Metabolic competition between lipid metabolism and histone methylation regulates sexual differentiation in human malaria parasites
biorxiv(2023)
摘要
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 Pf AP2-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 parasite’s 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.
![Figure][1]
### Competing Interest Statement
The authors have declared no competing interest.
* 3-DZA
: 3-deaza-adenosine
cho
: choline
CDP-cho
: cytidine diphosphate-choline
CK
: choline kinase
GlcNAC
: N-acetyl glucosamine
Glm
: glucosamine
hcys
: homocysteine
iRBC
: infected RBC
LysoPC
: lyso-phosphatidylcholine
met
: methionine
P-cho
: phospho-choline
P-etn
: phospho-ethanolamine
P-etn-me1/2
: mono/di-methylphosphoethanolamine
PMT
: phosphoethanolamine methyltransferase
PtdCho
: phosphatidylcholine
RBC
: red blood cell
SAH
: S-adenosylhomocysteine
SAHH
: S-adenosylhomocysteine hydrolase
SAM
: S-adenosylmethionine
SAMS
: S-adenosylmethionine synthetase
ser
: serine
TMP
: trimethoprim
uRBC
: uninfected RBC
[1]: pending:yes
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