Tetrahydromethanopterin
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| 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) |
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| ChEBI | |
| ChemSpider | |
| KEGG | |
PubChem CID |
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CompTox Dashboard (EPA) |
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| 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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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]
Structure
[edit]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
4MPT) is more difficult to reduce than methenyl-THFA (CH+
-H
4folate). 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
4MPT exchanges more slowly with the formyl from formaldehyde compared to the analogous CH2-H
4folate reaction. The epimerization of this methylene is also slower.[2] - Formyl (HCO)-H
4MPT is thermodynamically able to spontaneously cyclize to CH2-H
4MPT, 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
[edit]Steps in the biosynthesis of methanopetrin include:[4]
| Substrates | Products | Enzyme | EC number | Gene names | Notes |
|---|---|---|---|---|---|
| GTP + H 2O |
7,8-dihydro-D-neopterin 2′,3′-cyclic phosphate (H2Npt-cP) + HCOOH + pyrophosphate | GTP cyclohydrolase IV | 3.5.4.39 | MptA | 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 phosphodiesterase | 3.1.4.56 | MptB | 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 synthase | 2.4.2.54 | MptG | |
| 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 synthase | 2.5.1.105 | MJ0301 | 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 variant | 1.5.1.47 | dmrA | KEGG R03388, bacterial. Characterized 2004. Prefers NADPH.[10] |
| H2MPT + reduced acceptor | H4MPT + acceptor | dihydromethanopterin reductase (acceptor) | 1.5.99.15 | dmrX | KEGG R10802, archaeal. Characterized 2014. Likely uses a flavin acceptor.[11] |
Variations
[edit]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
4SPT), 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
4SPT 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
[edit]One-carbon carrier
[edit]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
[edit]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
[edit]- 1 2 Thauer RK (September 1998). "Biochemistry of methanogenesis: a tribute to Marjory Stephenson. 1998 Marjory Stephenson Prize Lecture". Microbiology. 144 (Pt 9): 2377–406. doi:10.1099/00221287-144-9-2377. PMID 9782487.
- 1 2 3 4 5 6 7 8 9 10 Maden, B. Edward H. (15 September 2000). "Tetrahydrofolate and tetrahydromethanopterin compared: functionally distinct carriers in C1 metabolism". Biochemical Journal. 350 (3): 609–629. doi:10.1042/bj3500609. PMC 1221290. PMID 10970772.
- 1 2 Korbas M, Vogt S, Meyer-Klaucke W, et al. (October 2006). "The iron-sulfur cluster-free hydrogenase (Hmd) is a metalloenzyme with a novel iron binding motif". J. Biol. Chem. 281 (41): 30804–13. doi:10.1074/jbc.M605306200. PMID 16887798.
- ↑ Graham, David E.; White, Robert H. (15 March 2002). "Elucidation of methanogenic coenzyme biosyntheses: from spectroscopy to genomics". Natural Product Reports. 19 (2): 133–147. doi:10.1039/B103714P. PMID 12013276.
- ↑ Grochowski, Laura L.; Xu, Huimin; Leung, Kapo; White, Robert H. (1 June 2007). "Characterization of an Fe 2+ -Dependent Archaeal-Specific GTP Cyclohydrolase, MptA, from Methanocaldococcus jannaschii". Biochemistry. 46 (22): 6658–6667. doi:10.1021/bi700052a. PMID 17497938.
- ↑ Iyer, LM; Aravind, L; Bork, P; Hofmann, K; Mushegian, AR; Zhulin, IB; Koonin, EV (2001). "Quod erat demonstrandum? The mystery of experimental validation of apparently erroneous computational analyses of protein sequences". Genome Biology. 2 (12) RESEARCH0051. doi:10.1186/gb-2001-2-12-research0051. PMC 64836. PMID 11790254.
- 1 2 Hove-Jensen, Bjarne; Andersen, Kasper R.; Kilstrup, Mogens; Martinussen, Jan; Switzer, Robert L.; Willemoës, Martin (28 December 2016). "Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance". Microbiology and Molecular Biology Reviews. 81 (1): 10.1128/mmbr.00040–16. doi:10.1128/mmbr.00040-16. PMC 5312242. PMID 28031352.
- 1 2 Braakman, Rogier; Smith, Eric (19 April 2012). "The Emergence and Early Evolution of Biological Carbon-Fixation". PLOS Computational Biology. 8 (4) e1002455. Bibcode:2012PLSCB...8E2455B. doi:10.1371/journal.pcbi.1002455. PMC 3334880. PMID 22536150.
- ↑ Allen, KD; Xu, H; White, RH (September 2014). "Identification of a unique radical S-adenosylmethionine methylase likely involved in methanopterin biosynthesis in Methanocaldococcus jannaschii". Journal of Bacteriology. 196 (18): 3315–23. doi:10.1128/JB.01903-14. PMC 4135684. PMID 25002541.
- ↑ Caccamo, Marco A.; Malone, Courtney S.; Rasche, Madeline E. (April 2004). "Biochemical Characterization of a Dihydromethanopterin Reductase Involved in Tetrahydromethanopterin Biosynthesis in Methylobacterium extorquens AM1". Journal of Bacteriology. 186 (7): 2068–2073. doi:10.1128/JB.186.7.2068-2073.2004. PMC 374392. PMID 15028691.
- ↑ Wang, S.; Tiongson, J.; Rasche, M. E. (15 January 2014). "Discovery and Characterization of the First Archaeal Dihydromethanopterin Reductase, an Iron-Sulfur Flavoprotein from Methanosarcina mazei". Journal of Bacteriology. 196 (2): 203–209. doi:10.1128/JB.00457-13. PMC 3911254. PMID 23995635.
- ↑ Acharya P, Warkentin E, Ermler U, Thauer RK, Shima S (March 2006). "The structure of formylmethanofuran: tetrahydromethanopterin formyltransferase in complex with its coenzymes". J. Mol. Biol. 357 (3): 870–9. doi:10.1016/j.jmb.2006.01.015. PMID 16466742.
- ↑ Price, MN; Deutschbauer, AM; Arkin, AP (February 2021). "Four families of folate-independent methionine synthases". PLOS Genetics. 17 (2) e1009342. doi:10.1371/journal.pgen.1009342. PMC 7857596. PMID 33534785.
- ↑ Laird, Maxime G.; Telimaa, Heta; Koivisto, Jari; Scheller, Silvan (19 May 2026). "Tetrahydromethanopterin as a Two-Carbon Carrier: Formation of N 5 -Ethyl- and N 5 , N 10 -Ethylene-Tetrahydromethanopterin in Methanothermobacter marburgensis". Biochemistry. 65 (10): 1652–1657. doi:10.1021/acs.biochem.6c00178. PMC 13192316. PMID 42053226.