title: Mis-sesnse mutations in Tafazzin (TAZ) that escort to mild clinical symptoms of Barth syndrome is owed to the minimal inhibitory effect of the mutations on the enzyme function: In-silico evidence.
abstract: Tafazzin (EC 2.3.1.23) is a Phospholipid Transacylase involved in Cardiolipin remodeling on mitochondrial membrane and coded by TAZ gene (Cytogenetic Location: Xq28) in human. Its mutations cause Barth syndrome (MIM ID: #302060)/3-Methyl Glutaconyl Aciduria Type II, an inborn error of metabolism often leading to foetal or infantile fatality. Nevertheless, some mis-sense mutations result in mild clinical symptoms. To evaluate the rationale of mild symptoms and for an insight of Tafazzin active site, sequence based and structure based ramifications of wild and mutant Tafazzins were compared in-silico. Sequence based domain predictions, surface accessibilities on substitution & conserved catalytic sites with statistical drifts, as well as thermal stability changes for the mutations and the interaction analysis of Tafazzin were performed. Crystal structure of Tafazzin is not yet resolved experimentally, therefore 3D coordinates of Tafazzin and its mutants were spawned through homology modeling. Energetically minimized and structurally validated models were used for comparative docking simulations. We analyzed active site geometry of the models in addition to calculating overall substrate binding efficiencies for each of the enzyme-ligand complex deduced from binding energies instead of comparing only the docking scores. Also, individual binding energies of catalytic residues on conserved HX4D motif of Acyltransferase superfamily present in Tafazzins were estimated. This work elucidates the basis of mild symptoms in patients with mis-sense mutations, identifies the most pathogenic mutant among others in the study and also divulges the critical role of HX4D domain towards successful transacylation by Taffazin. The in-silico observations are in complete agreement with clinical findings reported for the patients with mutations.
authors.affiliation: Department of Medical Laboratory Technology, Women's Polytechnic, Govt. of Tripura Hapania, P.O: Amtali, Tripura (W), PIN: 799130, India, surajit03@yahoo.co.in.
authors.forename: Surajit
authors.initials: S
authors.lastname: Debnath
authors.forename: Soma
authors.initials: S
authors.lastname: Addya
mesh_terms: D000217:Acyltransferases / Q000737:chemistry; D000595:Amino Acid Sequence; D056889:Barth Syndrome / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002308:Cardiolipins / Q000378:metabolism; D020134:Catalytic Domain; D003198:Computer Simulation; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000737:chemistry*
chemical_list: D002308:Cardiolipins; D014157:Transcription Factors; D000217:Acyltransferases; C108675:TAFAZZIN protein, human