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Science 11 July 1997:
Vol. 277. no. 5323, pp. 202 - 206
DOI: 10.1126/science.277.5323.202
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Research Articles

Orbital Steering in the Catalytic Power of Enzymes: Small Structural Changes with Large Catalytic Consequences

Andrew D. Mesecar, Barry L. Stoddard, Daniel E. Koshland Jr.

Small structural perturbations in the enzyme isocitrate dehydrogenase (IDH) were made in order to evaluate the contribution of precise substrate alignment to the catalytic power of an enzyme. The reaction trajectory of IDH was modified (i) after the adenine moiety of nicotinamide adenine dinucleotide phosphate was changed to hypoxanthine (the 6-amino was changed to 6-hydroxyl), and (ii) by replacing Mg2+, which has six coordinating ligands, with Ca2+, which has eight coordinating ligands. Both changes make large (10-3 to 10-5) changes in the reaction velocity but only small changes in the orientation of the substrates (both distance and angle) as revealed by cryocrystallographic trapping of active IDH complexes. The results provide evidence that orbital overlap produced by optimal orientation of reacting orbitals plays a major quantitative role in the catalytic power of enzymes.

A. D. Mesecar and D. E. Koshland Jr. are in the Department of Molecular and Cell Biology, Stanley Hall, University of California, Berkeley, CA 94720, and Center for Advanced Materials, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. B. L. Stoddard is at the Division of Basic Sciences, Program in Structural Biology, Fred Hutchinson Cancer Research Center, 1124 Columbia Street A3-023, Seattle, WA 98104, USA.

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