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MetaCyc Chimeric Pathway: superpathway of penicillin, cephalosporin and cephamycin biosynthesis
Traceable author statement to experimental support

Pathway diagram: superpathway of penicillin, cephalosporin and cephamycin biosynthesis

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

Superclasses: BiosynthesisSecondary Metabolites BiosynthesisAntibiotic Biosynthesis

Some taxa known to possess parts of the pathway include : Acremonium chrysogenum, Amycolatopsis lactamdurans, Aspergillus nidulans, Penicillium chrysogenum, Streptomyces clavuligerus

Expected Taxonomic Range: Bacteria , Fungi

Note: This is a chimeric pathway, comprising reactions from multiple organisms, and typically will not occur in its entirety in a single organism. The taxa listed here are likely to catalyze only subsets of the reactions depicted in this pathway.

Please note: This pathway does not represent a single organism. Rather, it is a superpathway assembled from pathways found in several different organisms. Its purpose is to provide an overview of the diversity of ways that organisms can biosynthesize β-lactam antibiotics.

Antibiotics are secondary metabolites, a diverse group of chemicals that are produced by a few common biosynthetic pathways. Naturally occurring β-lactam antibiotics contain the β-lactam ring and are classified into five groups according to their chemical structure: penams (e.g. penicillins), ceph-3-ems (e.g. cephalosporins, cephamycins), clavams (e.g. clavulanate), carbapenems (e.g. thienamycins), and monolactams (e.g. nocardicins, monobactams). Penams are only produced by filamentous fungi. Ceph-3-ems are produced by both filamentous fungi and bacteria, while the remaining three classes of beta-lactams are produced by bacteria. Reviewed in [Keller05] and [Brakhage98]. The pathways for biosynthesis of the bicyclic carbapenem and clavam antibiotics differ from this classic β-lactam pathway (see pathways (5R)-carbapenem carboxylate biosynthesis and clavulanate biosynthesis). The pathway for nocardicin A biosynthesis is also different, but it has only been partially elucidated and the order of some known reactions is unclear. However, some of the enzymes of nocardicin A biosynthesis have been purified and characterized (see enzymes AdoMet:nocardicin 3-amino-3-carboxypropyltransferase and nocardicin C-9'-epimerase).

Penicillins, cephalosporins and cephamycins are produced by different organisms from branches of the common β-lactam pathway shown here. The pathway branches at isopenicillin N to form penicillins and branches again at deacetylcephalosporin to form cephalosporins and cephamycins. The antibacterial mechanism of action of β-lactam antibiotics involves inhibition of the transpeptidation reaction during bacterial peptidoglycan biosynthesis, which leads to cell lysis. This reaction is catalyzed by class A and class B penecillin binding proteins. It is specifically inhibited by penicillin and other β-lactam antibiotics via formation of a covalent complex with the active serine of the transpeptidation domain of penicillin binding proteins. This prevents crosslinking and weakens the peptidoglycan polymer (in [Di03]). See pathways peptidoglycan biosynthesis I (meso-diaminopimelate containing) and peptidoglycan biosynthesis II (staphylococci). Bacterial resistance to β-lactam antibiotics can involve alterations in penicillin binding proteins, reduced antibiotic permeation across the membrane, or the production of β-lactamase enzymes (in [Majiduddin02]). See enzymes β-lactamase; penicillin resistance, PSE-4 β-lactamase and carbapenemase.

Subpathways: isopenicillin N biosynthesis, penicillin K biosynthesis, deacetylcephalosporin C biosynthesis, cephalosporin C biosynthesis, cephamycin C biosynthesis

Created 21-Aug-2007 by Fulcher CA, SRI International


Brakhage98: Brakhage AA (1998). "Molecular regulation of beta-lactam biosynthesis in filamentous fungi." Microbiol Mol Biol Rev 62(3);547-85. PMID: 9729600

Di03: Di Guilmi AM, Dessen A, Dideberg O, Vernet T (2003). "The glycosyltransferase domain of penicillin-binding protein 2a from Streptococcus pneumoniae catalyzes the polymerization of murein glycan chains." J Bacteriol 185(15);4418-23. PMID: 12867450

Keller05: Keller NP, Turner G, Bennett JW (2005). "Fungal secondary metabolism - from biochemistry to genomics." Nat Rev Microbiol 3(12);937-47. PMID: 16322742

Majiduddin02: Majiduddin FK, Materon IC, Palzkill TG (2002). "Molecular analysis of beta-lactamase structure and function." Int J Med Microbiol 292(2);127-37. PMID: 12195735

Thykaer03: Thykaer J, Nielsen J (2003). "Metabolic engineering of beta-lactam production." Metab Eng 5(1);56-69. PMID: 12749845

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

Alvarez87: Alvarez E, Cantoral JM, Barredo JL, Diez B, Martin JF (1987). "Purification to homogeneity and characterization of acyl coenzyme A:6-aminopenicillanic acid acyltransferase of Penicillium chrysogenum." Antimicrob Agents Chemother 31(11);1675-82. PMID: 2829713

Alvarez93: Alvarez E, Meesschaert B, Montenegro E, Gutierrez S, Diez B, Barredo JL, Martin JF (1993). "The isopenicillin-N acyltransferase of Penicillium chrysogenum has isopenicillin-N amidohydrolase, 6-aminopenicillanic acid acyltransferase and penicillin amidase activities, all of which are encoded by the single penDE gene." Eur J Biochem 215(2);323-32. PMID: 8344300

Aplin93: Aplin RT, Baldwin JE, Cole SC, Sutherland JD, Tobin MB (1993). "On the production of alpha, beta-heterodimeric acyl-coenzyme A: isopenicillin N-acyltransferase of Penicillium chrysogenum. Studies using a recombinant source." FEBS Lett 319(1-2);166-70. PMID: 8384123

