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MetaCyc Pathway: phosphinothricin tripeptide biosynthesis
Traceable author statement to experimental supportInferred from experiment

Pathway diagram: phosphinothricin tripeptide biosynthesis

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

Synonyms: PTT biosynthesis, bialaphos biosynthesis

Superclasses: BiosynthesisSecondary Metabolites BiosynthesisAntibiotic Biosynthesis

Some taxa known to possess this pathway include : Streptomyces hygroscopicus, Streptomyces hygroscopicus ATCC 21705, Streptomyces viridochromogenes, Streptomyces viridochromogenes DSM 40736

Expected Taxonomic Range: Actinobacteria

L-phophinothricin is a non-proteinogenic amino acid that is a structural analogue of L-glutamate . As such, it is a potent inhibitor of glutamine synthetase, an enzyme central to nitrogen regulation in many bacterial and plant species [Bayer72, Lea84]. It is the active ingredient in several nonselective systemic herbicides, including Basta, Rely, Finale, Challenge and Liberty.

Phosphinothricin is currently the only known naturally occurring compound in which a C-P-C bond motif (phosphorus linked to two carbons) is found.

L-phophinothricin is produced by at least three species of actinomycetes as a component of non-ribosomally synthesized peptides. These include phosalacine, produced by Kitasatospora phosalacinea [Omura84] and bialaphos (PTT), also known as bialaphos, which is produced by some strains of Streptomyces hygroscopicus [Seto82] and Streptomyces viridochromogenes [Bayer72]. The peptides are potent antibiotics and herbicides, transported into cells via the oligopeptide transport system, and hydrolyzed intracellularly by peptidases, releasing the toxic L-phophinothricin.

Studies of bialaphos biosynthesis in either of these two organisms suggest that it involves no less than 18 discrete enzymatically catalyzed reactions, starting from the common metabolite phosphoenolpyruvate. These enzymatic steps have been linked to a chromosomal gene cluster about 35 kb in length that includes at least 24 genes that are essential for the process [Schwartz04, Blodgett05]. Most of the steps have been ellucidated, and many of the enzymes have been identified [Schwartz96, Schwartz98, Heinzelmann01, Blodgett05, Blodgett07, Cicchillo09]. The pathway includes several unusual transformations, including a C(sp3)-C(sp3) bond cleavage by the phpD-encoded dioxygenase, the formation of two phosphorus-carbon bonds by phosphoenolpyruvate phosphomutase ( ppm) and N-acetyl-demethylphophinothricin P-methyltransferase ( bcpD), and the assembley of the peptide backbone by three nonribosomal peptide sythetases, encoded by phsA, phsB and phsC.

Different iterations of the pathway have been published over the years. A major revision of the upper part of the pathway, specifically the portion from phosphonoacetaldehyde to carboxyphosphonoenolpyruvate, has been suggested in 2007 by [Blodgett07]. A role for two small thioesterase-like genes ( phpL and phpM) was proposed in 2015 [Blodgett15].

Created 24-Aug-2009 by Caspi R, SRI International
Revised 21-Sep-2015 by Caspi R, SRI International


Bayer72: Bayer E, Gugel KH, Hagele K, Hagenmaier H, Jessipow S, Konig WA, Zahner H (1972). "[Metabolic products of microorganisms. 98. Phosphinothricin and phosphinothricyl-alanyl-analine]." Helv Chim Acta 55(1);224-39. PMID: 5010035

Blodgett05: Blodgett JA, Zhang JK, Metcalf WW (2005). "Molecular cloning, sequence analysis, and heterologous expression of the phosphinothricin tripeptide biosynthetic gene cluster from Streptomyces viridochromogenes DSM 40736." Antimicrob Agents Chemother 49(1);230-40. PMID: 15616300

Blodgett07: Blodgett JA, Thomas PM, Li G, Velasquez JE, van der Donk WA, Kelleher NL, Metcalf WW (2007). "Unusual transformations in the biosynthesis of the antibiotic phosphinothricin tripeptide." Nat Chem Biol 3(8);480-5. PMID: 17632514

Blodgett15: Blodgett JA, Zhang JK, Yu X, Metcalf WW (2015). "Conserved biosynthetic pathways for phosalacine, bialaphos and newly discovered phosphonic acid natural products." J Antibiot (Tokyo). PMID: 26328935

