In-silico approaches to sequence and structure based scrutiny of nonsynonymous SNPs and synteny of ACAA2 for its implicated role in metabolomics

The science of metabolomics is exponentially growing with the boost in knowledge base of metabolites and development of bioinformatics data analysis tools. Human ACAA2 gene codes for a 397 amino acid protein, 3Ketoacyl-CoA thiolase, which is a mitochondrial enzyme responsible for catalyzing the thiolytic cleavage of 3-ketoacyl-CoA by thiolase, the last reaction of fatty-acid β-oxidation. Bioinformatics approaches were used to scrutinize the human ACAA2 protein. The tertiary structure of the protein was predicted using a multitude of structure prediction servers including PHYRE2, (PS)-v2, ITASSER and SAM-T08. Generated structures were then evaluated using ERRAT2, VERIFY3D, PROVE, PROCHECK and MoLProbity servers. PolyPhen-2 and SIFT servers were used to sort the damaging missense SNPs from the tolerable ones. The structural model of mutated sequence was also generated and superimposed on the normal structure using UCSF Chimera in order to find the regions of deviations. PoPMuSiC was used to analyze thermodynamic stability changes in mutated structure. Finally, syntenic analysis was performed using Cinteny in order to study the physical co-localization of the genetic loci with the ACAA2 gene. The model generated by PHYRE2 (normal mode) was found to be the best model so far which was selected for further studies. As a result of mutational analysis, substitution of D31Y caused by SNP rs11549282 was found to be damaging. Genomic context of Human and mouse ACAA2 was found to be the same up to 36 genes as predicted by Cinteny. This work will be helpful in detailed comprehension of the role of ACAA2 in fatty acid metabolism related disorders. Proceedings IWBBIO 2014. Granada 7-9 April, 2014 1555