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MetaCyc Pathway: tetrahydromethanopterin biosynthesis
Inferred from experiment

Pathway diagram: tetrahydromethanopterin biosynthesis

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: H4MPT biosynthesis

Superclasses: BiosynthesisCofactors, Prosthetic Groups, Electron Carriers Biosynthesis

Some taxa known to possess this pathway include : Methanobacterium thermoautotrophicum Marburg, Methanocaldococcus jannaschii, Methanosarcina mazei, Methanosarcina thermophila, Methanothermobacter thermautotrophicus, Methanothermobacter thermautotrophicus Delta H, Methanothermobacter thermautotrophicus Winter, Methylobacterium extorquens

Expected Taxonomic Range: Methanobacteria, Methanococci, Methanomicrobia, Methylobacterium extorquens group

Methanopterin is one of several modified folates that have been identified in Archaea [vanBeelen84, RaemakersFranke89, RaemakersFranke91, RaemakersFranke91a, White93] (see also sarcinapterin). While common in all methanogenic archaea, some C1-oxidizing members of the domain Bacteria also contain an tetrahydromethanopterin-related carrier, which they use in energy metabolism (see formaldehyde oxidation V (H4MPT pathway)).

Serving a similar role to the one that folates serve in bacteria and eukaryotes, methanopterin carries C1 (single carbon) fragments between formyl and methyl oxidation levels in methanogens and several other Archaea (see methanogenesis from H2 and CO2). Despite the similarities, there are clear differences between tetrahydropteroyl mono-L-glutamate and tetrahydromethanopterin. In the reductive direction, ATP is consumed in the entry of carbon from CO2 into the tetrahydropteroyl mono-L-glutamate pathway, but not in entry into the tetrahydromethanopterin pathway.

In the oxidative direction, methyl groups are much more readily oxidized on tetrahydromethanopterin than on tetrahydropteroyl mono-L-glutamate. Moreover, the redox reactions on tetrahydromethanopterin are coupled to more negative reductants than the pyridine nucleotides which are used in the tetrahydropteroyl mono-L-glutamate pathway [Maden00].

The biosynthetic pathway for the synthesis of methanopterin was initially illucidated by the use of labeled isotopes studies and azo dye derivatives [White96] and has been refined incremently ever since [Rasche98, Mashhadi09, White11, Allen14a]. The identification of the enzymes that catalyze the pathway's reactions has proved very difficult, and while all of the enzymes from the early part of the pathway have been identified, most of the enzymes in the later part of the pathway are still unknown.

The methyl groups at C-7 and C-9 of the pterin ring of methanopterin distinguish it from all other pterin-containing natural products. The methyltransferase that methylates these positions has been one of the enigmatic enzymes of the pathway. The enzyme from Methanocaldococcus jannaschii has been identified, and it has been suggested that in this organism methylation occurs early in the pathway, most likely at the level of 6-hydroxymethyl-7,8-dihydropterin [Allen14a]. Thus, all compounds in the pathway shown here are dimethylated starting with that intermediate. However, methylation may occur at different steps of the pathway in different organisms. It has been shown that methylation can occur at 7,8-H2pterin-6-ylmethyl-l-(4-aminophenyl)-1-deoxy-D-ribitol 5'-phosphate in Methanothermobacter thermautotrophicus Delta H and Methanobacterium thermoautotrophicum Marburg [White98].

Created 05-Mar-2009 by Caspi R, SRI International
Revised 06-Aug-2014 by Caspi R, SRI International


Allen14a: Allen KD, Xu H, White RH (2014). "Identification of a unique radical SAM methylase likely involved in methanopterin biosynthesis in Methanocaldococcus jannaschii." J Bacteriol. PMID: 25002541

Maden00: Maden BE (2000). "Tetrahydrofolate and tetrahydromethanopterin compared: functionally distinct carriers in C1 metabolism." Biochem J 350 Pt 3;609-29. PMID: 10970772

