Tetrahydrofolate and tetrahydromethanopterin compared: functionally distinct carriers in C1 metabolism

In most organisms, tetrahydrofolate (H₄folate) is the carrier of C₁ fragments between formyl and methyl oxidation levels. The C₁ fragments are utilized in several essential biosynthetic processes. In addition, C₁ flux through H₄folate is utilized for energy metabolism in some groups of anaerobic bacteria. In methanogens and several other Archaea, tetrahydromethanopterin (H₄MPT) carries C₁ fragments between formyl and methyl oxidation levels. At first sight H₄MPT appears to resemble H₄folate at the sites where C₁ fragments are carried. However, the two carriers are functionally distinct, as discussed in the present review. In energy metabolism, H₄MPT permits redox-flux features that are distinct from the pathway on H₄folate. In the reductive direction, ATP is consumed in the entry of carbon from CO₂ into the H₄folate pathway, but not in entry into the H₄MPT pathway. In the oxidative direction, methyl groups are much more readily oxidized on H₄MPT than on H₄folate. Moreover, the redox reactions on H₄MPT are coupled to more negative reductants than the pyridine nucleotides which are generally used in the H₄folate pathway. Thermodynamics of the reactions of C₁ reduction via the two carriers differ accordingly. A major underlying cause of the thermodynamic differences is in the chemical properties of the arylamine nitrogen N¹⁰ on the two carriers. In H₄folate, N¹⁰ is subject to electron withdrawal by the carbonyl group of p-aminobenzoate, but in H₄MPT an electron-donating methylene group occurs in the corresponding position. It is also proposed that the two structural methyl groups of H₄MPT tune the carrier's thermodynamic properties through an entropic contribution. H₄MPT appears to be unsuited to some of the biosynthetic functions of H₄folate, in particular the transfer of activated formyl groups, as in purine biosynthesis. Evidence bearing upon whether H₄MPT participates in thymidylate synthesis is discussed. Findings on the biosynthesis and phylogenetic distribution of the two carriers and their evolutionary implications are briefly reviewed. Evidence suggests that the biosynthetic pathways to the two carriers are largely distinct, suggesting the possibility of (ancient) separate origins rather than divergent evolution. It has recently been discovered that some eubacteria which gain energy by oxidation of C₁ compounds contain an H₄MPT-related carrier, which they are thought to use in energy metabolism, as well as H₄folate, which they are thought to use for biosynthetic reactions.