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African sleeping sickness and related diseases can be treated only with toxic and sometimes ineffective drugs. Now, University of Connecticut researchers show in Nucleic Acids Research that a crucial enzyme could be the key to safer, more effective medicines.
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Sleeping sickness, Chagas disease and leishmaniasis are all caused by trypanosomes and leishmanias, a group of single-celled microorganisms distantly related to animals. They're parasites that typically slip into human bodies via insect bites. Trypanosomes tend to use the same basic machinery to express their genes as our cells do, so finding medications that kill these parasites but don't hurt us is difficult.
UConn School of Medicine molecular biologist Arthur Gunzl and his research group have found a small but important difference in trypanosomes' cellular machinery. It happens when messenger RNA (mRNA) is stitched together. mRNA carries messages from DNA to a cell's protein-making machinery. Like any important message, it needs to be spelled properly.
A splicing enzyme stands apart
Both trypanosomes and human cells have to splice together RNA pieces to make precise mRNA messages. What Gunzl's team found was that trypanosomes use an enzyme for this process that is quite different from the one humans use. The trypanosome version of the enzyme, a cyclin-dependent kinase called CRK9, is insensitive to a compound that inhibits the human version.
This suggests that the active sites of these enzymes differ and that an inhibitor could be found to work against the trypanosome kinase without affecting its human counterpart.
An ancient role comes into view
The discovery is particularly surprising because other single-celled organisms, such as yeast, don't use a cyclin-dependent kinase for mRNA splicing at all. It was thought to be unique to multicellular organisms. Gunzl's group is the first to show this enzyme at work in trypanosomes. The fact that we share it with these very different organisms suggests it is evolutionarily ancient.
More information: Kazuya Machida et al, SF3B1 phosphorylation is an evolutionarily conserved step in spliceosome activation carried out by the divergent, OTS964-insensitive kinase CRK9 in trypanosomes, Nucleic Acids Research (2026). DOI: 10.1093/nar/gkag541
Provided by University of Connecticut
This story was originally published on Phys.org.
