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MetaCyc Pathway: deacetylcephalosporin C biosynthesis
Traceable author statement to experimental support

Enzyme View:

Pathway diagram: deacetylcephalosporin C biosynthesis

This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. 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 this pathway include : Acremonium chrysogenum, Amycolatopsis lactamdurans, Streptomyces clavuligerus

Expected Taxonomic Range: Bacteria , Fungi

General Background

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. (5R)-carbapen-2-em-3-carboxylate, 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].

Penicillins, cephalosporins and cephamycins are produced by different organisms from branches of a common pathway. The pathway branches at isopenicillin N to form penicillins and branches again at deacetylcephalosporin to form cephalosporins and cephamycins (see superpathway of penicillin, cephalosporin and cephamycin biosynthesis).

The pathways for biosynthesis of the bicyclic carbapenem and clavam antibiotics see (5R)-carbapenem carboxylate biosynthesis and clavulanate biosynthesis) differ from the classic β-lactam pathway (see superpathway of penicillin, cephalosporin and cephamycin 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).

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.

About This Pathway

Deacetylcephalosporin C is a branch point in the pathway that leads not only to cephalosporins, but also to bacterial cephamycins (as shown in the pathway links). The first two reactions in the cephalosporin C biosynthesis pathway that produce isopenicillin N are shared with penicillin and cephamycin biosynthesis (shown in the pathway link). The next reaction is the first committed step in cephalosporin and cephamycin biosynthesis in which the L-α-aminoadipate side chain in isopenicillin N is isomerized to the D enantiomer, producing penicillin N. In subsequent steps the penam thiazolidine ring is oxidatively opened and expanded to a six-membered dihydrothiazine ring characteristic of ceph-3-ems. In Acremonium chrysogenum these two reactions are catalyzed by a single enzyme. As shown in the pathway link, acetylation of deacetylcephalosporin C produces cephalosporin C. Other cephalosporins are produced by bacteria such as Streptomyces clavuligerus. Reviewed in [Brakhage98] and [Thykaer03]

Superpathways: superpathway of penicillin, cephalosporin and cephamycin 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

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

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

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

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

Ghag96: Ghag SK, Brems DN, Hassell TC, Yeh WK (1996). "Refolding and purification of Cephalosporium acremonium deacetoxycephalosporin C synthetase/hydroxylase from granules of recombinant Escherichia coli." Biotechnol Appl Biochem 24 ( Pt 2);109-19. PMID: 8865604

Kovacevic89: Kovacevic S, Weigel BJ, Tobin MB, Ingolia TD, Miller JR (1989). "Cloning, characterization, and expression in Escherichia coli of the Streptomyces clavuligerus gene encoding deacetoxycephalosporin C synthetase." J Bacteriol 171(2);754-60. PMID: 2644235

Kovacevic90: Kovacevic S, Tobin MB, Miller JR (1990). "The beta-lactam biosynthesis genes for isopenicillin N epimerase and deacetoxycephalosporin C synthetase are expressed from a single transcript in Streptomyces clavuligerus." J Bacteriol 172(7);3952-8. PMID: 1694525

Kovacevic91: Kovacevic S, Miller JR (1991). "Cloning and sequencing of the beta-lactam hydroxylase gene (cefF) from Streptomyces clavuligerus: gene duplication may have led to separate hydroxylase and expandase activities in the actinomycetes." J Bacteriol 173(1);398-400. PMID: 1987130

Laiz90: Laiz L, Liras P, Castro JM, Martin JF (1990). "Purification and characterization of the isopenicillin N epimerase from Nocardia lactamdurans." Journal of General Microbiology 136, 663-671.

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

Lloyd04: Lloyd MD, Lipscomb SJ, Hewitson KS, Hensgens CM, Baldwin JE, Schofield CJ (2004). "Controlling the substrate selectivity of deacetoxycephalosporin/deacetylcephalosporin C synthase." J Biol Chem 279(15);15420-6. PMID: 14734549

Martin04: Martin JF, Ullan RV, Casqueiro J (2004). "Novel genes involved in cephalosporin biosynthesis: the three-component isopenicillin N epimerase system." Adv Biochem Eng Biotechnol 88;91-109. PMID: 15719553

Usui89: Usui S, Yu CA (1989). "Purification and properties of isopenicillin N epimerase from Streptomyces clavuligerus." Biochim Biophys Acta 999(1);78-85. PMID: 2804141

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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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