Evolution: The biochemical architecture of an ancient adaptive landscape

Mark Lunzer, Stephen P. Miller, Roderick Felsheim, Antony M. Dean

Research output: Contribution to journalArticlepeer-review

176 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)499-501
Number of pages3
Issue number5747
StatePublished - Oct 21 2005


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