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The Biochemical Architecture of an Ancient Adaptive Landscape
Mark Lunzer,1Stephen P. Miller,1Roderick Felsheim,1,2Antony M. Dean1,3*
Molecular evolution is moving from statistical descriptionsof adaptive molecular changes toward predicting the fitnesseffects of mutations. Here, we characterize the fitness landscapeof the six amino acids controlling coenzyme use in isopropylmalatedehydrogenase (IMDH). Although all natural IMDHs use nicotinamideadenine dinucleotide (NAD) as a coenzyme, they can be engineeredto use nicotinamide adenine dinucleotide phosphate (NADP) instead.Intermediates between these two phenotypic extremes show thateach amino acid contributes additively to enzyme function, withepistatic contributions confined to fitness. The genotype-phenotype-fitnessmap shows that NAD use is a global optimum.
1 BioTechnology Institute 2 Department of Entomology 3 Department of Ecology, Evolution and Behavior, University of Minnesota, St. Paul, MN 55108, USA.
* To whom correspondence should be addressed. E-mail: adean{at}biosci.umn.edu
