecular interaction between GPAT and its receptor provides new insights into the elucidation of structural domains and development of functional analogues with higher binding affinity and new drug combination therapies for the treatment of obesity. Keywords: GPAT, Inhibitor designing, Molecular docking, Obesity, TG, Vlife MDS. 1. Introduction GPAT enzyme (EC 2.3.1.15) catalyzes the first step in TG biosynthesis in most tissues, the conversion of glycerol-3- phosphate and acyl-CoA to 1-acylglycerol-3-phosphate (lysophosphatidate) [1-4]. In 1953 Kennedy and Kornberg first reported on the sn-glycerol- 3 phosphate acyltransferase activity [5-13]. As GPAT exhibits the lowest specific activity of enzymes in the pathway, it has been considered to be rate limiting step of glycerolipid metabolism. GPAT catalyzes the transfer of a fatty acid from an acyl donor to the sn-1 position of glycerol 3 phosphate to yield 1-acylglycerol 3 phosphate (LPA) [14- 15]. Subsequently different enzymes function and lead to the formation of triacylglycerol. Triglycerides are the major form of lipids. A triglyceride consists of three molecules of fatty acid combined with a molecule of glycerol. Triglycerides serve as the backbone of many types of lipids [16-17]. In the human body, high levels of triglycerides in the bloodstream have been reported to be associated to atherosclerosis, and, by extension, the risk of heart disease, stroke, obesity and hypertension [18- 21]. In eukaryotes, triacylglycerol (TAG) is synthesized through two major pathways, the glycerol phosphate pathway and the monoacylglycerol pathway [22-23]. The glycerol phosphate pathway, first described more than half a century ago, is the major pathway utilized by most cell types [24]. Acylation of glycerol 3-phosphate occurs through a stepwise addition of fatty acyl groups, each of which is catalyzed by a distinct enzyme (Fig. 1) [9]. By contrast, the monoacylglycerol pathway functions predominantly in small intestine to generate TAG from monoacylglycerol derived from dietary fat [25- 26]. GPAT, glycerol-3-phosphate acyltransferase; LPA, lysophosphatidic acid; AGPAT, 1-acylglycerol-3-phosphate acyltransferase; PI, phosphatidylinositol; PG, phosphatidylglycerol; CL, cardiolipin; PA, phosphatidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphatidylserine; DAG, diacylglycerol; DGAT, diacylglycerol acyltransferase. Fig 1: Glycerol phosphate pathway for de novo triacylglycerol (TAG) and glycerophospholipid synthesis