January 2011

ASBMB research on venom proteins

GelbMichael H. Gelb

Harry and Catherine Jaynne Boand Endowed Professor of Chemistry
University of Washington, Seattle

Snakes may elicit a lot of fear due to their venomous nature, but in fact, the innocuous-looking honeybee kills more people each year in the U.S.

Of course, the threat of a bee sting is not the toxins themselves but rather the allergic reaction (anaphylaxis) that can occur following injection. This is due in large part to the presence of significant amounts of the allergen phospholipase A2, an enzyme that breaks down phospholipids found on cell membranes.

Over the years, bee venom has been a favorite system for allergy research, and scientists have made strides in adapting bee venom as an immunotherapy agent for insect stings and other immune conditions like arthritis.

However, it was in the 1980s, when researchers had found evidence that mammalian secreted phospholipases A2 might be involved in producing arachidonic acid, the precursor to prostaglandins and other eicosanoids (key inflammatory agents), that even more people took notice, including Michael H. Gelb.

Gelb, whose multifaceted interests include medicinal enzymology, drug design and protein prenylation, was interested in the link to inflammation and decided to use bee phospholipase as a model of the mammalian enzymes.

The initial choice was a pragmatic one. “Back then it was quite a challenge to engineer to express these proteins because of their many disulfide bonds,” he says. “But we were able to express the bee PLA2 in E. coli and so we went with that, even though the enzyme is more distant to humans than PLA2 found in snakes.”

The choice proved to be quite fruitful, and since his first experiments some 20 years ago, Gelb’s group has discovered numerous insights into phospholipase biochemistry with the help of the bee model. This work has included structural studies on the enzyme (with renowned structural biologist Paul Sigler of Yale University), which revealed that PLA2 has distinct lipid binding and active sites and that catalysis likely occurs through diffusion of a single phospholipid substrate into the active site slot without a conformational change to the PLA2 upon binding to the membrane surface. His group also has identified mechanisms underlying both membrane binding and antibody binding.

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