Interaction between sulphur mobilisation proteins SufB and SufC: Evidence for an iron–sulphur cluster biogenesis pathway in the apicoplast of Plasmodium falciparum

Kumar, Bikash; Chaubey, Sushma; Shah, Priyanka; Tanveer, Aiman; Charan, Manish; Siddiqi, Mohammad Imran; Habib, Saman

doi:10.1016/j.ijpara.2011.05.006

Cited by 48 publications

(58 citation statements)

References 56 publications

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“…It harbors unique pathways such as the type II fatty acid biosynthesis pathway, the DOXP pathway of isoprenoid synthesis, and the heme biosynthesis pathway (3)(4)(5), that offer potential novel sites for drug intervention at different stages of the infection cycle. In addition, experimental evidence of the existence of the sulfur mobilization (SUF) pathway for biogenesis of Fe-S clusters on organellar proteins was provided by our laboratory (6), and this pathway has recently been shown to be essential for apicoplast maintenance in erythrocytic stages of Plasmodium falciparum (7).…”

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confidence: 99%

“…encode the ISC and SUF pathways (8,17), some of whose constituent proteins have recently been shown to partition to the parasite mitochondrion and apicoplast, respectively (6,7). The 35-kb genome of the apicoplast carries the gene encoding SufB, while all of the other proteins of the SUF pathway are encoded by the nucleus.…”

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confidence: 99%

“…The 35-kb genome of the apicoplast carries the gene encoding SufB, while all of the other proteins of the SUF pathway are encoded by the nucleus. In P. falciparum, the targeting of SufC, SufS, and SufE to the apicoplast and the interaction of apicoplastencoded SufB with SufC have been demonstrated (6,7). Nucleusencoded SufA and SufD homologues carrying apicoplast-targeting signal and transit peptide sequences have been identified in P. falciparum (6,17).…”

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confidence: 99%

“…In P. falciparum, the targeting of SufC, SufS, and SufE to the apicoplast and the interaction of apicoplastencoded SufB with SufC have been demonstrated (6,7). Nucleusencoded SufA and SufD homologues carrying apicoplast-targeting signal and transit peptide sequences have been identified in P. falciparum (6,17). In P. berghei, a scaffold NifU homologue has been shown to target to the apicoplast but is proposed to play only an auxiliary or redundant role in Fe-S formation (18).…”

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Sulfur Mobilization for Fe-S Cluster Assembly by the Essential SUF Pathway in the Plasmodium falciparum Apicoplast and Its Inhibition

Charan

Singh

Kumar

et al. 2014

Antimicrob Agents Chemother

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bThe plastid of the malaria parasite, the apicoplast, is essential for parasite survival. It houses several pathways of bacterial origin that are considered attractive sites for drug intervention. Among these is the sulfur mobilization (SUF) pathway of Fe-S cluster biogenesis. Although the SUF pathway is essential for apicoplast maintenance and parasite survival, there has been limited biochemical investigation of its components and inhibitors of Plasmodium SUFs have not been identified. We report the characterization of two proteins, Plasmodium falciparum SufS (PfSufS) and PfSufE, that mobilize sulfur in the first step of Fe-S cluster assembly and confirm their exclusive localization to the apicoplast. The cysteine desulfurase activity of PfSufS is greatly enhanced by PfSufE, and the PfSufS-PfSufE complex is detected in vivo. Structural modeling of the complex reveals proximal positioning of conserved cysteine residues of the two proteins that would allow sulfide transfer from the PLP (pyridoxal phosphate) cofactor-bound active site of PfSufS. Sulfide release from the L-cysteine substrate catalyzed by PfSufS is inhibited by the PLP inhibitor D-cycloserine, which forms an adduct with PfSufS-bound PLP. D-Cycloserine is also inimical to parasite growth, with a 50% inhibitory concentration close to that reported for Mycobacterium tuberculosis, against which the drug is in clinical use. Our results establish the function of two proteins that mediate sulfur mobilization, the first step in the apicoplast SUF pathway, and provide a rationale for drug design based on inactivation of the PLP cofactor of PfSufS.

