title: The moderately efficient enzyme: evolutionary and physicochemical trends shaping enzyme parameters.
abstract: The kinetic parameters of enzymes are key to understanding the rate and specificity of most biological processes. Although specific trends are frequently studied for individual enzymes, global trends are rarely addressed. We performed an analysis of k(cat) and K(M) values of several thousand enzymes collected from the literature. We found that the "average enzyme" exhibits a k(cat) of ~0 s(-1) and a k(cat)/K(M) of ~10(5) s(-1) M(-1), much below the diffusion limit and the characteristic textbook portrayal of kinetically superior enzymes. Why do most enzymes exhibit moderate catalytic efficiencies? Maximal rates may not evolve in cases where weaker selection pressures are expected. We find, for example, that enzymes operating in secondary metabolism are, on average, ~30-fold slower than those of central metabolism. We also find indications that the physicochemical properties of substrates affect the kinetic parameters. Specifically, low molecular mass and hydrophobicity appear to limit K(M) optimization. In accordance, substitution with phosphate, CoA, or other large modifiers considerably lowers the K(M) values of enzymes utilizing the substituted substrates. It therefore appears that both evolutionary selection pressures and physicochemical constraints shape the kinetic parameters of enzymes. It also seems likely that the catalytic efficiency of some enzymes toward their natural substrates could be increased in many cases by natural or laboratory evolution.
authors.affiliation: Department of Plant Sciences, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Arren
authors.initials: A
authors.lastname: Bar-Even
authors.forename: Elad
authors.initials: E
authors.lastname: Noor
authors.forename: Yonatan
authors.initials: Y
authors.lastname: Savir
authors.forename: Wolfram
authors.initials: W
authors.lastname: Liebermeister
authors.forename: Dan
authors.initials: D
authors.lastname: Davidi
authors.forename: Dan S
authors.initials: DS
authors.lastname: Tawfik
authors.forename: Ron
authors.initials: R
authors.lastname: Milo
mesh_terms: D005075:Biological Evolution; D004798:Enzymes / Q000378:metabolism*; D007700:Kinetics; D011312:Pressure
chemical_list: D004798:Enzymes