Cicchillo09: Cicchillo RM, Zhang H, Blodgett JA, Whitteck JT, Li G, Nair SK, van der Donk WA, Metcalf WW (2009). "An unusual carbon-carbon bond cleavage reaction during phosphinothricin biosynthesis." Nature 459(7248);871-4. PMID: 19516340

Heinzelmann01: Heinzelmann E, Kienzlen G, Kaspar S, Recktenwald J, Wohlleben W, Schwartz D (2001). "The phosphinomethylmalate isomerase gene pmi, encoding an aconitase-like enzyme, is involved in the synthesis of phosphinothricin tripeptide in Streptomyces viridochromogenes." Appl Environ Microbiol 67(8);3603-9. PMID: 11472937

Lea84: Lea, P. J., Joy, K. W., Ramos, J. L., Guerrero, M. G. (1984). "The action of 2-amino-4-(methylphosphonyl)-butanoic acid (phosphinothricin) and its 2-oxo-derivative on the metabolism of cyanobacteria and higher plants." Phytochemistry 23:1-6.

Omura84: Omura S, Murata M, Hanaki H, Hinotozawa K, Oiwa R, Tanaka H (1984). "Phosalacine, a new herbicidal antibiotic containing phosphinothricin. Fermentation, isolation, biological activity and mechanism of action." J Antibiot (Tokyo) 37(8);829-35. PMID: 6480502

Schwartz04: Schwartz D, Berger S, Heinzelmann E, Muschko K, Welzel K, Wohlleben W (2004). "Biosynthetic gene cluster of the herbicide phosphinothricin tripeptide from Streptomyces viridochromogenes Tu494." Appl Environ Microbiol 70(12);7093-102. PMID: 15574905

Schwartz96: Schwartz D, Alijah R, Nussbaumer B, Pelzer S, Wohlleben W (1996). "The peptide synthetase gene phsA from Streptomyces viridochromogenes is not juxtaposed with other genes involved in nonribosomal biosynthesis of peptides." Appl Environ Microbiol 62(2);570-7. PMID: 8593056

Schwartz98: Schwartz D, Recktenwald J, Pelzer S, Wohlleben W (1998). "Isolation and characterization of the PEP-phosphomutase and the phosphonopyruvate decarboxylase genes from the phosphinothricin tripeptide producer Streptomyces viridochromogenes Tu494." FEMS Microbiol Lett 163(2);149-57. PMID: 9673017

Seto82: Seto H, Imai S, Tsuruoka T, Satoh A, Kojima M, Inouye S, Sasaki T, Otake N (1982). "Studies on the biosynthesis of bialaphos (SF-1293). 1. Incorporation of 13C- and 2H-labeled precursors into bialaphos." J Antibiot (Tokyo) 35(12);1719-21. PMID: 7166539

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

Anzai87: Anzai H, Murakami T, Imai S, Satoh A, Nagaoka K, Thompson CJ (1987). "Transcriptional regulation of bialaphos biosynthesis in Streptomyces hygroscopicus." J Bacteriol 169(8);3482-8. PMID: 3611020

Booker09: Booker SJ (2009). "Anaerobic functionalization of unactivated C-H bonds." Curr Opin Chem Biol 13(1);58-73. PMID: 19297239

Borisova10: Borisova SA, Circello BT, Zhang JK, van der Donk WA, Metcalf WW (2010). "Biosynthesis of rhizocticins, antifungal phosphonate oligopeptides produced by Bacillus subtilis ATCC6633." Chem Biol 17(1);28-37. PMID: 20142038

Botterman91: Botterman J, Gossele V, Thoen C, Lauwereys M (1991). "Characterization of phosphinothricin acetyltransferase and C-terminal enzymatically active fusion proteins." Gene 102(1);33-7. PMID: 1864506

Bowman88: Bowman E, McQueney M, Barry RJ, Dunaway-Mariano D (1988). "Catalysis and thermodynamics of the phosphoenolpyruvate/phosphonopyruvate rearrangement. Entry into the phosphonate class of naturally occurring organophosphorus compounds." J. Am. Chem. Soc. 110, 5575-5576.