Aplin93a: Aplin RT, Baldwin JE, Roach PL, Robinson CV, Schofield CJ (1993). "Investigations into the post-translational modification and mechanism of isopenicillin N:acyl-CoA acyltransferase using electrospray mass spectrometry." Biochem J 294 ( Pt 2);357-63. PMID: 8396910

Baker91: Baker BJ, Dotzlaf JE, Yeh WK (1991). "Deacetoxycephalosporin C hydroxylase of Streptomyces clavuligerus. Purification, characterization, bifunctionality, and evolutionary implication." J Biol Chem 266(8);5087-93. PMID: 2002049

Baldwin85: Baldwin JE, Gagnon J, Ting H (1985). "N-terminal amino acid sequence and some properties of isopenicillin-N synthetase from Cephalosporium acremonium." FEBS Lett 188(2);253-6. PMID: 3839755

Baldwin87: Baldwin JE, Adlington RM, Coates JB, Crabbe MJ, Crouch NP, Keeping JW, Knight GC, Schofield CJ, Ting HH, Vallejo CA (1987). "Purification and initial characterization of an enzyme with deacetoxycephalosporin C synthetase and hydroxylase activities." Biochem J 245(3);831-41. PMID: 3663194

Barredo89: Barredo JL, van Solingen P, Diez B, Alvarez E, Cantoral JM, Kattevilder A, Smaal EB, Groenen MA, Veenstra AE, Martin JF (1989). "Cloning and characterization of the acyl-coenzyme A: 6-aminopenicillanic-acid-acyltransferase gene of Penicillium chrysogenum." Gene 83(2);291-300. PMID: 2555269

Brakhage04: Brakhage AA, Sprote P, Al-Abdallah Q, Gehrke A, Plattner H, Tuncher A (2004). "Regulation of penicillin biosynthesis in filamentous fungi." Adv Biochem Eng Biotechnol 88;45-90. PMID: 15719552

Brewer80: Brewer SJ, Taylor PM, Turner MK (1980). "An adenosine triphosphate-dependent carbamoylphosphate--3-hydroxymethylcephem O-carbamoyltransferase from Streptomyces clavuligerus." Biochem J 185(3);555-64. PMID: 6248024

Castro88: Castro JM, Liras P, Laiz L, Cortes J, Martin JF (1988). "Purification and characterization of the isopenicillin N synthase of Streptomyces lactamdurans." J Gen Microbiol 134(1);133-41. PMID: 3183613

Coque91: Coque JJ, Martin JF, Calzada JG, Liras P (1991). "The cephamycin biosynthetic genes pcbAB, encoding a large multidomain peptide synthetase, and pcbC of Nocardia lactamdurans are clustered together in an organization different from the same genes in Acremonium chrysogenum and Penicillium chrysogenum." Mol Microbiol 5(5);1125-33. PMID: 1956290

Coque93: Coque JJ, Martin JF, Liras P (1993). "Characterization and expression in Streptomyces lividans of cefD and cefE genes from Nocardia lactamdurans: the organization of the cephamycin gene cluster differs from that in Streptomyces clavuligerus." Mol Gen Genet 236(2-3);453-8. PMID: 8437592

Coque95: Coque JJ, Enguita FJ, Martin JF, Liras P (1995). "A two-protein component 7 alpha-cephem-methoxylase encoded by two genes of the cephamycin C cluster converts cephalosporin C to 7-methoxycephalosporin C." J Bacteriol 177(8);2230-5. PMID: 7721717

Coque95a: Coque JJ, Perez-Llarena FJ, Enguita FJ, Fuente JL, Martin JF, Liras P (1995). "Characterization of the cmcH genes of Nocardia lactamdurans and Streptomyces clavuligerus encoding a functional 3'-hydroxymethylcephem O-carbamoyltransferase for cephamycin biosynthesis." Gene 162(1);21-7. PMID: 7557411

Diez90: Diez B, Gutierrez S, Barredo JL, van Solingen P, van der Voort LH, Martin JF (1990). "The cluster of penicillin biosynthetic genes. Identification and characterization of the pcbAB gene encoding the alpha-aminoadipyl-cysteinyl-valine synthetase and linkage to the pcbC and penDE genes." J Biol Chem 265(27);16358-65. PMID: 2129535

Dotzlaf87: Dotzlaf JE, Yeh WK (1987). "Copurification and characterization of deacetoxycephalosporin C synthetase/hydroxylase from Cephalosporium acremonium." J Bacteriol 169(4);1611-8. PMID: 3558321

Dotzlaf89: Dotzlaf JE, Yeh WK (1989). "Purification and properties of deacetoxycephalosporin C synthase from recombinant Escherichia coli and its comparison with the native enzyme purified from Streptomyces clavuligerus." J Biol Chem 264(17);10219-27. PMID: 2656705

Esmahan94: Esmahan C, Alvarez E, Montenegro E, Martin JF (1994). "Catabolism of lysine in Penicillium chrysogenum leads to formation of 2-aminoadipic acid, a precursor of penicillin biosynthesis." Appl Environ Microbiol 60(6);1705-10. PMID: 8031073

Fernandez03: Fernandez FJ, Cardoza RE, Montenegro E, Velasco J, Gutierrez S, Martin JF (2003). "The isopenicillin N acyltransferases of Aspergillus nidulans and Penicillium chrysogenum differ in their ability to maintain the 40-kDa alphabeta heterodimer in an undissociated form." Eur J Biochem 270(9);1958-68. PMID: 12709055

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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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