ArticleMolecular microbiology2008
An atypical orthologue of 6-pyruvoyltetrahydropterin synthase can provide the missing link in the folate biosynthesis pathway of malaria parasites.
Article in Molecular microbiology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 43 citations in OpenAlex.
- CRISPR-based functional profiling of the Toxoplasma gondii genome during acute murine infection.Nature microbiology · 2024Article
- Computational Studies on 6-Pyruvoyl Tetrahydropterin Synthase (6-PTPS) ofBioinformatics and biology insights · 2024Article
- The genomic architecture of antimalarial drug resistance.Briefings in functional genomics · 2019Review
- WhollymBio · 2017Article
- Tetrahydrobiopterin Supplementation Improves Phenylalanine Metabolism in a Murine Model of Severe Malaria.ACS infectious diseases · 2016Article
- Exceptionally long-range haplotypes in Plasmodium falciparum chromosome 6 maintained in an endemic African population.Malaria journal · 2016Article
- Functional Annotations of Paralogs: A Blessing and a Curse.Life (Basel, Switzerland) · 2016Article
- Possible selection of host folate pathway gene polymorphisms in patients with malaria from a malaria endemic region in North East India.Transactions of the Royal Society of Tropical Medicine and Hygiene · 2016Article
- The Rickettsia Endosymbiont of Ixodes pacificus Contains All the Genes of De Novo Folate Biosynthesis.PloS one · 2015Article
- Utility of the Biosynthetic Folate Pathway for Targets in Antimicrobial Discovery.Antibiotics (Basel, Switzerland) · 2014Review
- Transition-state inhibitors of purine salvage and other prospective enzyme targets in malaria.Future medicinal chemistry · 2013Review
- Simple topological properties predict functional misannotations in a metabolic network.Bioinformatics (Oxford, England) · 2013Article
- Organic cofactors in the metabolism of Dehalococcoides mccartyi strains.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2013Article
- Comparative genomics guided discovery of two missing archaeal enzyme families involved in the biosynthesis of the pterin moiety of tetrahydromethanopterin and tetrahydrofolate.ACS chemical biology · 2012Article
- Functional promiscuity of the COG0720 family.ACS chemical biology · 2012Article
- Quantitative mass spectrometry catalogues Salmonella pathogenicity island-2 effectors and identifies their cognate host binding partners.The Journal of biological chemistry · 2011Article
- The complete genome sequence of 'Candidatus Liberibacter solanacearum', the bacterium associated with potato zebra chip disease.PloS one · 2011Article
- Use of thermal melt curves to assess the quality of enzyme preparations.Analytical biochemistry · 2010Article
- 6-pyruvoyltetrahydropterin synthase paralogs replace the folate synthesis enzyme dihydroneopterin aldolase in diverse bacteria.Journal of bacteriology · 2009Article
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7 authors at 1 institution in 2 countries.
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Abstract
Folate metabolism in malaria parasites is a long-standing, clinical target for chemotherapy and prophylaxis. However, despite determination of the complete genome sequence of the lethal species Plasmodium falciparum, the pathway of de novo folate biosynthesis remains incomplete, as no candidate gene for dihydroneopterin aldolase (DHNA) could be identified. This enzyme catalyses the third step in the well-characterized pathway of plants, bacteria, and those eukaryotic microorganisms capable of synthesizing their own folate. Utilizing bioinformatics searches based on both primary and higher protein structures, together with biochemical assays, we demonstrate that P. falciparum cell extracts lack detectable DHNA activity, but that the parasite possesses an unusual orthologue of 6-pyruvoyltetrahydropterin synthase (PTPS), which simultaneously gives rise to two products in comparable amounts, the predominant of which is 6-hydroxymethyl-7,8-dihydropterin, the substrate for the fourth step in folate biosynthesis (catalysed by 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase; PPPK). This can provide a bypass for the missing DHNA activity and thus a means of completing the biosynthetic pathway from GTP to dihydrofolate. Supported by site-directed mutagenesis experiments, we ascribe the novel catalytic activity of the malarial PTPS to a Cys to Glu change at its active site relative to all previously characterized PTPS molecules, including that of the human host.
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