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Tetrahydromethanopterin

Chemical compound From Wikipedia, the free encyclopedia

5,6,7,8-Tetrahydromethanopterin (THMPT, H
4MPT) is a coenzyme in methanogenesis. It is the carrier of the C1 group as it is reduced to the methyl level, before transferring to the coenzyme M.[1]

Quick facts Names, Identifiers ...
Tetrahydromethanopterin
Names
IUPAC name
(2S)-2-[[(2R,3S,4R,5S)-5-[(2R,3S,4S)-5-[4-[[(1R)-1-[(6S,7S)-2-amino-7-methyl-4-oxo-5,6,7,8-tetrahydro-1H-pteridin-6-yl]ethyl]amino]phenyl]-2,3,4-trihydroxypentoxy]-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxypentanedioic acid
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
KEGG
  • InChI=1S/C30H45N6O16P/c1-12(21-13(2)33-26-22(34-21)27(44)36-30(31)35-26)32-15-5-3-14(4-6-15)9-16(37)23(41)17(38)10-49-29-25(43)24(42)19(51-29)11-50-53(47,48)52-18(28(45)46)7-8-20(39)40/h3-6,12-13,16-19,21,23-25,29,32,34,37-38,41-43H,7-11H2,1-2H3,(H,39,40)(H,45,46)(H,47,48)(H4,31,33,35,36,44)/t12-,13+,16+,17-,18+,19-,21?,23+,24-,25-,29+/m1/s1 checkY
    Key: SCBIBGUJSMHIAI-FDLOOEGASA-N checkY
  • InChI=1/C30H45N6O16P/c1-12(21-13(2)33-26-22(34-21)27(44)36-30(31)35-26)32-15-5-3-14(4-6-15)9-16(37)23(41)17(38)10-49-29-25(43)24(42)19(51-29)11-50-53(47,48)52-18(28(45)46)7-8-20(39)40/h3-6,12-13,16-19,21,23-25,29,32,34,37-38,41-43H,7-11H2,1-2H3,(H,39,40)(H,45,46)(H,47,48)(H4,31,33,35,36,44)/t12-,13+,16+,17-,18+,19-,21?,23+,24-,25-,29+/m1/s1
    Key: SCBIBGUJSMHIAI-FDLOOEGABF
  • O=C2/N=C(/N)NC=1N[C@@H](C)C(NC=12)[C@H](Nc3ccc(cc3)C[C@H](O)[C@H](O)[C@H](O)CO[C@H]4O[C@@H]([C@@H](O)[C@H]4O)COP(=O)(O[C@H](C(=O)O)CCC(=O)O)O)C
Properties
C
30H
45N
6O
16P
Molar mass 776.682661
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Structure

The structure of H
4MPT is analogous to that of tetrahydrofolate (THFA, H4folate). Both share a core derived from dihydropteroate (H2Pte), but where H4folate acid has a glutamyl tail attached to the 1' carbonyl group of H2Pte, H
4MPT instead has a "a ribitol residue linked to ribose 5-phosphate and thence to hydroxyglutarate". The pteroate part also sees two additional chiral methyl groups: carbon #12 on the branch connecting it to the phenyl ring (position 11, corresponds to folate position 9) and carbon #13 on the pterin core (position 7 in both MPT and folate).[2]

The lack of a electron-withdrawing carbonyl group para to N10 increases the electron density at this 10-position. The pKa for this atom in H
4MPT is -1.2, compared to +2.4 for H4folate. The biochemical redox potential E'
0 is more negative in reactions that involve one-carbon units bound to this atom. In contrast, the chemical environment of N5 is largely unchanged as far as enthalpy is concerned.[2] This difference has the effects including but not limited to:

  • Methenyl-THMPT (CH+
    -H
    4    MPT    ) is more difficult to reduce than methenyl-THFA (CH+
    -H
    4    folate). Reduction is effected by a so-called iron-sulfur cluster free hydrogenase. The cumbersome name distinguishes this hydrogenase from the other hydrogenases that do contain Fe-S cluster.[3] Steric hinderince from the 11-methyl group may also play a role.[2]
  • The methylene of CH2-H
    4    MPT     exchanges more slowly with the formyl from formaldehyde compared to the analogous CH2-H
    4    folate reaction. The epimerization of this methylene is also slower.[2]
  • Formyl (HCO)-H
    4    MPT     is thermodynamically able to spontaneously cyclize to CH2-H
    4    MPT    , unlike the folate analogos which requires energy input from ATP.[2]
  • Unlike in THF where the formyl group attaches to position 10, the formyl group attaches to position 5 on THMPT.[2]

Biosynthesis

Steps in the biosynthesis of methanopetrin include:[4]

