KEGG   PATHWAY: map00332
Entry
map00332                    Pathway                                

Name
Carbapenem biosynthesis
Description
Carbapenems are broad-spectrum beta-lactam antibiotics, which are often considered as the antibiotics of last resort. A naturally occurring carbapenem, thienamycin, was first discovered in Streptomyces cattleya. This diagram shows how a simple carbapenem, carbapenem-3-carboxylate, is synthesized from malonyl-CoA and pyrroline-5-carboxylate [MD:M00675]. For structurally complex carbapenems, such as thienamycin, olivanic acid, epi-thienamycin and carbapenems of the OA-6129 group, uncertainty remains about the mechanism and timing for the inversion of the C-5 carbapenam bridgehead, the desaturation of the C-2/C-3 bond and the attachment of the C-2 and C-6 side chains.
Class
Metabolism; Biosynthesis of other secondary metabolites
Pathway map
map00332  Carbapenem biosynthesis
map00332

Module
M00675  Carbapenem-3-carboxylate biosynthesis, pyrroline-5-carboxylate + malonyl-CoA => carbapenem-3-carboxylate [PATH:map00332]
Other DBs
GO: 1901769
Reference
  Authors
Stapon A, Li R, Townsend CA
  Title
Carbapenem biosynthesis: confirmation of stereochemical assignments and the role of CarC in the ring stereoinversion process from L-proline.
  Journal
J Am Chem Soc 125:8486-93 (2003)
DOI:10.1021/ja034248a
Reference
  Authors
Sleeman MC, Smith P, Kellam B, Chhabra SR, Bycroft BW, Schofield CJ
  Title
Biosynthesis of carbapenem antibiotics: new carbapenam substrates for carbapenem synthase (CarC).
  Journal
Chembiochem 5:879-82 (2004)
DOI:10.1002/cbic.200300908
Reference
  Authors
Sleeman MC, Schofield CJ
  Title
Carboxymethylproline synthase (CarB), an unusual carbon-carbon bond-forming enzyme of the crotonase superfamily involved in carbapenem biosynthesis.
  Journal
J Biol Chem 279:6730-6 (2004)
DOI:10.1074/jbc.M311824200
Reference
  Authors
Hamed RB, Batchelar ET, Mecinovic J, Claridge TD, Schofield CJ
  Title
Evidence that thienamycin biosynthesis proceeds via C-5 epimerization: ThnE catalyzes the formation of (2S,5S)-trans-carboxymethylproline.
  Journal
Chembiochem 10:246-50 (2009)
DOI:10.1002/cbic.200800652
Reference
  Authors
Bodner MJ, Li R, Phelan RM, Freeman MF, Moshos KA, Lloyd EP, Townsend CA
  Title
Definition of the common and divergent steps in carbapenem beta-lactam antibiotic biosynthesis.
  Journal
Chembiochem 12:2159-65 (2011)
DOI:10.1002/cbic.201100366
Reference
  Authors
Derzelle S, Duchaud E, Kunst F, Danchin A, Bertin P
  Title
Identification, characterization, and regulation of a cluster of genes involved in carbapenem biosynthesis in Photorhabdus luminescens.
  Journal
Appl Environ Microbiol 68:3780-9 (2002)
DOI:10.1128/AEM.68.8.3780-3789.2002
Reference
  Authors
Rodriguez M, Nunez LE, Brana AF, Mendez C, Salas JA, Blanco G
  Title
Mutational analysis of the thienamycin biosynthetic gene cluster from Streptomyces cattleya.
  Journal
Antimicrob Agents Chemother 55:1638-49 (2011)
DOI:10.1128/AAC.01366-10
Reference
PMID:3988730
  Authors
Williamson JM, Inamine E, Wilson KE, Douglas AW, Liesch JM, Albers-Schonberg G
  Title
Biosynthesis of the beta-lactam antibiotic, thienamycin, by Streptomyces cattleya.
  Journal
J Biol Chem 260:4637-47 (1985)
Reference
  Authors
Nunez LE, Mendez C, Brana AF, Blanco G, Salas JA
  Title
The biosynthetic gene cluster for the beta-lactam carbapenem thienamycin in Streptomyces cattleya.
  Journal
Chem Biol 10:301-11 (2003)
DOI:10.1016/S1074-5521(03)00069-3
Reference
  Authors
Bodner MJ, Phelan RM, Freeman MF, Li R, Townsend CA
  Title
Non-heme iron oxygenases generate natural structural diversity in carbapenem antibiotics.
  Journal
J Am Chem Soc 132:12-3 (2010)
DOI:10.1021/ja907320n
Reference
  Authors
Freeman MF, Moshos KA, Bodner MJ, Li R, Townsend CA
  Title
Four enzymes define the incorporation of coenzyme A in thienamycin biosynthesis.
  Journal
Proc Natl Acad Sci U S A 105:11128-33 (2008)
DOI:10.1073/pnas.0804500105
Reference
  Authors
Buller AR, Labonte JW, Freeman MF, Wright NT, Schildbach JF, Townsend CA
  Title
Autoproteolytic activation of ThnT results in structural reorganization necessary for substrate binding and catalysis.
  Journal
J Mol Biol 422:508-18 (2012)
DOI:10.1016/j.jmb.2012.06.012
Reference
  Authors
Li R, Lloyd EP, Moshos KA, Townsend CA
  Title
Identification and characterization of the carbapenem MM 4550 and its gene cluster in Streptomyces argenteolus ATCC 11009.
  Journal
Chembiochem 15:320-31 (2014)
DOI:10.1002/cbic.201300319
Related
pathway
map00330  Arginine and proline metabolism
KO pathway
ko00332   

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