KEGG   PATHWAY: sma00332
Entry
sma00332                    Pathway                                

Name
Carbapenem biosynthesis - Streptomyces avermitilis
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
sma00332  Carbapenem biosynthesis
sma00332

Other DBs
GO: 1901769
Organism
Streptomyces avermitilis [GN:sma]
Gene
SAVERM_5471  proB; putative glutamate 5-kinase [KO:K00931] [EC:2.7.2.11]
SAVERM_5473  proA; putative gamma-glutamyl phosphate reductase [KO:K00147] [EC:1.2.1.41]
Compound
C00010  CoA
C00025  L-Glutamate
C00083  Malonyl-CoA
C00097  L-Cysteine
C00148  L-Proline
C00831  Pantetheine
C01134  Pantetheine 4'-phosphate
C01165  L-Glutamate 5-semialdehyde
C03287  L-Glutamyl 5-phosphate
C03912  (S)-1-Pyrroline-5-carboxylate
C06664  Thienamycin
C06669  (5R)-Carbapen-2-em-3-carboxylate
C11755  Epithienamycin E
C17366  (2S,5S)-trans-Carboxymethylproline
C17367  (3S,5S)-Carbapenam-3-carboxylic acid
C17368  8-Dehydroxythienamycin
C17369  Northienamycin
C17373  OA-6129 B1
C17374  OA-6129 B2
C17377  N-Acetylthienamycin
C17399  Epithienamycin F
C20813  OA-6129 A
C20814  OA-6129 C
C20815  MM 4550
C20816  Deacetylepithienamycin F
C20817  C20817
C20818  C20818
C20819  C20819
C20820  2,3-Dihydrothienamycin
C20821  C20821
C20822  C20822
C20823  C20823
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
sma00330  Arginine and proline metabolism
KO pathway
ko00332   

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