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APYRASES
Ok, so what is an apyrase?
My research centers around extracellular nucleotidases referred to as apyrases; these are plasma membrane or soluble enzymes with active nucleotide
hydrolysis sites facing the exterior of the cell. Apyrases have a
broad nucleotide substrate range (e.g. ATP, ADP, UTP, UDP) and require divalent cations such as calcium or magnesium
for activity.
What do apyrases do?
With the intense amount of study
devoted to these enzymes within the last several years, it is becoming clear that the physiological
roles of these enzymes are many. There is
convincing evidence to suggest that these enzymes inactivate extracellular nucleotide signals, both in the cardiovascular
system and associated smooth muscle. Extracellular nucleotides like
ATP have been shown to be very effective regulators of blood vessel vascular
tone by binding to specific P2 purine receptors, causing blood vessels to dilate in some
instances and to constrict in other cases. This directly modulates
blood pressure. Presumably extracellular nucleotidases function to
"clear" the nucleotide stimulus from the receptor after the appropriate
response has been generated.
And...
With respect to function in the vasculature,
extracellular ADP is a well known agonist of the P2Y12 receptor on blood platelets. At least one extracellular nucleotidase (NTPDase 1 or CD39) is present in the endothelial cells of the vascular system, and it has
been shown to play an important role in maintaining blood hemostasis (prevention
of blood loss) and preventing thrombosis (abnormal blood clotting).
Hydrolyzing the nucleotide ADP (which is a potent agonist
of blood platelets), the nucleotidase likely prevents excess platelet aggregation and keeps the event very localized. Soluble forms of these enzymes have also been found
in the salivary glands of blood-feeding insects such as mosquitoes,
ticks, bedbugs, and "sand flies" (Culicoides). Injection of the soluble nucleotidase by these creatures
presumably functions to prevent platelet aggregation by degrading the extracellular
nucleotides, allowing for easier feeding from the host. In fact,
my collaborators and I have produced a soluble form of a human apyrase that is very similar to the salivary apyrases of blood-feeding arthropods, and have shown the ability of this mutant enzyme to prevent platelet aggregation.
So what's happening now in the extracellular apyrase field?
Recently I succeeded in isolating
a new human apyrase, SCAN-1, GenBank Accession Number
AF328554.
This enzyme, which is homologous to the salivary apyrase of the blood-feeding bedbug, may play a totally unrelated role in human nucleotide metabolism in the endoplasmic reticulum and Golgi apparatus.
Currently
my research is involved in analyzing the properties of these soluble nucleotidases as potential anti-thrombotic agents. This is a
very exciting time in the extracellular apyrase field and future
work may elucidate the role of these enzymes in the body, as well as contribute a new therapeutic mechanism for prevention of damage from excess platelet activation.
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