title: The biochemical architecture of an ancient adaptive landscape.
abstract: Molecular evolution is moving from statistical descriptions of adaptive molecular changes toward predicting the fitness effects of mutations. Here, we characterize the fitness landscape of the six amino acids controlling coenzyme use in isopropylmalate dehydrogenase (IMDH). Although all natural IMDHs use nicotinamide adenine dinucleotide (NAD) as a coenzyme, they can be engineered to use nicotinamide adenine dinucleotide phosphate (NADP) instead. Intermediates between these two phenotypic extremes show that each amino acid contributes additively to enzyme function, with epistatic contributions confined to fitness. The genotype-phenotype-fitness map shows that NAD use is a global optimum.
authors.affiliation: BioTechnology Institute, Evolution and Behavior, University of Minnesota, St. Paul, MN 55108, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Lunzer
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Miller
authors.forename: Roderick
authors.initials: R
authors.lastname: Felsheim
authors.forename: Antony M
authors.initials: AM
authors.lastname: Dean
mesh_terms: D050539:3-Isopropylmalate Dehydrogenase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D000704:Analysis of Variance; D002384:Catalysis; D004843:Epistasis, Genetic; D004926:Escherichia coli / Q000201:enzymology; D019143:Evolution, Molecular; D005838:Genotype; D007700:Kinetics; D007930:Leucine / Q000096:biosynthesis; D008433:Mathematics; D008956:Models, Chemical; D009154:Mutation; D009243:NAD / Q000378:metabolism*; D009249:NADP / Q000378:metabolism*; D010084:Oxidation-Reduction; D010641:Phenotype; D015202:Protein Engineering; D012641:Selection, Genetic; D013816:Thermodynamics
chemical_list: D009243:NAD; D009249:NADP; D050539:3-Isopropylmalate Dehydrogenase; D007930:Leucine