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Abstract
BackgroundFolate synthesis and salvage pathways are relatively well known from classical biochemistry and genetics but they have not been subjected to comparative genomic analysis. The availability of genome sequences from hundreds of diverse bacteria, and from Arabidopsis thaliana, enabled such an analysis using the SEED database and its tools. This study reports the results of the analysis and integrates them with new and existing experimental data.ResultsBased on sequence similarity and the clustering, fusion, and phylogenetic distribution of genes, several functional predictions emerged from this analysis. For bacteria, these included the existence of novel GTP cyclohydrolase I and folylpolyglutamate synthase gene families, and of a trifunctional p-aminobenzoate synthesis gene. For plants and bacteria, the predictions comprised the identities of a 'missing' folate synthesis gene (folQ) and of a folate transporter, and the absence from plants of a folate salvage enzyme. Genetic and biochemical tests bore out these predictions.ConclusionFor bacteria, these results demonstrate that much can be learnt from comparative genomics, even for well-explored primary metabolic pathways. For plants, the findings particularly illustrate the potential for rapid functional assignment of unknown genes that have prokaryotic homologs, by analyzing which genes are associated with the latter. More generally, our data indicate how combined genomic analysis of both plants and prokaryotes can be more powerful than isolated examination of either group alone.
Highlights
Folate synthesis and salvage pathways are relatively well known from classical biochemistry and genetics but they have not been subjected to comparative genomic analysis
Are folates essential in all bacteria? As folate-dependent formylation of the initiator tRNA is a hallmark of bacterial translation and bacteria cannot import formylmethionyl-tRNA [28], we investigated the distribution of the fmt gene encoding methionyl-tRNA formyltransferase (EC 2.1.2.9) as a signature gene for a folate requirement
Note that the compartmentation of the pathway and of its folate end products implies the existence of pterin or folate carriers in the mitochondria, chloroplast, and vacuolar membranes
Summary
Folate synthesis and salvage pathways are relatively well known from classical biochemistry and genetics but they have not been subjected to comparative genomic analysis. Folates are tripartite molecules comprising pterin, p-aminobenzoate (pABA), and glutamate moieties to which one-carbon units at various oxidation levels can be attached at the N5 and N10 positions (Figure 1). In natural folates the pterin ring is in the dihydro or tetrahydro state, and a short, γ-linked polyglutamyl tail of up to about eight residues is usually attached to the first glutamate. Tetrahydrofolates serve as cofactors in one-carbon transfer reactions during the synthesis of purines, formylmethionyl-tRNA, thymidylate, pantothenate, glycine, serine, and methionine [1] (Figure 2). Folate pABA γ-Glu tail Glu O HN H2N N H N 56 CH2 H
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