Subsystem: Folate Biosynthesis

This subsystem's description is:

1. De novo pathway
Fungi and plants, as well as most bacteria, have the full THF biosynthesis pathway (variant 111). In E. coli and S. cerevisiae, genes have been identified for all but one step of the pathway, the conversion of 7,8-dihydroneopterin triphosphate to the corresponding monophosphate (folQ); removal of the last phosphate is believed to be mediated by a non-specific phosphatase (J. Biol. Chem. 1974 249:2405-10).

Missing and alternative genes
A folQ gene was recently identified in L. lactis (J. Biol. Ch: em. 2005 280:5274-80) as part of the folKEPQC gene cluster (Type 1 in the SS). This gene belongs to a large and functionally heterogeneous Nudix hydrolase superfamily hardly amenable to projection of annotations just by homology. Recently the FolQ of E. coli was identified by Bessman and col. (Structure. 2007 Aug;15(8):1014-22) annotated as type 2 here. There again the annotation cannot be propagated to far. Several Nudix hydrolase gene candidates can be identified in folate gene clusters, and these should be tested experimentally. Other putative phosphohydrolases unrelated to FolQ are found in some of the folate-related gene clusters, e.g., peg1083 in Clostridium perfringens. R

DHFR
DHFRs are known to be encoded by several gene families. In addition to the most common folA family, a pteridine reductase-like folM (“DHFR1” in our subsystem; J. Bacteriol. 2003 185:7015-8), and a flavin-dependent reductase (“altDHFR2”; Mol. Microbiol. 2004 54:1307-18) have been identified. DHFR1 enzymes belong to the large superfamily of short-chain dehydrogenases-reductases (SDR) involved in a variety of reactions. A FolM-specific sequence motif TGXXXRXG was used to discriminate DHFR1 subfamily from other SDRs (featuring a TGXXXGXG motif). The FolM enzyme is involved in the reducation of dihydroMonapterin (J Bacteriol. 2010 Jan;192(2):475-82). Even after propagation of all known DHFR families, respective genes are still missing in several organisms (see variant 006,106,116). One gene candidate (altDHFR3) is embedded in the FolEKPB gene cluster in Streptomyces coelicolor. This prediction was made by A. Hanson and it is currently being tested in his laboratory.

GCYHI
GTP cyclohydrolase I is the first step of the folate pathway (annotated as type 1). It is found in mammals that have a biopterin (BH4) pathway, but it is still a missing gene in many species containing an otherwise complete set of folate biosynthetic genes. A second gene family (GCYHIB annoated as type 2) was identified by genome context analysis techniques in conjunction with a tRNA modification pathway (see comments to Queuosine-Archaeosine Biosynthesis subsystem) (El YAcoubi et al.,J Biol Chem. 2006 Dec 8;281(49):37586-93. Several organisms are still lacking either form of GCYHI (see variant 702,701).

DHNA
Homologs of folB gene (encoding DHNA) appear to be missing in many organisms. Genome and functional context analysis allowed A. Hanson to infer that this role may be played by some homologs of E. coli fructose-6-phosphate aldolase (“FSA” in subsystem, This prediction is weaker now that other aldolase genes are being found (see below). Recent work in Plasmodium has shown that the aldolase activity is carried by a 6-pyruvoyl tetrahydrobiopterin synthase (EC 4.2.3.12) like enzyme that acts directly on H2-neopterin triphosphate and not on H2-neopterin, we call this enzyme for the moment (Folate biosynthesis, PTPS-III). Genome analysis and experimental validation shows that PTPS-III type aldolase found in many bacteria replace folB and that some of these PTPS-III have dual actitivity as QueD/PTPS-I involved in Queuosine biosynthesis (Pribat et al 2009 J Bacteriol 191, 4158-4165 and Phillips et al 2012, ACS Chem Biol 7, 197-209 . Some organisms still lack any DHNA gene candidates (variant 401,411,)

Some organisms have two folB in cases like Burkholderia xenovorans LB400 one of them might have specialized to methanopterin . In a few of the methanopterin organisms such as Aurantimonas, FolB is fused to "duf556 family protein" a potential methanopterin enzymes (see Methanopterin2 SS
Multiple missing genes

