This is to announce a preprint available for the following
publication:
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Molecular characterization of Ancylostoma inhibitors of coagulation
factor Xa: hookworm anticoagulant activity in vitro predicts parasite
bloodfeeding in vivo.
Lisa M. Harrison, Andrew Nerlinger, Richard D. Bungiro, José Luis
Córdova(+), Petr Kuzmic(#), and Michael Cappello *
Yale University School of Medicine, New Haven, CT 06520-8081
(+) Fundación Ciencia para la Vida, Santiago, Chile
(#) Biokin Ltd., Pullman WA 99163
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To be published in March 2002 in the Journal of Biological Chemistry
(manuscript No. M1 09908)
In this paper we used the software DYNAFIT [1] to identify a complex
molecular mechanism of inhibition for a novel inhibitor of the blood
coagulation Factor Xa. The mechanism is distinguished by the
following features:
o "tight-binding" inhbition;
o partial hyperbolic non-competitive;
o (at least) two binding sites for the inhibitor.
I think it is unusual to see "tight-binding" enzyme inhibitor that is
also a partial inhibitor.
Another very interesting (to us) aspect of this work is that we
compared small protein inhibitors from two different kinds of
blood-feeding hookworms: one feeding on humans, and one feeding on
dogs. These two kinds of hookworms cause damage to a different
extent.
Importantly, the worm which secretes a more potent (stronger binding,
strictly competitive) inhibitor of the blood coagulation Factor Xa is
more dangerous then the other worm, which secretes only a partial
inhibitor of Factor Xa (less tightly bound overall).
Thus, we claim that "hookworm anticoagulant activity in vitro predicts
parasite bloodfeeding in vivo". I think it is a very nice example of
how a molecular property such as the kinetic mechanism of inhibition
results in different health outcomes.
The preprint is available online in HTML [2] and PDF [3] formats.
Also available is some supplementary material [4] showing not only the
experimental data, but also the DYNAFIT scripts that were used to
analyze the data and come up with the mechanism.
Best regards,
- Petr Kuzmic
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P e t r K u z m i c, Ph. D. * BioKin Ltd.
1652 S. Grand Ave. * Suite 337 * Pullman, WA 99163
509.334.4131 * 509.332.3493 fax * http://www.biokin.com
REFERENCES:
[1] http://www.biokin.com/dynafit
[2] http://www.biokin.com/papers/JBC-M109908/
[3] http://www.biokin.com/papers/JBC-M109908/JBC-M109908.pdf
[4] http://www.biokin.com/papers/JBC-M109908/suppl.html
*
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