Human Enzyme Cuts Platelet "Stickiness" in a Whole New Way; Offers Potential Approach to Treating Stroke and Thrombosis
Mar 2, 2004
Researchers at Weill Cornell Medical College have determined the 3-dimensional structure of a human enzyme that is similar to one found in the saliva of mosquitoes and other biting insects.
In insects, enzymes of this family called apyrases are produced in the saliva and allow the pests to sip blood easily by keeping their meal free of blood clots.
Dr. Min Lu, Associate Professor of Biochemistry at Weill Cornell Medical College in New York, and colleagues report in the journal Cell that they have used a technique called X-ray crystallography to work out the 3-D structure of apyrase in humans.
Normally, the human version of the enzyme does nothing to prevent blood clots. However, by re-engineering the human apyrase structure, the researchers were able to achieve a 100-fold boost in its ability to inhibit a blood clot-promoting compound called adenosine diphosphate (ADP).
Any type of injury boosts ADP levels, including damage or blockage of blood vessels in the heart, brain, or elsewhere in the body. ADP causes platelets to morph from their normal disc-shape into spiky spheres that tend to stick together. The ADP boost is designed to keep bleeding under control, a distinct disadvantage for thirsty bugs.
Insect enzymes have a high ADP neutralizing activity, designed to keep blood flowing. The human enzyme has a different job that's totally unrelated, said Dr. Lu.
Using what we call a comparative structural biology approach, we compared the sequence of amino acids the building blocks of proteins in humans and insects.
Based on the sequence alignments of our crystal structure, we pinpointed which amino acids are required for ADPase activity in the insects, and then we replaced the key amino acids in the human version with the amino acids from the insect version, he said. We took advantage of sucking insects, who use this strategy to maximize their blood-taking from their host.
Our engineered version of human apyrase, known as HB-apyrase, is a potent inhibitor of platelets, cells crucial for clot formation, said Dr. Lu. In the future, versions of our HB-apyrase might find applications as therapeutics for stroke or heart attack, which is often caused by blood clots.
However, much more research is needed before any such applications are real. The researchers have so far tested the compounds only on platelets in laboratory culture dishes. This research is fundamental research, Dr. Lu emphasized. While a therapeutic drug would be a Holy Grail, we don't know if we can achieve that goal tomorrow, in 10 years, or 50 years.
Study co-authors include Weill Cornell's Jiayin Dai, Jie Liu, and Yiqun Deng. Thomas Smith of Wyeth Research was also a co-author.
The work was supported by grants from the National Institutes of Health (NIH) and the Irma T. Hirschl Trust.