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Sulfur Mobilization for Fe-S Cluster Assembly by the Essential SUF Pathway in the Plasmodium falciparum Apicoplast and Its Inhibition

Charan

Singh

Kumar

et al. 2014

Antimicrob Agents Chemother

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“…Since a functional apicoplast is essential for a viable parasite cell, inhibition of housekeeping functions of the plastid leads to parasite death, although this often follows a 'delayed-death' phenotype wherein the blood-stage parasite dies in the cycle subsequent to the one in which it has been exposed to the drug. The apicoplast harbours biosynthetic pathways such as type II fatty acid synthesis (Waller et al 2000;Surolia and Surolia 2001), the synthesis of heme (Sato et al 2004;Dhanasekaran et al 2004) as well as [Fe-S] complexation (Kumar et al 2011). However, the production of isopentenyl pyrophosphate (IPP) via the nonmevalonate isoprenoid biosynthesis pathway seems to be the only essential function of the apicoplast (Yeh and DeRisi 2011).…”

Section: Translation Components As Targets For Drug Intervention Agaimentioning

confidence: 99%

Translation in Mitochondria and Apicoplasts of Apicomplexan Parasites

Gupta

Haider

Vaishya

et al. 2013

Translation in Mitochondria and Other Organelles

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Protozoan parasites of the phylum apicomplexa are the causal organisms for several important infectious diseases. They contain three cellular compartments -the cytoplasm, mitochondrion, and the relic plastid called the apicoplast, where active translation takes place. Early investigations of the components and activities of the translation machinery in parasite organelles have provided evidence for intriguing variations from other systems. Understanding these mechanisms also offers novel possibilities for drug intervention. In this article, we discuss the translation machinery in the apicoplast and mitochondrion of the apicomplexan cell, with emphasis on current knowledge from Plasmodium and Toxoplasma.

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A putative RNA binding protein from Plasmodium vivax apicoplast

et al. 2017

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Malaria is caused by Apicomplexa protozoans from the Plasmodium genus entering the bloodstream of humans and animals through the bite of the female mosquitoes. The annotation of the Plasmodium vivax genome revealed a putative RNA binding protein (apiRBP) that was predicted to be trafficked into the apicoplast, a plastid organelle unique to Apicomplexa protozoans. Although a 3D structural model of the apiRBP corresponds to a noncanonical RNA recognition motif with an additional C‐terminal α‐helix (α 3 ), preliminary protein production trials were nevertheless unsuccessful. Theoretical solvation analysis of the apiRBP model highlighted an exposed hydrophobic region clustering α 3 . Hence, we used a C‐terminal GFP‐fused chimera to stabilize the highly insoluble apiRBP and determined its ability to bind U‐rich stretches of RNA. The affinity of apiRBP toward such RNAs is highly dependent on ionic strength, suggesting that the apiRBP–RNA complex is driven by electrostatic interactions. Altogether, apiRBP represents an attractive tool for apicoplast transcriptional studies and for antimalarial drug design.

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Interaction between sulphur mobilisation proteins SufB and SufC: Evidence for an iron–sulphur cluster biogenesis pathway in the apicoplast of Plasmodium falciparum

Cited by 48 publications

References 56 publications

Sulfur Mobilization for Fe-S Cluster Assembly by the Essential SUF Pathway in the Plasmodium falciparum Apicoplast and Its Inhibition

Sulfur Mobilization for Fe-S Cluster Assembly by the Essential SUF Pathway in the Plasmodium falciparum Apicoplast and Its Inhibition

Translation in Mitochondria and Apicoplasts of Apicomplexan Parasites

A putative RNA binding protein from Plasmodium vivax apicoplast

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