ENTRY ko00261 Pathway NAME Monobactam biosynthesis DESCRIPTION Monobactams are beta-lactam antibiotics containing a monocyclic beta-lactam nucleus, which is structurally different from penicillin and cephalosporin core structures with another fused ring. This diagram shows biosynthesis of nocardicin A, a naturally occurring monobactam, via the pentapeptide formed by condensation of L-4-hydroxyphenylglycine (L-pHPG), L-arginine and L-serine [MD:M00736]. Other naturally occurring monobactams are also shown but the biosynthetic pathway is not yet fully characterized. Sulfazecin and other 3-aminomonobactamic acid derivatives are derived from serine or threonine, and tabtoxinine-beta-lactam is a phytotoxin. Aztreonam, a synthetic monobactam originally isolated as SQ 26,180 from Chromobacterium violaceum, is the first clinically used monobactam. CLASS Metabolism; Biosynthesis of other secondary metabolites PATHWAY_MAP ko00261 Monobactam biosynthesis MODULE M00736 Nocardicin A biosynthesis, L-pHPG + arginine + serine => nocardicin A [PATH:ko00261] ORTHOLOGY K16421 4-hydroxymandelate synthase [EC:1.13.11.46] K16422 4-hydroxymandelate oxidase [EC:1.1.3.46] K16423 (S)-3,5-dihydroxyphenylglycine transaminase [EC:2.6.1.103] K19102 nocardicin nonribosomal peptide synthetase NocA K19103 nocardicin nonribosomal peptide synthetase NocB K05375 MbtH protein K19104 isonocardicin synthase [EC:2.5.1.38] K19105 nocardicin-A epimerase [EC:5.1.1.14] K19106 nocardicin N-oxygenase [EC:1.14.13.-] K13811 3'-phosphoadenosine 5'-phosphosulfate synthase [EC:2.7.7.4 2.7.1.25] K00955 bifunctional enzyme CysN/CysC [EC:2.7.7.4 2.7.1.25] K00956 sulfate adenylyltransferase subunit 1 [EC:2.7.7.4] K00957 sulfate adenylyltransferase subunit 2 [EC:2.7.7.4] K00958 sulfate adenylyltransferase [EC:2.7.7.4] K00928 aspartate kinase [EC:2.7.2.4] K12524 bifunctional aspartokinase / homoserine dehydrogenase 1 [EC:2.7.2.4 1.1.1.3] K12525 bifunctional aspartokinase / homoserine dehydrogenase 2 [EC:2.7.2.4 1.1.1.3] K12526 bifunctional diaminopimelate decarboxylase / aspartate kinase [EC:4.1.1.20 2.7.2.4] K00133 aspartate-semialdehyde dehydrogenase [EC:1.2.1.11] K01714 4-hydroxy-tetrahydrodipicolinate synthase [EC:4.3.3.7] K00215 4-hydroxy-tetrahydrodipicolinate reductase [EC:1.17.1.8] K19107 putative acetyltransferase [EC:2.3.1.-] K19108 decarboxylase [EC:4.1.1.-] K19109 putative beta-lactam synthetase K19110 putative 2-oxoglutarate oxygenase K19111 putative tabtoxin peptidase [EC:3.4.-.-] K19112 L-Amino acid ligase [EC:6.3.2.-] K19113 acetyltransferase [EC:2.3.1.