YHM2

PF3D7_1223800 (YHM2) is a putative mitochondrial carboxylic acid carrier in Plasmodium falciparum that contributes to feeding glutamine-derived carbon into the mitochondrial TCA cycle during asexual blood-stage growth (PMID:40398604). Genetic knockout of YHM2, either alone or in combination with the dicarboxylate/tricarboxylate carrier DTC and both mitochondrial pyruvate carriers (PfMPCs) as a quadruple knockout, only mildly impairs asexual replication, indicating YHM2 is not individually essential for blood-stage proliferation (PMID:40398604). Isotopic metabolite tracing by HPLC-MS in the quadruple knockout showed a large reduction in glutamine-derived label in TCA cycle metabolites, establishing that YHM2 (together with DTC) imports glutamine derivatives into the mitochondrion rather than being required for glucose-derived carbon import (PMID:40398604). Beyond this metabolic role, no direct biochemical demonstration of YHM2 transport activity, substrate specificity, or its subcellular localization has been characterized in the available corpus.

1. 2025 Medium

   It was unknown which mitochondrial carriers route glutamine-derived carbon into the P. falciparum TCA cycle; combining genetic ablation with isotopic tracing showed YHM2 contributes to this import while being dispensable for glucose-derived carbon entry, defining its metabolic role rather than an essential proliferative one.

   Evidence Genetic knockout of YHM2 alone and in a quadruple KO with DTC and both PfMPCs, combined with glutamine isotopic tracing via HPLC-MS metabolomics and blood-stage growth assays

   PMID:40398604

   Open questions at the time

   • No direct biochemical reconstitution of YHM2 transport activity or substrate specificity (citrate vs alpha-ketoglutarate vs glutamine derivatives)
   • Contributions of YHM2 versus DTC to glutamine import not resolved individually
   • Subcellular localization of YHM2 not experimentally confirmed in the corpus

• Whether YHM2 directly transports a defined substrate, and its specific contribution independent of DTC and other mitochondrial carriers, remains unresolved.
• No in vitro transport assay or reconstituted-liposome demonstration of substrate handling
• No single-gene metabolic phenotype separating YHM2 from DTC
• No structural or localization data