Mashhadi09: Mashhadi Z, Xu H, White RH (2009). "An Fe2+-dependent cyclic phosphodiesterase catalyzes the hydrolysis of 7,8-dihydro-D-neopterin 2',3'-cyclic phosphate in methanopterin biosynthesis." Biochemistry 48(40);9384-92. PMID: 19746965

RaemakersFranke89: Raemakers-Franken PC, Voncken FG, Korteland J, Keltjens JT, van der Drift C, Vogels GD (1989). "Structural characterization of tatiopterin, a novel pterin isolated from Methanogenium tationis." Biofactors 2(2);117-22. PMID: 2624671

RaemakersFranke91: Raemakers-Franken PC, van Elderen CH, van der Drift C, Vogels GD (1991). "Identification of a novel tatiopterin derivative in Methanogenium tationis." Biofactors 3(2);127-30. PMID: 1910453

RaemakersFranke91a: Raemakers-Franken PC, Bongaerts R, Fokkens R, van der Drift C, Vogels GD (1991). "Characterization of two pterin derivatives isolated from Methanoculleus thermophilicum." Eur J Biochem 200(3);783-7. PMID: 1915350

Rasche98: Rasche ME, White RH (1998). "Mechanism for the enzymatic formation of 4-(beta-D-ribofuranosyl)aminobenzene 5'-phosphate during the biosynthesis of methanopterin." Biochemistry 37(32);11343-51. PMID: 9698382

vanBeelen84: van Beelen P, Stassen AP, Bosch JW, Vogels GD, Guijt W, Haasnoot CA (1984). "Elucidation of the structure of methanopterin, a coenzyme from Methanobacterium thermoautotrophicum, using two-dimensional nuclear-magnetic-resonance techniques." Eur J Biochem 138(3);563-71. PMID: 6319137

White11: White RH (2011). "The conversion of a phenol to an aniline occurs in the biochemical formation of the 1-(4-aminophenyl)-1-deoxy-D-ribitol moiety in methanopterin." Biochemistry 50(27);6041-52. PMID: 21634403

White93: White RH (1993). "Structures of the modified folates in the extremely thermophilic archaebacterium Thermococcus litoralis." J Bacteriol 175(11);3661-3. PMID: 8501071

White96: White RH (1996). "Biosynthesis of methanopterin." Biochemistry 35(11);3447-56. PMID: 8639495

White98: White RH (1998). "Methanopterin biosynthesis: methylation of the biosynthetic intermediates." Biochim Biophys Acta 1380(2);257-67. PMID: 9565696

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Adams14: Adams NE, Thiaville JJ, Proestos J, Juarez-Vazquez AL, McCoy AJ, Barona-Gomez F, Iwata-Reuyl D, de Crecy-Lagard V, Maurelli AT (2014). "Promiscuous and adaptable enzymes fill "holes" in the tetrahydrofolate pathway in Chlamydia species." MBio 5(4). PMID: 25006229

Bauer04: Bauer S, Schott AK, Illarionova V, Bacher A, Huber R, Fischer M (2004). "Biosynthesis of tetrahydrofolate in plants: crystal structure of 7,8-dihydroneopterin aldolase from Arabidopsis thaliana reveals a novel aldolase class." J Mol Biol 339(4);967-79. PMID: 15165863

BRENDA14: BRENDA team (2014). Imported from BRENDA version existing on Aug 2014.

Brown71: Brown GM (1971). "The biosynthesis of pteridines." Adv Enzymol Relat Areas Mol Biol 1971;35;35-77. PMID: 4361155

Caccamo04: Caccamo MA, Malone CS, Rasche ME (2004). "Biochemical characterization of a dihydromethanopterin reductase involved in tetrahydromethanopterin biosynthesis in Methylobacterium extorquens AM1." J Bacteriol 186(7);2068-73. PMID: 15028691

deCrecyLagard12: de Crecy-Lagard V, Phillips G, Grochowski LL, El Yacoubi B, Jenney F, Adams MW, Murzin AG, White RH (2012). "Comparative genomics guided discovery of two missing archaeal enzyme families involved in the biosynthesis of the pterin moiety of tetrahydromethanopterin and tetrahydrofolate." ACS Chem Biol 7(11);1807-16. PMID: 22931285