-] COMPOUND C00019 S-Adenosyl-L-methionine C00022 Pyruvate C00049 L-Aspartate C00059 Sulfate C00062 L-Arginine C00065 L-Serine C00082 L-Tyrosine C00188 L-Threonine C00224 Adenylyl sulfate C00441 L-Aspartate 4-semialdehyde C00927 Isonocardicin A C01179 3-(4-Hydroxyphenyl)pyruvate C01739 Nocardicin E C01941 Nocardicin A C03082 4-Phospho-L-aspartate C03198 (S)-4-Hydroxymandelate C03590 4-Hydroxyphenylglyoxylate C03972 2,3,4,5-Tetrahydrodipicolinate C05539 N-Acetyl-L-2-amino-6-oxopimelate C12323 L-4-Hydroxyphenylglycine C16842 SQ 26180 C17351 Nocardicin C C17352 Isonocardicin C C17355 Nocardicin G C20258 (2S,4S)-4-Hydroxy-2,3,4,5-tetrahydrodipicolinate C20911 C20911 C20912 C20912 C20913 C20913 C20914 C20914 C20915 C20915 C20916 C20916 C20917 Tabtoxin C20918 Tabtoxinine-beta-lactam C20919 Isotabtoxin C20920 Tabtoxinine-delta-lactam C20921 N1-Acetyl-tabtoxinine-beta-lactam C20927 Sulfazecin C20928 MM 42842 C20929 3alpha-Hydroxy-3-aminoacylmonobactamic acid REFERENCE PMID:23135477 AUTHORS Hamed RB, Gomez-Castellanos JR, Henry L, Ducho C, McDonough MA, Schofield CJ TITLE The enzymes of beta-lactam biosynthesis. JOURNAL Nat Prod Rep 30:21-107 (2013) DOI:10.1039/c2np20065a REFERENCE PMID:15271351 AUTHORS Gunsior M, Breazeale SD, Lind AJ, Ravel J, Janc JW, Townsend CA TITLE The biosynthetic gene cluster for a monocyclic beta-lactam antibiotic, nocardicin A. JOURNAL Chem Biol 11:927-38 (2004) DOI:10.1016/j.chembiol.2004.04.012 REFERENCE PMID:15252031 AUTHORS Kelly WL, Townsend CA TITLE Mutational analysis and characterization of nocardicin C-9' epimerase. JOURNAL J Biol Chem 279:38220-7 (2004) DOI:10.1074/jbc.M405450200 REFERENCE PMID:15629944 AUTHORS Kelly WL, Townsend CA TITLE Mutational analysis of nocK and nocL in the nocardicin a producer Nocardia uniformis. JOURNAL J Bacteriol 187:739-46 (2005) DOI:10.1128/JB.187.2.739-746.2005 REFERENCE PMID:9804844 AUTHORS Reeve AM, Breazeale SD, Townsend CA TITLE Purification, characterization, and cloning of an S-adenosylmethionine-dependent 3-amino-3-carboxypropyltransferase in nocardicin biosynthesis. JOURNAL J Biol Chem 273:30695-703 (1998) DOI:10.1074/jbc.273.46.30695 REFERENCE PMID:12105888 AUTHORS Kelly WL, Townsend CA TITLE Role of the cytochrome P450 NocL in nocardicin A biosynthesis. JOURNAL J Am Chem Soc 124:8186-7 (2002) DOI:10.1021/ja025926g REFERENCE PMID:11137816 AUTHORS Hubbard BK, Thomas MG, Walsh CT TITLE Biosynthesis of L-p-hydroxyphenylglycine, a non-proteinogenic amino acid constituent of peptide antibiotics. JOURNAL Chem Biol 7:931-42 (2000) DOI:10.1016/S1074-5521(00)00043-0 REFERENCE PMID:25624104 AUTHORS Gaudelli NM, Long DH, Townsend CA TITLE beta-Lactam formation by a non-ribosomal peptide synthetase during antibiotic biosynthesis. JOURNAL Nature 520:383-7 (2015) DOI:10.1038/nature14100 REFERENCE PMID:24531841 AUTHORS Gaudelli NM, Townsend CA TITLE Epimerization and substrate gating by a TE domain in beta-lactam antibiotic biosynthesis. JOURNAL Nat Chem Biol 10:251-8 (2014) DOI:10.1038/nchembio.1456 REFERENCE PMID:22365611 AUTHORS Davidsen JM, Townsend CA TITLE In vivo characterization of nonribosomal peptide synthetases NocA and NocB in the biosynthesis of nocardicin