An enzyme common to parasites and people would hardly seem a promising drug target. Yes, a drug that could interfere with such an enzyme might kill a deadly parasite, but it might as easily harm the parasite’s host. So, when it comes to blocking the activity of common enzymes, forbearance is the better part of care.

But perhaps not always. Consider pyruvate kinase, an enzyme common to parasites, bacteria, and mammals that is essential for converting nutrients into energy. It turns out that it may be possible to block pyruvate kinase activity in parasites while preserving it in humans, including patients suffering from sleeping sickness and Chagas disease—not to mention all the other diseases that are spread by parasites and afflict millions of people in the developing world.

According to researchers at the University of Edinburgh, pyruvate kinase has different mechanisms of activation in different species. Having a distinct means of activating pyruvate kinase, say the researchers, could make parasites vulnerable to specially designed drugs.

This finding appeared September 23 in the first edition of the journal Royal Society Open Science, in an article entitled, “Structures of pyruvate kinases display evolutionarily divergent allosteric strategies.” The “divergent allosteric strategies” refer to different ways of transitioning between active and inactive forms of pyruvate kinase, or PYK.

“A detailed kinetic and structural comparison between the potential drug target PYKs from the pathogenic protists [Trypanosoma] cruzi, T. brucei, and Leishmania mexicana shows that their allosteric mechanism is conserved,” wrote the authors. “By contrast, a structural comparison of trypanosomatid PYKs with the evolutionarily divergent PYKs of humans and of bacteria shows that they have adopted different allosteric strategies.”

All species, the authors explained, accomplish a similar task. They transition pyruvate kinase to an active state by reorienting the enzyme’s four subunits (and enhancing its specificity) by stabilizing and rigidifying them, arriving at an “active R-state conformation.” However, bacterial and mammalian pyruvate kinases have evolved alternative ways of locking the tetramers together.

The researchers summarized the differences as follows:

  • Bacterial PYKs as exemplified by the GsPYK tetramer are stabilized by the rotation of a series of additional domains (domain C') which bridge across the C–C interface thereby stabilizing the tetramer.
  • Trypanosomatid PYKs possess simple loops (effector loops) which again form a series of bridges across the C–C interface enhancing tetramer stability.
  • Human M2PYK has evolved in a different direction whereby it is able to dissociate into inactive monomers, and the active tetramer is formed and stabilized in response to effector binding.

“Selective disruption of these allosteric mechanisms may provide new and specific drug targets which avoid the problem of developing selective inhibitors against similar active sites,” the authors of the Royal Society Open Science article concluded. “Such inhibitors/activators could be used to tackle trypanosomiasis, cancer (M2PYK), anaemia (RPYK) and bacterial infection (methicillin-resistant Staphylococcus aureus PYK).”

Professor Malcolm Walkinshaw, Chair of Structural Biology at the University of Edinburgh, who led the study, said: “With this discovery, we’ve found an Achilles heel for sleeping sickness and many other conditions. Fresh discoveries about this key enzyme—pyruvate kinase—could enable the design of treatments to tackle disease without harm to the patient.”

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