KEGG PATHWAY: rn00332

PATHWAY: rn00332

Entry

rn00332                     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

rn00332

Carbapenem biosynthesis

Module

M00675

Carbapenem-3-carboxylate biosynthesis, pyrroline-5-carboxylate + malonyl-CoA => carbapenem-3-carboxylate [PATH:rn00332]

Other DBs

GO:

1901769

Reaction

R00239

ATP:L-glutamate 5-phosphotransferase

R03313

L-glutamate-5-semialdehyde:NADP+ 5-oxidoreductase (phosphorylating)

R03314

R10415

(3S,5S)-carbapenam-3-carboxylate,2-oxoglutarate:oxygen oxidoreductase (dehydrating)

R10485

malonyl-CoA:(S)-1-pyrroline-5-carboxylate malonyltransferase (cyclizing)

R10507

L-proline:(acceptor) oxidoreductase

R10556

(2S,5S)-5-carboxymethylproline cyclo-ligase (AMP-forming)

R10735

OA-6129-A,2-oxoglutarate:oxygen oxidoreductase (8-hydroxylating)

R10739

R10740

2,3-dihydrothienamycin,2-oxoglutarate:oxygen oxidoreductase (dehydrating)

R10741

epithienamycin-F,2-oxoglutarate:oxygen oxidoreductase (dehydrating)

R10742

epithienamycin-E,2-oxoglutarate:oxygen oxidoreductase (sulfoxidation)

R10745

acetyl-CoA:thienamycin N-acetyltransferase

R10746

acetyl-CoA:deacetyl-MM17880 N-acetyltransferase

R10747

CoA nucleotidohydrolase

R10748

pantetheine-4'-phosphate phosphohydrolase

R10749

R10750

R10751

3'-phosphoadenylyl-sulfate:OA-6129-B1 sulfotransferase

R10752

OA-6129-C amidohydrolase

R10753

R10754

R10755

R10756

R13357

S-adenosyl-L-methionine:(2R,3R,5S)-2-(S-pantetheinyl)-carbapenam-3-carboxylate 6-C-methyltransferase

R13358

S-adenosyl-L-methionine:(2R,3R,5S,6R)-6-(methyl)-2-(S-pantetheinyl)-carbapenam-3-carboxylate 6-C-methyltransferase

R13537

(2R,3R,5S)-2-(S-pantetheinyl)-carbapenam-3-carboxylate lyase

R13547

R13548

R13553

R13554

R13555

Compound

C00010

CoA

C00025

L-Glutamate

C00083

Malonyl-CoA

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

C17370

PS-5

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

C20818

C20819

C20820

2,3-Dihydrothienamycin

C20821

C20822

C20823

C22946

(2R,3R,5R)-2-(S-Pantetheinyl)-carbapenam-3-carboxylate

C22947

(2R,3R,5S,6R)-6-(Methyl)-2-(S-pantetheinyl)-carbapenam-3-carboxylate

C22948

(2R,3R,5S,6R)-6-(Ethyl)-2-(S-pantetheinyl)-carbapenam-3-carboxylate

C23073

Reference

PMID:12848554

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

PMID:15174175

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

PMID:14625287

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

PMID:19090510

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

PMID:21913298

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

PMID:12147472

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

PMID:21263049

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

PMID:12725858

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

PMID:35969793

Authors

Sinner EK, Li R, Marous DR, Townsend CA.

Title

ThnL, a B12-dependent radical S-adenosylmethionine enzyme, catalyzes thioether bond formation in carbapenem biosynthesis.

Journal

Proc Natl Acad Sci U S A 119:e2206494119 (2022)
DOI:10.1073/pnas.2206494119

Reference

PMID:20017478

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

PMID:18678912

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

PMID:22706025

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

PMID:24420617

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

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

Related
pathway

rn00330

Arginine and proline metabolism

KO pathway

ko00332

DBGET integrated database retrieval system