Vanheer, L. N. | Search bioRxiv

bioRxiv2022

Metabolic competition between lipid metabolism and histone methylation regulates sexual differentiation in human malaria parasites.

For Plasmodium falciparum, the most widespread and virulent malaria parasite that infects humans, persistence depends on continuous asexual replication in red blood cells, while transmission to their mosquito vector requires asexual blood-stage parasites to differentiate into non-replicating gametocytes. This decision is controlled by stochastic de-repression of a heterochromatin-silenced locus encoding PfAP2-G, the master transcription factor of sexual differentiation. The frequency of pfap2-g de-repression was shown to be responsive to extracellular phospholipid precursors but the mechanism linking these metabolites to epigenetic regulation of pfap2-g was unknown. Here we show that this response is mediated by metabolic competition for the methyl donor S-adenosylmethionine between histone methyltransferases and phosphoethanolamine methyltransferase, a critical enzyme in the parasites pathway for de novo phosphatidylcholine synthesis. When phosphatidylcholine precursors are scarce, increased consumption of SAM for de novo phosphatidylcholine synthesis impairs maintenance of the histone methylation responsible for silencing pfap2-g, increasing the frequency of derepression and sexual differentiation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/476397v3_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@5e2c69org.highwire.dtl.DTLVardef@b5a7d6org.highwire.dtl.DTLVardef@1e118aorg.highwire.dtl.DTLVardef@1191a6_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2020

Activity of epigenetic inhibitors against Babesia divergens.

Babesiosis in a tick-borne parasitic disease of humans and livestock, that has dramatically increased in frequency and geographical range over the past few decades. Infection of cattle often causes large economic losses, and human infection can be fatal in immunocompromised patients. Unlike for malaria, another disease caused by hemoprotozoan parasites, limited treatment options exist for Babesia infections. As epigenetic regulation is a promising target for new anti-parasitic drugs, we screened 324 epigenetic inhibitors against Babesia divergens blood stages and identified 75 (23%) and 17 (5%) compounds that displayed [≥]90% inhibition at 10 {micro}M and 1 {micro}M, respectively, including over a dozen compounds with activity in the low nanomolar range. We observed differential activity of some inhibitor classes against Babesia divergens and Plasmodium falciparum parasites and identified pairs of compounds with a high difference in activity, despite a high similarity in chemical structure, highlighting new insights into the development of epigenetic inhibitors as anti-parasitic drugs.

microbiology↗