title: Multivariate sequence analysis reveals additional function impacting residues in the SDR superfamily.
abstract: The "extended" type of short chain dehydrogenases/reductases (SDR), share a remarkable similarity in their tertiary structures inspite of being highly divergent in their functions and sequences. We have carried out principal component analysis (PCA) on structurally equivalent residue positions of 10 SDR families using information theoretic measures like Jensen-Shannon divergence and average shannon entropy as variables. The results classify residue positions in the SDR fold into six groups, one of which is characterized by low Shannon entropies but high Jensen-Shannon divergence against the reference family SDR1E, suggesting that these positions are responsible for the specific functional identities of individual SDR families, distinguishing them from the reference family SDR1E. Site directed mutagenesis of three residues from this group in the enzyme UDP-Galactose 4-epimerase belonging to SDR1E shows that the mutants promote the formation of NADH containing abortive complexes. Finally, molecular dynamics simulations have been used to suggest a mechanism by which the mutants interfere with the re-oxidation of NADH leading to the formation of abortive complexes.
authors: School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110 067, India.
authors: Pratibha
authors: P
authors: Tiwari
authors: Noopur
authors: N
authors: Singh
authors: Aparna
authors: A
authors: Dixit
authors: Devapriya
authors: D
authors: Choudhury
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D055162:Biocatalysis; D020134:Catalytic Domain; D017124:Conserved Sequence; D030562:Databases, Protein; D019277:Entropy; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015999:Multivariate Analysis; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D010088:Oxidoreductases / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism; D025341:Principal Component Analysis; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017385:Sequence Homology; D009626:Terminology as Topic; D014534:UDPglucose 4-Epimerase / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism
chemical_list: D029968:Escherichia coli Proteins; D007527:Isoenzymes; D050505:Mutant Proteins; D011994:Recombinant Proteins; C464423:DHRS1 protein, human; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D014534:UDPglucose 4-Epimerase; C020551:galactose epimerase
keywords: Jensen-Shannon divergence; abortive complexes; hydride transfer; molecular dynamics; principal component analysis