Direct demonstration of an adaptive constraint

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

Research output: Contribution to journalArticlepeer-review

61 Scopus citations


The role of constraint in adaptive evolution is an open question. Directed evolution of an engineered β-isopropylmalate dehydrogenase (IMDH), with coenzyme specificity switched from nicotinamide adenine dinucleotide (NAD) to nicotinamide adenine dinucleotide phosphate (NADP), always produces mutants with lower affinities for NADP. This result is the correlated response to selection for relief from inhibition by NADPH (the reduced form of NADP) expected of an adaptive landscape subject to three enzymatic constraints: an upper limit to the rate of maximum turnover (kcat), a correlation in NADP and NADPH affinities, and a trade-off between NAD and NADP usage. Two additional constraints, high intracellular NADPH abundance and the cost of compensatory protein synthesis, have ensured the conserved use of NAD by IMDH throughout evolution. Our results show that selective mechanisms and evolutionary constraints are to be understood in terms of underlying adaptive landscapes.

Original languageEnglish (US)
Pages (from-to)458-461
Number of pages4
Issue number5798
StatePublished - Oct 20 2006


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