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. Synthesis and use of the one-carbon unit in folateThe glycine-cleavage complex (GCV) and serine hydroxymethyltransferase [SHMT, also called glycine hydroxymethyltransferase (EC 2.1.2.1)] form part of the folic acid biosynthesis pathway, generating one-carbon units from cleavage of the small amino acids glycine and serine, respectively. These one-carbon units are transferred onto folate coenzymes that carry and donate them, primarily for the synthesis of pyrimidines [e.g. thymidylate (5′-TMP)] and methionine in the malaria parasite [1]. SHMT can reversibly interconvert glycine and serine, and glycine itself is a precursor of the synthesis of glutathione, tryptophan and phospholipids in eukaryotes [2]. The importance of the ubiquitous GCV enzymatic complex is exemplified by its role in essential homeostatic processes. For instance, the synthesis of glutathione to maintain the redox balance of the erythrocyte plasma membrane needs an active but regulated glycine supply [3], the mitochondrial processing of high concentrations of phosphorespiration glycine in plants relies on plant GCVs [4], and a dys-functional GCV in humans caused by specific point mutations is related to an inherited condition known as nonketotic hyperglycinemia or glycine encephalopathy [5].Whereas serine, through the reaction catalysed by SHMT, is the main source of one-carbon units in the cytoplasm, glycine is equally relevant in the mitochondrion, and the GCV . The activation and use of folate depend on covalent linkage to a one-carbon unit -a byproduct of the balanced flux of carbon between serine and glycine -through SHMT and GCV, two independent but functionally related enzyme systems (Figure 1). The de novo production of fully reduced and glutamated (and, hence, functional) folate in Plasmodium falciparum is the result of the actions of six enzymatic activities...

Although the folate metabolic pathway in malaria parasites is a major chemotherapeutic target, resistance to currently available antifolate drugs is an increasing problem. This pathway, however, includes a number of enzymes that, to date, have not been characterized despite their potential for clinical exploitation. As a step towards evaluation of additional targets in this pathway, we report the isolation and characterization of 3 new genes that encode homologues of GTP cyclohydrolase I (GTP-CH), dihydrofolate synthase/folylpolyglutamate synthase (DHFS/FPGS) and serine hydroxymethyltransferase (SHMT). The genes encoding GTP-CH and SHMT are unambiguously assigned to chromosome 12, while that for DHFS/FPGS is tentatively assigned to chromosome 13. All 3 genes are expressed in blood-stage parasites, yielding transcripts of which only ca 60-70% is accounted for by coding sequence. All 3 of the proteins predicted to be encoded by these genes display sequence differences compared to the human host homologues that may be of functional significance. These data bring the complement of cloned genes that encode activities in the pathway to seven, leaving only the gene encoding dihydroneopterin aldolase (DHNA) to be identified in the route from GTP to folate synthesis and folate turnover in the thymidylate cycle.

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The genetic polymorphisms rs2395185 and rs2097432 in HLA genes have been associated with the response to anti-TNF treatment in inflammatory bowel disease (IBD). The aim was to analyze the association between these variants and the long-term response to anti-TNF drugs in pediatric IBD. We performed an observational, multicenter, ambispective study in which we selected 340 IBD patients under 18 years of age diagnosed with IBD and treated with anti-TNF drugs from a network of Spanish hospitals. Genotypes and failure of anti-TNF drugs were analyzed using Kaplan-Meier curves and Cox logistic regression. The homozygous G allele of rs2395185 and the C allele of rs2097432 were associated with impaired long-term response to anti-TNF drugs in children with IBD after 3 and 9 years of follow-up. Being a carrier of both polymorphisms increased the risk of anti-TNF failure. The SNP rs2395185 but not rs2097432 was associated with response to infliximab in adults with CD treated with infliximab but not in children after 3 or 9 years of follow-up. Conclusions: SNPs rs2395185 and rs2097432 were associated with a long-term response to anti-TNFs in IBD in Spanish children. Differences between adults and children were observed in patients diagnosed with CD and treated with infliximab.