Transition state structure of arginine kinase: Implications for catalysis of bimolecular reactions

Genfa Zhou, Thayumanasamy Somasundaram, Eric Blanc, Golapakrishnan Parthasarathy, W. Ross Ellington, Michael S. Chapman

Research output: Contribution to journalArticle

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Abstract

Arginine kinase belongs to the family of enzymes, including creatine kinase, that catalyze the buffering of ATP in cells with fluctuating energy requirements and that has been a paradigm for classical enzymological studies. The 1.86-Å resolution structure of its transition-state analog complex, reported here, reveals its active site and offers direct evidence for the importance of precise substrate alignment in the catalysis of bimolecular reactions, in contrast to the unimolecular reactions studied previously. In the transition-state analog complex studied here, a nitrate mimics the planar γ-phosphoryl during associative in-line transfer between ATP and arginine. The active site is unperturbed, and the reactants are not constrained covalently as in a bisubstrate complex, so it is possible to measure how precisely they are pre-aligned by the enzyme. Alignment is exquisite. Entropic effects may contribute to catalysis, but the lone-pair orbitals are also aligned close enough to their optimal trajectories for orbital steering to be a factor during nucleophilic attack. The structure suggests that polarization, strain toward the transition state, and acid- base catalysis also contribute, but, in contrast to unimolecular enzyme reactions, their role appears to be secondary to substrate alignment in this bimolecular reaction.

Original languageEnglish (US)
Pages (from-to)8449-8454
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number15
DOIs
StatePublished - Jul 21 1998

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