A. JOURNAL Chem Biol 19:297-306 (2012) DOI:10.1016/j.chembiol.2011.10.020 REFERENCE PMID:23330869 AUTHORS Davidsen JM, Bartley DM, Townsend CA TITLE Non-ribosomal propeptide precursor in nocardicin A biosynthesis predicted from adenylation domain specificity dependent on the MbtH family protein NocI. JOURNAL J Am Chem Soc 135:1749-59 (2013) DOI:10.1021/ja307710d REFERENCE PMID:6805424 AUTHORS O'Sullivan J, Gillum AM, Aklonis CA, Souser ML, Sykes RB TITLE Biosynthesis of monobactam compounds: origin of the carbon atoms in the beta-lactam ring. JOURNAL Antimicrob Agents Chemother 21:558-64 (1982) DOI:10.1128/AAC.21.4.558 REFERENCE PMID:6859838 AUTHORS O'Sullivan J, Souser ML, Kao CC, Aklonis CA TITLE Sulfur metabolism in the biosynthesis of monobactams. JOURNAL Antimicrob Agents Chemother 23:598-602 (1983) DOI:10.1128/AAC.23.4.598 REFERENCE PMID:16506699 AUTHORS Kinscherf TG, Willis DK TITLE The biosynthetic gene cluster for the beta-lactam antibiotic tabtoxin in Pseudomonas syringae. JOURNAL J Antibiot (Tokyo) 58:817-21 (2005) DOI:10.1038/ja.2005.109 REFERENCE PMID:22994681 AUTHORS Wencewicz TA, Walsh CT TITLE Pseudomonas syringae self-protection from tabtoxinine-beta-lactam by ligase TblF and acetylase Ttr. JOURNAL Biochemistry 51:7712-25 (2012) DOI:10.1021/bi3011384 REFERENCE PMID:23770908 AUTHORS Arai T, Arimura Y, Ishikura S, Kino K TITLE L-amino acid ligase from Pseudomonas syringae producing tabtoxin can be used for enzymatic synthesis of various functional peptides. JOURNAL Appl Environ Microbiol 79:5023-9 (2013) DOI:10.1128/AEM.01003-13 REFERENCE PMID:1515668 AUTHORS Engst K, Shaw PD TITLE Identification of a lysA-like gene required for tabtoxin biosynthesis and pathogenicity in Pseudomonas syringae pv. tabaci strain PTBR2.024. JOURNAL Mol Plant Microbe Interact 5:322-9 (1992) DOI:10.1094/mpmi-5-322 REFERENCE PMID:8990304 AUTHORS Liu L, Shaw PD TITLE Characterization of dapB, a gene required by Pseudomonas syringae pv. tabaci BR2.024 for lysine and tabtoxinine-beta-lactam biosynthesis. JOURNAL J Bacteriol 179:507-13 (1997) DOI:10.1128/JB.179.2.507-513.1997 REFERENCE PMID:9294453 AUTHORS Liu L, Shaw PD TITLE A possible role for acetylated intermediates in diaminopimelate and tabtoxinine-beta-lactam biosynthesis in Pseudomonas syringae pv. tabaci BR2.024. JOURNAL J Bacteriol 179:5922-7 (1997) DOI:10.1128/JB.179.18.5922-5927.1997 REFERENCE PMID:2881927 AUTHORS Unkefer CJ, London RE, Durbin RD, Uchytil TF, Langston-Unkefer PJ TITLE The biosynthesis of tabtoxinine-beta-lactam. Use of specifically 13C-labeled glucose and 13C NMR spectroscopy to identify its biosynthetic precursors. JOURNAL J Biol Chem 262:4994-9 (1987) REL_PATHWAY ko00250 Alanine, aspartate and glutamate metabolism ko00260 Glycine, serine and threonine metabolism ko00300 Lysine biosynthesis ko00400 Phenylalanine, tyrosine and tryptophan biosynthesis ///