A glycine-cleavage complex as part of the folate one-carbon metabolism of Plasmodium falciparum

Abstract

The glycine-cleavage complex (GCV) and serine hydroxymethyltransferase represent the two systems of one-carbon transfer that are employed in the biosynthesis of active folate cofactors in eukaryotes. Although the understanding of this area of metabolism in Plasmodium falciparum is still at an early stage, we discuss evidence that genes and transcription products of the GCV are present and expressed in this parasite. The potential role of the GCV and its relevance to the life cycle and pathogenesis of the malaria erythrocytic stages are also considered. According to its expression profile, the GCV seems to be particularly active in gametocytes. The GCV enzyme dihydrolipoamide dehydrogenase has two isoforms encoded by two different genes. It has been demonstrated recently that both genes are functional, with one of them identified as being part of a pyruvate dehydrogenase complex that is present exclusively in the apicoplast of Plasmodium species. The other isoform probably forms part of the Plasmodium GCV. The GCV is the first enzyme complex involved in folate metabolism in this parasite that can be assumed, with a good degree of certainty, to be located in the mitochondria.

Figure 1

The Plasmodium falciparum one-carbon enzyme systems SHMT and GCV, as deduced from enzymes found in other eukaryotes. The proteins for which genes have been identified are PfGCVH, PfGCVT, PfLPD1, PfSHMT [6,11] and the putative PfSHMTm. A candidate gene for the P-protein (P?) has not yet been identified in P. falciparum. Of the two L-protein isoforms that have been found, PfLPD1 is the enzyme that would be involved primarily in the mitochondrial GCV, catalysing the reoxidation of the lipoamide arm that is covalently bound to PfGCVH. The main use ascribed to folate derivates in this parasite is the synthesis of thymidine 5′-monophosphate (5′-TMP) and methionine (Met). Both compounds are necessary in cell compartments, including mitochondria. The complex of PfGCV enzymes would carry out the decarboxylation of glycine, whereas SHMT would undertake the reversible conversion of serine to glycine. A dual presence of cytosolic and mitochondrial PfSHMT is proposed, whereas PfGCV is confined to mitochondria. This compartmentalization implies the transport of glycine, serine and one of several possible intermediate folate metabolites (Fol) through mitochondrial membranes, as has been shown for other eukaryotes [31].

Figure 2

Origin of the dihydrolipoamide dehydrogenases (PfLPD1 and PfLPD2) in Plasmodium species. A tree originated with homologous proteins by Minimum Evolution, as implemented in Mega version 2.1, is shown [32]. Scores on branches are from bootstraps to 1000 repetitions. GenBank accession numbers are shown within square brackets after taxon unit names. The mitochondrial group contains Rickettsia prowazekii (an α-proteobacterium and the closest known descendent of the mitochondrial ancestor). Synechocystis sp. clusters with the plastid isoforms and supports a cyanobacterial origin for the PfLPD2 protein. Names in bold indicate species with several isoforms of LPD proteins, except Saccharomyces cerevisiae (which encodes only one isoform and is highlighted as a model organism), and Synechocystis sp. and Rickettsia prowazekii (the importance of which is explained above). Scale bar shows proportion of amino acid differences.