Bowman90: Bowman ED, McQueney MS, Scholten JD, Dunaway-Mariano D (1990). "Purification and characterization of the Tetrahymena pyriformis P-C bond forming enzyme phosphoenolpyruvate phosphomutase." Biochemistry 29(30);7059-63. PMID: 2121271

Circello10: Circello BT, Eliot AC, Lee JH, van der Donk WA, Metcalf WW (2010). "Molecular cloning and heterologous expression of the dehydrophos biosynthetic gene cluster." Chem Biol 17(4);402-11. PMID: 20416511

Eliot08: Eliot AC, Griffin BM, Thomas PM, Johannes TW, Kelleher NL, Zhao H, Metcalf WW (2008). "Cloning, expression, and biochemical characterization of Streptomyces rubellomurinus genes required for biosynthesis of antimalarial compound FR900098." Chem Biol 15(8);765-70. PMID: 18721747

Eys08: Eys S, Schwartz D, Wohlleben W, Schinko E (2008). "Three thioesterases are involved in the biosynthesis of phosphinothricin tripeptide in Streptomyces viridochromogenes Tu494." Antimicrob Agents Chemother 52(5);1686-96. PMID: 18285472

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

Grammel98: Grammel N, Schwartz D, Wohlleben W, Keller U (1998). "Phosphinothricin-tripeptide synthetases from Streptomyces viridochromogenes." Biochemistry 37(6);1596-603. PMID: 9484230

Hidaka90: Hidaka T, Imai S, Hara O, Anzai H, Murakami T, Nagaoka K, Seto H (1990). "Carboxyphosphonoenolpyruvate phosphonomutase, a novel enzyme catalyzing C-P bond formation." J Bacteriol 172(6);3066-72. PMID: 2160937

Hidaka92: Hidaka T, Hidaka M, Uozumi T, Seto H (1992). "Nucleotide sequence of a carboxyphosphonoenolpyruvate phosphonomutase gene isolated from a bialaphos-producing organism, Streptomyces hygroscopicus, and its expression in Streptomyces lividans." Mol Gen Genet 233(3);476-8. PMID: 1320191

Hidaka95: Hidaka T, Goda M, Kuzuyama T, Takei N, Hidaka M, Seto H (1995). "Cloning and nucleotide sequence of fosfomycin biosynthetic genes of Streptomyces wedmorensis." Mol Gen Genet 249(3);274-80. PMID: 7500951

Hidaka95a: Hidaka T, Hidaka M, Kuzuyama T, Seto H (1995). "Sequence of a P-methyltransferase-encoding gene isolated from a bialaphos-producing Streptomyces hygroscopicus." Gene 158(1);149-50. PMID: 7789803

Imai85: Imai S, Seto H, Sasaki T, Tsuruoka T, Ogawa H, Satoh A, Inouye S, Niida T, Otake N (1985). "Studies on the biosynthesis of bialaphos (SF-1293). 6. Production of N-acetyl-demethylphosphinothricin and N-acetylbialaphos by blocked mutants of Streptomyces hygroscopicus SF-1293 and their roles in the biosynthesis of bialaphos." J Antibiot (Tokyo) 38(5);687-90. PMID: 4019315

Jia99: Jia Y, Lu Z, Huang K, Herzberg O, Dunaway-Mariano D (1999). "Insight into the mechanism of phosphoenolpyruvate mutase catalysis derived from site-directed mutagenesis studies of active site residues." Biochemistry 38(43);14165-73. PMID: 10571990

Kamigiri92: Kamigiri K, Hidaka T, Imai S, Murakami T, Seto H (1992). "Studies on the biosynthesis of bialaphos (SF-1293) 12. C-P bond formation mechanism of bialaphos: discovery of a P-methylation enzyme." J Antibiot (Tokyo) 45(5);781-7. PMID: 1624380

Kim96: Kim J, Dunaway-Mariano D (1996). "Phosphoenolpyruvate mutase catalysis of phosphoryl transfer in phosphoenolpyruvate: kinetics and mechanism of phosphorus-carbon bond formation." Biochemistry 35(14);4628-35. PMID: 8605214

Kim98b: Kim A, Kim J, Martin BM, Dunaway-Mariano D (1998). "Isolation and characterization of the carbon-phosphorus bond-forming enzyme phosphoenolpyruvate mutase from the mollusk Mytilus edulis." J Biol Chem 273(8);4443-8. PMID: 9468496

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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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