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Science 14 December 1990:
Vol. 250. no. 4987, pp. 1541 - 1546
DOI: 10.1126/science.2274785
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Articles

Science, Vol 250, Issue 4987, 1541-1546
Copyright © 1990 by American Association for the Advancement of Science

articles

Interfacial catalysis: the mechanism of phospholipase A2

DL Scott, SP White, Z Otwinowski, W Yuan, MH Gelb, and PB Sigler

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511.

A chemical description of the action of phospholipase A2 (PLA2) can now be inferred with confidence from three high-resolution x-ray crystal structures. The first is the structure of the PLA2 from the venom of the Chinese cobra (Naja naja atra) in a complex with a phosphonate transition-state analogue. This enzyme is typical of a large, well-studied homologous family of PLA2S. The second is a similar complex with the evolutionarily distant bee-venom PLA2. The third structure is the uninhibited PLA2 from Chinese cobra venom. Despite the different molecular architectures of the cobra and bee-venom PLA2s, the transition-state analogue interacts in a nearly identical way with the catalytic machinery of both enzymes. The disposition of the fatty-acid side chains suggests a common access route of the substrate from its position in the lipid aggregate to its productive interaction with the active site. Comparison of the cobra-venom complex with the uninhibited enzyme indicates that optimal binding and catalysis at the lipid-water interface is due to facilitated substrate diffusion from the interfacial binding surface to the catalytic site rather than an allosteric change in the enzyme's structure. However, a second bound calcium ion changes its position upon the binding of the transition-state analogue, suggesting a mechanism for augmenting the critical electrophile.


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