More information Substrates, Products ...
Biosynthesis of methanopetrin
SubstratesProductsEnzymeEC numberGene namesNotes
GTP + H
2O		 7,8-dihydro-D-neopterin 2′,3′-cyclic phosphate (H2Npt-cP) + HCOOH + pyrophosphate GTP cyclohydrolase IV3.5.4.39MptA New type of GTP cyclohydrolase in 2007.[5]
H2Npt-cP + H
2O		 7,8-dihydro-D-neopterin (2′ or 3′) phosphate (H2Npt-P) H2Npt-cP phosphodiesterase3.1.4.56MptB IUBMB reports a in vitro product ratio of 4:1 for 2' vs 3'.
4-aminobenzoate (PABA) + PRPP Beta-ribofuranosylphenol 5'-phosphate (β-RFA-P) + PPi + CO
2		 β-RFA-P synthase2.4.2.54MptG
β-RFA-P + H2Npt-3'-P 7,8-dihydropterin-6-yl-methyl-4-((β-)D-ribofuranosyl)aminobenzene 5'-phosphate + PPi (H2Pte-6-yl)-RFA-P synthase2.5.1.105MJ0301 A MptH/MJ0107 was originally proposed for this activity due to similarity to dihydropteroate synthase. However, lab testing reveals the Metallo-beta-lactamase protein fold MJ0301 to be actually responsible.[6]
(H2Pte-6-yl)-RFA-P + 2 H
2O?		 N-[(7,8-dihydropterin-6-yl)methyl]-4-(1-deoxy-d-ribulosyl)aminobenzene + Pi + ? Unidentified lyase-.-.-.-Unk Unidentified ring-opening reaction that turns the closed ribose ring (ribofuranosyl) into an open ribulose chain ((H2Pte-6-yl)-RA).[7]
(H2Pte-6-yl)-RA + PRPP (1-(4-{N-[(7,8-dihydropterin-6-yl)methyl]amino}phenyl)-5-(5-phospho-α-d-ribulosyl)-1-deoxyribitol + PPi Unidentified ((H2Pte-6-yl)-RA)-PRPP synthase-.-.-.-Unk Unidentified condensation reaction.[7]
((H2Pte-6-yl)-RA)-PRPP + α-Ketoglutaric acid (AKG) 7,11-dinor-H2MPT + H
2O + PPi		 Also unidentified-.-.-.-Unk "7,11-dinor" refers to the lack of two methyl groups compared to dihydromethanopterin. See nor-.
7,11-dinor-H2MPT + 2 AdoMet + ? H2MPT + 2 AdoHcy + ? Unidentified methyltransferases-.-.-.-Unk Position 11 is methylated first, based on observation of variant molecules.[8] MJ0619 is a candidate gene.[9]
H2MPT + 2 NAD(P)H + 2 H+ H4MPT + 2 NAD(P)+ dihydromethanopterin reductase or acceptor variant1.5.1.47dmrA KEGG R03388, bacterial. Characterized 2004. Prefers NADPH.[10]
H2MPT + reduced acceptor H4MPT + acceptor dihydromethanopterin reductase (acceptor)1.5.99.15dmrX KEGG R10802, archaeal. Characterized 2014. Likely uses a flavin acceptor.[11]
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Variations

There are numerous variations on H
4MPT in archaea (bacteria tend to stick to the standard molecule):[8]

  • Pyrococcus and Thermococcus have a poly-β3(l→4)-linked N-acetylglucosamine side chain instead of the hydroxyglutamic acid terminus. There can be 1–5 units.
  • In (tetrahydro)sarcinapterin (H
    4    SPT    ), a glutamyl group is linked to the 2-hydroxyglutaric acid terminus of MPT. This reaction is mediated by EC 6.3.2.33 tetrahydrosarcinapterin synthase.
  • (H4)tatiopterin-0 differs from H
    4    SPT     by the lack of 7-methylation. Tatiopterin-1 has one more glutamyl group attached to the α carboxyl of the additional glutamyl.
  • (H4)thermopterin differs from tatiopterin-0 by the addition of an electron-withdrawing phenyl group in the 3' position, ortho to the pterin part and meta to the ribulose chain.
  • (H4)sulfopterin of Sulfolobus has neither methyl group. The molecule has only been characterized to the ribulose, with the rest being unknown.

Biochemical function

One-carbon carrier

N-Formylmethanofuran donates the C1 group to the N5 site of the pterin to give the 5-formyl-THMPT (5-CHO-H
4MPT).[12] (This is different from THF, which tends to give 10-formyl-THF. The difference is due to the aforementioned local chemical difference.)[2] The formyl group subsequently condenses intramolecularly to give 5,10-methenyl-THMPT+
 (5,10-CH+
-H
4MPT), which is then reduced to 5,10-methylene-THMPT (5,10-CH
2-H
4MPT) by 5,10-methenyl-THMPT+
 hydrogenase with H
2 as the electron donor.[3] 5,10-Methylene-MPT is subsequently converted, using coenzyme F420 as the electron source, to methyl-THMPT (5-CH3-H
4MPT), catalyzed by F420-dependent methylene-THMPT reductase. 5-Methyl-THMPT is the methyl donor to coenzyme M, a conversion mediated by methyl-THMPT: coenzyme M methyltransferase.[1]

Like THF, the C1 transformations of THMPT can lead to acetyl-CoA as well as convert glycine to serine. It does not feed into purine metabolism, glycine production, or ketoglutarate production, however.[2]

Evidence for MPT participation in methionine synthesis is weak (as of 2000).[2] Further genetic work has not identified a methyl-THMPT-using methionine synthase (though the split-MetE versions remain candidates) but has instead found many that use a corrinoid protein to carry the methyl group. In methanogens with the MesA synthase, the methyl group likely comes from the aforementioned methyl-THMPT: coenzyme M methyltransferase, so ultimately these organisms do obtain their methyl from methyl-THMPT.[13]

How (and whether) MPT relates to thymidylate biosynthesis is also unclear. Cell-free extracts of various archaea are able to convert dUMP to dTMP when given MPT (or sulfopterin fragments, in the case of Sulfolobus) and isotope-labeled formaldehyde, but no enzyme has been identified.[2]

C2

N5,N10-(1,1-ethylene)H
4MPT (5,10-ethylene-H
4MPT) and N5-ethyl-H
4MPT have been detected in Methanothermobacter marburgensis, indicating that H
4MPT can also serve as a two-carbon carrier. Under standard conditions, H
4MPT spontaneously reacts with acetaldehyde to yield ethylene-H
4MPT. M. marburgensis lysate contains an enzyme that catalyzes this product's reduction to ethyl-H
4MPT.[14]

References

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