Vitamin B1 and B6 in the malaria parasite: requisite or dispensable?

Wrenger, Carsten; Knöckel, Julia; Walter, Rolf D.; Müller, Ingrid

doi:10.1590/s0100-879x2008005000006

Cited by 26 publications

(14 citation statements)

References 57 publications

(69 reference statements)

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“…Whereas in E. coli TMP is subsequently phosphorylated to TPP by the thiamine phosphate kinase (ThiL) [6], yeast and Plasmodium do not possess ThiL, but instead a thiamine pyrophosphokinase (TPK). Previous data from P. falciparum also demonstrate that TMP synthesised de novo is dephosphorylated prior to pyrophosphorylation by TPK [9].…”

Section: Introductionmentioning

confidence: 77%

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The Vitamin B1 Metabolism of Staphylococcus aureus Is Controlled at Enzymatic and Transcriptional Levels

et al. 2009

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Vitamin B1 is in its active form thiamine pyrophosphate (TPP), an essential cofactor for several key enzymes in the carbohydrate metabolism. Mammals must salvage this crucial nutrient from their diet in order to complement the deficiency of de novo synthesis. In the human pathogenic bacterium Staphylococcus aureus, two operons were identified which are involved in vitamin B1 metabolism. The first operon encodes for the thiaminase type II (TenA), 4-amino-5-hydroxymethyl-2-methylpyrimidine kinase (ThiD), 5-(2-hydroxyethyl)-4-methylthiazole kinase (ThiM) and thiamine phosphate synthase (ThiE). The second operon encodes a phosphatase, an epimerase and the thiamine pyrophosphokinase (TPK). The open reading frames of the individual operons were cloned, their corresponding proteins were recombinantly expressed and biochemically analysed. The kinetic properties of the enzymes as well as the binding of TPP to the in vitro transcribed RNA of the proposed operons suggest that the vitamin B1 homeostasis in S. aureus is strongly regulated at transcriptional as well as enzymatic levels.

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Section: Introductionmentioning

confidence: 77%

“…In eukaryotes (such as yeast and the malaria pathogen P. falciparum ) thiamine is diphosphorylated by TPK [9], [10], [16]. The presence of a TPK in S. aureus suggested a similar vitamin B1 metabolism, as is known for yeast.…”

Section: Resultsmentioning

confidence: 99%

The Vitamin B1 Metabolism of Staphylococcus aureus Is Controlled at Enzymatic and Transcriptional Levels

et al. 2009

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“…Plants, fungi and some microorganisms [e.g. Mycobacterium tuberculosis (Dick et al ., 2010) and Plasmodium falciparum (Wrenger et al ., 2008)] can synthesise vitamin B 6 de novo either from deoxyxylulose 5‐phosphate and 4‐phosphohydroxy‐ l ‐threonine or from ribulose 5‐phosphate, dihydroxyacetone phosphate and glutamine. In contrast, other organisms, including humans, salvage pyridoxal from their diet (Fitzpatrick et al ., 2010).…”

Section: Introductionmentioning

confidence: 99%

Chemical, genetic and structural assessment of pyridoxal kinase as a drug target in the African trypanosome

Jones

Alphey

Wyllie

et al. 2012

Molecular Microbiology

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Pyridoxal-5′-phosphate (vitamin B6) is an essential cofactor for many important enzymatic reactions such as transamination and decarboxylation. African trypanosomes are unable to synthesise vitamin B6de novo and rely on uptake of B6 vitamers such as pyridoxal and pyridoxamine from their hosts, which are subsequently phosphorylated by pyridoxal kinase (PdxK). A conditional null mutant of PdxK was generated in Trypanosoma brucei bloodstream forms showing that this enzyme is essential for growth of the parasite in vitro and for infectivity in mice. Activity of recombinant T. brucei PdxK was comparable to previously published work having a specific activity of 327 ± 13 mU mg−1 and a Kmapp with respect to pyridoxal of 29.6 ± 3.9 µM. A coupled assay was developed demonstrating that the enzyme has equivalent catalytic efficiency with pyridoxal, pyridoxamine and pyridoxine, and that ginkgotoxin is an effective pseudo substrate. A high resolution structure of PdxK in complex with ATP revealed important structural differences with the human enzyme. These findings suggest that pyridoxal kinase is an essential and druggable target that could lead to much needed alternative treatments for this devastating disease.

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“…Recent work, however, demonstrated that depletion of thiamine from erythrocytes is detrimental to parasite growth. Therefore, although the parasite is capable of synthesizing thiamine, its capacity to do so appears to be insufficient to meet its requirements 6 . The parasite's thiamine biosynthesis pathway has been suggested to be a target for novel and much-needed antimalarials, either by direct inhibition of the enzymes or by channelling prodrugs into this parasite specific pathway 7 .…”

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confidence: 99%

Chemical and genetic validation of thiamine utilization as an antimalarial drug target

et al. 2013

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Thiamine is metabolized into an essential cofactor for several enzymes. Here we show that oxythiamine, a thiamine analog, inhibits proliferation of the malaria parasite Plasmodium falciparum in vitro via a thiamine-related pathway and significantly reduces parasite growth in a mouse malaria model. Overexpression of thiamine pyrophosphokinase (the enzyme that converts thiamine into its active form, thiamine pyrophosphate) hypersensitizes parasites to oxythiamine by up to 1,700-fold, consistent with oxythiamine being a substrate for thiamine pyrophosphokinase and its conversion into an antimetabolite. We show that parasites overexpressing the thiamine pyrophosphate-dependent enzymes oxoglutarate dehydrogenase and pyruvate dehydrogenase are up to 15-fold more resistant to oxythiamine, consistent with the antimetabolite inactivating thiamine pyrophosphate-dependent enzymes. Our studies therefore validate thiamine utilization as an antimalarial drug target and demonstrate that a single antimalarial can simultaneously target several enzymes located within distinct organelles.

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Vitamin B1 and B6 in the malaria parasite: requisite or dispensable?

Cited by 26 publications

References 57 publications

The Vitamin B1 Metabolism of Staphylococcus aureus Is Controlled at Enzymatic and Transcriptional Levels

The Vitamin B1 Metabolism of Staphylococcus aureus Is Controlled at Enzymatic and Transcriptional Levels

Chemical, genetic and structural assessment of pyridoxal kinase as a drug target in the African trypanosome

Chemical and genetic validation of thiamine utilization as an antimalarial drug target

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