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.

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