Ding04a: Ding YH, Ferry JG (2004). "Flavin mononucleotide-binding flavoprotein family in the domain Archaea." J Bacteriol 186(1);90-7. PMID: 14679228

Dumitru04: Dumitru RV, Ragsdale SW (2004). "Mechanism of 4-(beta-D-ribofuranosyl)aminobenzene 5'-phosphate synthase, a key enzyme in the methanopterin biosynthetic pathway." J Biol Chem 279(38);39389-95. PMID: 15262968

Frey01: Frey PA (2001). "Radical mechanisms of enzymatic catalysis." Annu Rev Biochem 70;121-48. PMID: 11395404

Goyer04: Goyer A, Illarionova V, Roje S, Fischer M, Bacher A, Hanson AD (2004). "Folate biosynthesis in higher plants. cDNA cloning, heterologous expression, and characterization of dihydroneopterin aldolases." Plant Physiol 135(1);103-11. PMID: 15107504

Haussmann98: Haussmann C, Rohdich F, Schmidt E, Bacher A, Richter G (1998). "Biosynthesis of pteridines in Escherichia coli. Structural and mechanistic similarity of dihydroneopterin-triphosphate epimerase and dihydroneopterin aldolase." J Biol Chem 273(28);17418-24. PMID: 9651328

Holden02: Holden MJ, Mayhew MP, Gallagher DT, Vilker VL (2002). "Chorismate lyase: kinetics and engineering for stability." Biochim Biophys Acta 1594(1);160-7. PMID: 11825618

Kalyuzhnaya05: Kalyuzhnaya MG, Korotkova N, Crowther G, Marx CJ, Lidstrom ME, Chistoserdova L (2005). "Analysis of gene islands involved in methanopterin-linked C1 transfer reactions reveals new functions and provides evolutionary insights." J Bacteriol 187(13);4607-14. PMID: 15968072

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Mathis70: Mathis JB, Brown GM (1970). "The biosynthesis of folic acid. XI. Purification and properties of dihydroneopterin aldolase." J Biol Chem 1970;245(11);3015-25. PMID: 4912541

Miller00a: Miller JR, Busby RW, Jordan SW, Cheek J, Henshaw TF, Ashley GW, Broderick JB, Cronan JE, Marletta MA (2000). "Escherichia coli LipA is a lipoyl synthase: in vitro biosynthesis of lipoylated pyruvate dehydrogenase complex from octanoyl-acyl carrier protein." Biochemistry 39(49);15166-78. PMID: 11106496

Nichols92: Nichols BP, Green JM (1992). "Cloning and sequencing of Escherichia coli ubiC and purification of chorismate lyase." J Bacteriol 1992;174(16);5309-16. PMID: 1644758

Park06: Park YJ, Yoo CB, Choi SY, Lee HB (2006). "Purifications and characterizations of a ferredoxin and its related 2-oxoacid:ferredoxin oxidoreductase from the hyperthermophilic archaeon, Sulfolobus solfataricus P1." J Biochem Mol Biol 39(1);46-54. PMID: 16466637

Pfaff13: Pfaff C, Glindemann N, Gruber J, Frentzen M, Sadre R (2013). "Chorismate Pyruvate-Lyase and 4-Hydroxy-3-Solanesylbenzoate Decarboxylase are required for Plastoquinone Biosynthesis in the Cyanobacterium Synechocystis sp. PCC6803." J Biol Chem 289(5);2675-86. PMID: 24337576

Siebert92: Siebert M, Bechthold A, Melzer M, May U, Berger U, Schroder G, Schroder J, Severin K, Heide L (1992). "Ubiquinone biosynthesis. Cloning of the genes coding for chorismate pyruvate-lyase and 4-hydroxybenzoate octaprenyl transferase from Escherichia coli." FEBS Lett 307(3);347-50. PMID: 1644192

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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