Crystal Structure of Arginase from <i>Plasmodium falciparum</i> and Implications for <scp>l</scp>-Arginine Depletion in Malarial Infection,

Dowling, Daniel; Ilies, Monica; Olszewski, Kellen L.; Portugal, Sílvia; Mota, Maria M.; Llinás, Manuel; Christianson, D.W.

doi:10.1021/bi100390z

Cited by 41 publications

(52 citation statements)

References 59 publications

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“…falciparum and P. berghei ANKA both express a functional arginase enzyme that produces ornithine from arginine in vitro [7,19]. To determine whether parasite-expressed arginase is required for arginine depletion in vivo, we analyzed plasma amino acids from C57BL/6 mice infected with argKO or WT parasites.…”

Section: Evaluation Of Parasite Arginase Level As a Possible Cause Ofmentioning

confidence: 99%

Decreased Rate of Plasma Arginine Appearance in Murine Malaria May Explain Hypoargininemia in Children With Cerebral Malaria

et al. 2016

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Background. Plasmodium infection depletes arginine, the substrate for nitric oxide synthesis, and impairs endotheliumdependent vasodilation. Increased conversion of arginine to ornithine by parasites or host arginase is a proposed mechanism of arginine depletion.Methods. We used high-performance liquid chromatography to measure plasma arginine, ornithine, and citrulline levels in Malawian children with cerebral malaria and in mice infected with Plasmodium berghei ANKA with or without the arginase gene. Heavy isotope-labeled tracers measured by quadrupole time-of-flight liquid chromatography-mass spectrometry were used to quantify the in vivo rate of appearance and interconversion of plasma arginine, ornithine, and citrulline in infected mice.Results. Children with cerebral malaria and P. berghei-infected mice demonstrated depletion of plasma arginine, ornithine, and citrulline. Knock out of Plasmodium arginase did not alter arginine depletion in infected mice. Metabolic tracer analysis demonstrated that plasma arginase flux was unchanged by P. berghei infection. Instead, infected mice exhibited decreased rates of plasma arginine, ornithine, and citrulline appearance and decreased conversion of plasma citrulline to arginine. Notably, plasma arginine use by nitric oxide synthase was decreased in infected mice.Conclusions. Simultaneous arginine and ornithine depletion in malaria parasite-infected children cannot be fully explained by plasma arginase activity. Our mouse model studies suggest that plasma arginine depletion is driven primarily by a decreased rate of appearance.

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Section: Evaluation Of Parasite Arginase Level As a Possible Cause Ofmentioning

confidence: 99%

Decreased Rate of Plasma Arginine Appearance in Murine Malaria May Explain Hypoargininemia in Children With Cerebral Malaria

et al. 2016

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“…Interestingly, the corresponding residue is similarly nonpolar in two other parasitic arginases: P228 in Plasmodium falciparum arginase 58 and V149 in Leishmania mexicana arginase. 54 Differences in polarity and size at this position in parasitic arginases compared with human arginases may be a contributing factor to the alternative binding modes of α,α-disubstituted amino acid inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Crystal Structure of Schistosoma mansoni Arginase, a Potential Drug Target for the Treatment of Schistosomiasis

et al. 2014

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The X-ray crystal structure of arginase from Schistosoma mansoni (SmARG) and the structures of its complexes with several amino acid inhibitors have been determined at atomic resolution. SmARG is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of l-arginine to form l-ornithine and urea, and this enzyme is upregulated in all forms of the parasite that interact with the human host. Current hypotheses suggest that parasitic arginases could play a role in host immune evasion by depleting pools of substrate l-arginine that would otherwise be utilized for NO biosynthesis and NO-dependent processes in the immune response. Although SmARG shares only 42% overall amino acid sequence identity with human arginase I, residues important for substrate binding and catalysis are strictly conserved. In general, classical amino acid inhibitors such as 2(S)-amino-6-boronohexanoic acid (ABH) tend to bind more weakly to SmARG than to human arginase I despite identical inhibitor binding modes in each enzyme active site. The identification of a patch on the enzyme surface capable of accommodating the additional Cα-substitutent of an α,α-disubstituted amino acid inhibitor suggests that such inhibitors could exhibit higher affinity and biological activity. The structures of SmARG complexed with two different α,α-disubstituted derivatives of ABH are presented and provide proof-of-concept for this approach in the enhancement of enzyme-inhibitor affinity.

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“…Phosphopantothenoyl cysteine decarboxylase (XP_001349363.1) is an enzyme that has no homologs in humans and is one of the enzymes to be considered as a drug target (Plata et al, 2010). The inhibition of the enzymatic activity of arginase (XP_001351939.1) showed reduced liver infectivity in vivo and therefore arginase could be a drug candidate for antimalarial therapy with the availability of its protein structure (Dowling et al, 2010). Rhoptry associated proteins (XP_001352164.1) RAP-1 and RAP-2 are recommended as vaccine candidates for asexual blood-stage due to their low polymorphism in global population (Garzon-Ospina et al, 2010).…”

Section: Annotation Transfer By Homologymentioning

confidence: 99%

Annotation transfer by homology among closely related genomes helps to identify protein function in Plasmodium species

Devaraj

Chandramohan

2017

IJBRA

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Malaria is a major killer disease causing heavy loss in terms of life and medical expenditure. The genome of Plasmodium falciparum sequenced in 2002 but more than 60% of its meaning still remains unknown. We compared protein sequences from P. falciparum in the genomic sequences with P. vivax and P. knowlesi through standalone blast tool from NCBI. We found many proteins annotated in one species sharing high similarity with unannotated proteins in the other/s species. Based on the 'annotation transfer by homology' method we annotated 715 hypothetical proteins. By the latest information available as of 1st September our method annotated 343 protein sequences .Gene Ontology annotation with BLAST2GO revealed 128 proteins with Enzyme Codes among the 561 sequences mapped with GO terms. The kognitor results showed 542 proteins similar to proteins belonging to various KOG categories. More attention should be paid to these 'hypothetical' proteins as they can reveal unknown insights on the biology of organisms and have an impact in the field of drug discovery and medicine.

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Crystal Structure of Arginase from Plasmodium falciparum and Implications for l-Arginine Depletion in Malarial Infection,

Cited by 41 publications

References 59 publications

Decreased Rate of Plasma Arginine Appearance in Murine Malaria May Explain Hypoargininemia in Children With Cerebral Malaria

Decreased Rate of Plasma Arginine Appearance in Murine Malaria May Explain Hypoargininemia in Children With Cerebral Malaria

Crystal Structure of Schistosoma mansoni Arginase, a Potential Drug Target for the Treatment of Schistosomiasis

Annotation transfer by homology among closely related genomes helps to identify protein function in Plasmodium species

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