1q15

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Carbapenam Synthetase

<StructureSection load='1q15' size='340' side='right'caption='1q15, resolution 2.30Å' scene=>

Structural highlights

1q15 is a 4 chain structure with sequence from "bacillus_carotovorus"_jones_1901 "bacillus carotovorus" jones 1901. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[CARA_PECCA] Involved in the biosynthesis of carbapenam-3-carboxylate, a beta-lactam antibiotic of the carbapenem class. Catalyzes the ATP-dependent formation of (3S,5S)-carbapenam-3-carboxylate from (2S,5S)-5-carboxymethylproline.[1] [2] [3]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Carbapenam synthetase (CarA) is an ATP/Mg2+-dependent enzyme that catalyzes formation of the beta-lactam ring in (5R)-carbapenem-3-carboxylic acid biosynthesis. CarA is homologous to beta-lactam synthetase (beta-LS), which is involved in clavulanic acid biosynthesis. The catalytic cycles of CarA and beta-LS mediate substrate adenylation followed by beta-lactamization via a tetrahedral intermediate or transition state. Another member of this family of ATP/Mg2+-dependent enzymes, asparagine synthetase (AS-B), catalyzes intermolecular, rather than intramolecular, amide bond formation in asparagine biosynthesis. The crystal structures of apo-CarA and CarA complexed with the substrate (2S,5S)-5-carboxymethylproline (CMPr), ATP analog alpha,beta-methyleneadenosine 5'-triphosphate (AMP-CPP), and a single Mg2+ ion have been determined. CarA forms a tetramer. Each monomer resembles beta-LS and AS-B in overall fold, but key differences are observed. The N-terminal domain lacks the glutaminase active site found in AS-B, and an extended loop region not observed in beta-LS or AS-B is present. Comparison of the C-terminal synthetase active site to that in beta-LS reveals that the ATP binding site is highly conserved. By contrast, variations in the substrate binding pocket reflect the different substrates of the two enzymes. The Mg2+ coordination is also different. Several key residues in the active site are conserved between CarA and beta-LS, supporting proposed roles in beta-lactam formation. These data provide further insight into the structures of this class of enzymes and suggest that CarA might be a versatile target for protein engineering experiments aimed at developing improved production methods and new carbapenem antibiotics.

Crystal structure of carbapenam synthetase (CarA).,Miller MT, Gerratana B, Stapon A, Townsend CA, Rosenzweig AC J Biol Chem. 2003 Oct 17;278(42):40996-1002. Epub 2003 Jul 30. PMID:12890666[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Gerratana B, Stapon A, Townsend CA. Inhibition and alternate substrate studies on the mechanism of carbapenam synthetase from Erwinia carotovora. Biochemistry. 2003 Jul 1;42(25):7836-47. PMID:12820893 doi:http://dx.doi.org/10.1021/bi034361d
  2. ↑ Arnett SO, Gerratana B, Townsend CA. Rate-limiting steps and role of active site Lys443 in the mechanism of carbapenam synthetase. Biochemistry. 2007 Aug 14;46(32):9337-45. Epub 2007 Jul 21. PMID:17658887 doi:http://dx.doi.org/10.1021/bi0618464
  3. ↑ Raber ML, Arnett SO, Townsend CA. A conserved tyrosyl-glutamyl catalytic dyad in evolutionarily linked enzymes: carbapenam synthetase and beta-lactam synthetase. Biochemistry. 2009 Jun 9;48(22):4959-71. doi: 10.1021/bi900432n. PMID:19371088 doi:http://dx.doi.org/10.1021/bi900432n
  4. ↑ Miller MT, Gerratana B, Stapon A, Townsend CA, Rosenzweig AC. Crystal structure of carbapenam synthetase (CarA). J Biol Chem. 2003 Oct 17;278(42):40996-1002. Epub 2003 Jul 30. PMID:12890666 doi:10.1074/jbc.M307901200

Contents

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