Vitamin and cofactor biosynthesis pathways in Plasmodium and other apicomplexan parasites

Abstract

Vitamins are essential components of the human diet. By contrast, the malaria parasite Plasmodium falciparum and related apicomplexan parasites synthesize certain vitamins de novo, either completely or in parts. The various biosynthesis pathways are specific to different apicomplexan parasites and emphasize the distinct requirements of these parasites for nutrients and growth factors. The absence of vitamin biosynthesis in humans implies that inhibition of the parasite pathways might be a way to interfere specifically with parasite development. However, the roles of biosynthesis and uptake of vitamins in the regulation of vitamin homeostasis in parasites needs to be established first. In this article, the procurement of vitamins B(1), B(5) and B(6) by Plasmodium and other apicomplexan parasites is discussed.

Defining the structural requirements for ribose 5‐phosphate‐binding and intersubunit cross‐talk of the malarial pyridoxal 5‐phosphate synthase

“…Antibiotics were purchased from AppliChem (Darmstadt, FRG), imidazole, 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris), NaCl, NH 4 Cl, EDTA, Luria-Broth medium (LB), b-mercaptoethanol from Carl Roth (Karlsruhe, FRG), isopropyl b-D-1-thiogalactopyranoside (IPTG) was from PeqLab (Erlangen, FRG), L-glutamine, DL-G3P and R5P from Sigma-Aldrich (Taufkirchen, FRG). Restriction enzymes and DNA-polymerases were from New England Bioloabs (NEB, Schwalbach, FRG).…”

“…20 lM purified PfPdx1 or variants and 20 lM Pdx2 of Plasmodium falciparum (PfPdx2) were incubated in assay buffer in the presence of 1 mM R5P, 1 mM G3P and 10 mM L-glutamine. In the absence of PfPdx2, 10 mM NH 4 Cl was used as nitrogen source. G3P was not added for the analysis of I 320 -formation.…”

“…The biosynthesis of vitamins is of particular interest in this respect, since the absence of these pathways in humans implies that their inhibition exclusively affects the metabolism of the parasite and not that of the human host. Plasmodium is able to synthesize certain vitamins de novo, either completely or in parts [3,4]. Among these is vitamin B 6 [5,6].…”

Pantothenic Acid Biosynthesis in the Parasite Toxoplasma gondii: a Target for Chemotherapy

“…The algorithm for searching for homology, based on PRIAM profiles, is a highly sensitive method to detect orthologous enzymes. Similar genes in T. gondii were annotated in the ApiDB genome database (34) and are summarized in a review (35). Genes encoding 2-dehydropantoate 2-reductase, 3-methyl-2-oxobutanoate hydroxymethyltransferase, and pantothenate synthetase are detectable in the genome of T. gondii (Fig.…”

“…The growth inhibition was disrupted by the addition of pantothenate, demonstrating the specificity of the inhibitors for the pantothenate pathway in T. gondii. It is unclear how the exogenous pantothenate is imported into the parasites, but a computationally annotated gene in the genome of T. gondii (ToxoDB accession number 541.m01156), with some similarity to the human Na ϩ -pantothenate symporter, that could transport pantothenate was found (35). As the prediction of the specificity of membrane transporters is difficult and often impossible without testing, it is unclear whether this protein can take up pantothenate, but if it functions, even at low efficiency, then this could explain why the high levels of pantothenate used in these experiments could exacerbate inhibition.…”