HPPK

In the Roseobacter/Silibacter clade FolB is fused to a domain similar to delta "1-pyrroline-5-carboxylate synthetase" or a general aminoacid kinase found in Archaea and in methanopterin producers. As one of these organisms lacked FolK I looked in more details at the FolK in this clase and alignments show that there an internal insertion of around 35 aa in all FolK of the genomes that have this fusion FolB protein. The natural hypothesis is that in those organism the gene annotated as FolK does another function and the fusion kinase is the real FolK.


-Chlamydiae lack GCYHI and the
DHFS/FPGS
The sequenced chlamydiae all lack homologs of folC (DHFS/FPGS) Inspection revealed that a member of gene family COG1478 is clustered in chlamydiae with folate biosynthesis genes.This COG1478 family contains the F420:γ-glutamyl ligase CofE of Archaea and Mycobacteria [Biochemistry 2003, 42:9771-9778]. CofE catalyzes the GTP-dependent successive addition of two γ-linked L-glutamates to the L-lactyl phosphodiester of 7,8-didemethyl-8-hydroxy-5-deazariboflavin (F420), a reaction analogous to that mediated by FolC. Chlamydiae almost certainly do not make F420 since they lack all the other known cof genes []. We accordingly predicted that the CofE homolog in chlamydiae has FolC activity. A cofE homolog (CT611) was shown to complement the methionine and glycine requirements of the E. coli folC mutant BMC Genomics. 2007 Jul 23;8:245. FolC2 was named "Alternative Folylglutamate Synthase" in the SS.

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- A few organisms lack both DHNA and HPPK genes (variants 3)
2. Salvage pathways
The most studied salvage pathway is found in mammals and many other eukaryotes have just the DHFR and FPGS enzymes (see variant 1). Many relatively poorly studied bacteria also seem to rely on a salvage pathway. Many pathogenic and related bacteria have only the DHFS, FPGS and DHFR genes (variant 2), suggesting a salvage of 7,8-dihydropteroate. However, this compound is not expected to occur in their natural environment leaving us with an open problem for further studies.
In Borrelia (nonfunctional variant code “– 1”) no genes of the folate pathway can be detected, in agreement with the presence of the folate-independent thymidylate synthase (TS) of the thyX family. In most Mycoplasmas, DHFR and a folate-dependent TS gene are found, but FPGS appears to be a missing gene (variant 10). These species may salvage mono- or polyglutamylated folates from the host. A default variant code “0” is retained for those genomes where we were unable to rationalize gene patterns. Many of them are due to incomplete sequencing or sequencing mistakes, or even reflect the existence of pseudogenes

3. Folate in Archaea.
The situation in Archaea is even more complicated. Although many methanogens (e.g., M. jannaschii) produce tetrahydromethanopterin instead of folate (hence variant code “-1”), they contain homologs of some folate-related genes, likely reflecting a resemblance between some steps in the biosynthesis of these two cofactors. For example, a FolP-like gene family (FolP2, MJ0107) found mostly in Archaea, may be involved in methanopterin biosynthesis (M. Rasche, personal communication). On the other hand, the ThyA-like TS enzyme of M. jannaschii was shown to utilize folate rather than methanopterin derivatives as a cofactor (Nature Struct. Biol. 1999 6:750-4. This observation may indicate an existence of: (i) an alternative folate biosynthetic pathway, or (ii) an unidentified methanopterin-related methyl donor. In both cases one should anticipate an existence of an alternative reductase in those genomes that lack DHFR homologs. Several archaeal genomes (Thermoplasma and Ferroplasma, variant 13) containing almost all of the de novo pathway genes, lack recognizable homologs of DHFR and HPPK. Finally, one of the several archaeal species containing both ThyA-like TS and DHFR (variant 12), was shown to be dependent on folate or pABA for growth. Two non ortholgous families were recently identified that functionally replace FolB and FolK (de Crecy-lagard et al 2012 ACS Chem Biol. 7:1807-16).

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