SufS

PF3D7_0716600 (SufS) is a PLP-dependent cysteine desulfurase that localizes exclusively to the apicoplast, where it mobilizes sulfur from L-cysteine as the entry step of the SUF Fe-S cluster biosynthesis pathway and is essential for maintenance of the apicoplast organelle and its genome (PMID:24086138). Its desulfurase activity is greatly enhanced by the partner SufE, with which it forms an in vivo complex; structural modeling places conserved cysteines of SufS and SufE in proximity, consistent with sulfide transfer from the PLP-bound SufS active site to SufE (PMID:24709262). Beyond Fe-S biogenesis, SufS provides sulfur to the apicoplast tRNA-modifying enzyme MnmA for s2U/xm5s2U modification, and bacterial MnmA-plus-desulfurase complementation shows this tRNA-modification role—not Fe-S biosynthesis—accounts for the unique apicoplast- and organellar-genome-disrupting phenotype of SufS deletion (PMID:37166116, PMID:39763917). This dual role makes SufS essential across the parasite life cycle: it is refractory to deletion in asexual blood stages and its conditional knockout impairs sporozoite development in the mosquito vector (PMID:24586983, PMID:28695709). The PLP-directed inhibitors D- and L-cycloserine form adducts with SufS-bound PLP and block sulfide release, defining an antimalarial drug-target vulnerability (PMID:24709262, PMID:35395703).

1. 2013 High

   Established that SufS is an apicoplast-resident cysteine desulfurase and that its pathway is essential for organelle maintenance beyond isoprenoid biosynthesis, defining the first functional role for the gene.

   Evidence Fluorescence localization, complementation of desulfurase activity, dominant-negative disruption with IPP rescue in P. falciparum

   PMID:24086138

   Open questions at the time

   • Did not resolve which downstream product of sulfur mobilization is required for organelle maintenance
   • Enzymatic partners not yet identified
2. 2014 High

   Identified SufE as the functional partner that enhances SufS desulfurase activity and defined the sulfide-transfer geometry and PLP-directed inhibition, converting a lone enzyme into a characterized two-component sulfur-mobilization module.

   Evidence In vitro desulfurase assays, in vivo co-immunoprecipitation, structural modeling, and D-cycloserine adduct/inhibition assays in P. falciparum

   PMID:24709262

   Open questions at the time

   • Sulfide transfer to SufE inferred from modeling, not from a solved SufS-SufE structure
   • Downstream Fe-S assembly steps not reconstituted
3. 2014 Medium

   Genetic evidence that SufS is required for asexual blood-stage survival, establishing essentiality in the rodent malaria model.

   Evidence Failed targeted gene deletion and fluorescent apicoplast localization of tagged SUF proteins including SufS in P. berghei

   PMID:24586983

   Open questions at the time

   • Refractoriness to deletion does not by itself define the essential molecular function
   • Assessed alongside other SUF members rather than SufS in isolation
4. 2017 High

   Extended essentiality of SufS from blood stages to the mosquito vector, showing the gene is required across life-cycle transitions.

   Evidence Cre-lox conditional knockout in P. berghei mosquito stages with sporozoite development assay

   PMID:28695709

   Open questions at the time

   • Molecular basis of the sporozoite defect not resolved
   • Whether the requirement reflects Fe-S or tRNA-modification function not addressed
5. 2019 Low

   Showed the SufS-SufE sulfur-mobilization interaction is conserved in clinical parasite material despite sequence variation from lab strains.

   Evidence In vitro protein interaction assay using P. vivax clinical-isolate proteins

   PMID:30721667

   Open questions at the time

   • Single in vitro interaction assay without reciprocal or in vivo validation
   • No enzymatic or phenotypic readout for the P. vivax proteins
6. 2022 Medium

   Defined the distinct mechanisms by which D- and L-cycloserine inactivate SufS PLP chemistry, informing structure-based antimalarial design.

   Evidence Biochemical inhibition, X-ray crystallography, and active-site mutagenesis using B. subtilis SufS as a surrogate for the P. falciparum enzyme

   PMID:35395703

   Open questions at the time

   • Mechanistic detail extrapolated from a bacterial surrogate, not confirmed in P. falciparum SufS
   • Selectivity against host desulfurases not established
7. 2023 High

   Resolved why SufS deletion is uniquely lethal by showing its essential role is supplying sulfur to the tRNA-modifying enzyme MnmA rather than to Fe-S biosynthesis, distinguishing SufS from other pathway components.

   Evidence Conditional gene deletion with chemical bypass, organelle/genome integrity assays, MnmA localization, and cross-species bacterial MnmA-plus-desulfurase complementation in P. falciparum

   PMID:37166116

   Open questions at the time

   • Direct sulfur-transfer between SufS and MnmA not biochemically reconstituted
   • Relative contribution of Fe-S versus tRNA-modification pathways to viability not quantified
8. 2025 Medium

   Corroborated that SufS supplies sulfur for xm5s2U apicoplast tRNA modification by showing its deletion phenotype is mirrored by loss of MnmA, MnmE, and MnmG.

   Evidence Comparative genomics and genetic deletion with apicoplast-integrity readout in P. falciparum (preprint)

   PMID:39763917

   Open questions at the time

   • Preprint, single lab
   • Does not add direct biochemical demonstration of SufS-to-MnmA sulfur transfer

• How SufS partitions its mobilized sulfur between SufE/Fe-S assembly and MnmA/tRNA modification, and whether a direct SufS-MnmA transfer complex forms, remains unresolved.
• No reconstituted SufS-MnmA sulfur-transfer assay
• No solved structure of SufS in complex with SufE or MnmA
• Mechanism directing sulfur to competing acceptors unknown