β-Lactam synthetase: implications for β-lactamase evolution

Mcnaughton, H. J.; Thirkettle, Jan E.; Zhang, Zhihong; Schofield, Christopher J.; Jensen, Susan E.; Barton, Barry; Greaves, P.

doi:10.1039/a806713i

Cited by 38 publications

(36 citation statements)

References 18 publications

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“…Insight into the structure(s) of the ASNS synthetase site during catalytic turnover, and the potential role of residues involved in aspartate activation and ammonia addition, has been obtained, however, by recognizing the striking chemical similarity of the reactions employed to synthesize asparagine from aspartic acid and a functionalized β-lactam from the adenylated form of N 2 -(carboxyethyl)-L-arginine (CEA) 2 (Scheme 3) (123,124). Thus, the enzyme BLS, which is found in the biosynthetic pathway leading to the important secondary metabolite clavulanic acid (125), activates its substrate by forming an AMP derivative in which the carbonyl group is attacked intramolecularly by a nitrogen nucleophile.…”

Section: Using Structural Homology and Chemical Constraints To Model mentioning

confidence: 99%

Asparagine Synthetase Chemotherapy

Richards

Kilberg

2006

Annu. Rev. Biochem.

201

221

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Modern clinical treatments of childhood acute lymphoblastic leukemia (ALL) employ enzymebased methods for depletion of blood asparagine in combination with standard chemotherapeutic agents. Significant side effects can arise in these protocols and, in many cases, patients develop drug-resistant forms of the disease that may be correlated with up-regulation of the enzyme glutamine-dependent asparagine synthetase (ASNS). Though the precise molecular mechanisms that result in the appearance of drug resistance are the subject of active study, potent ASNS inhibitors may have clinical utility in treating asparaginase-resistant forms of childhood ALL. This review provides an overview of recent developments in our understanding of (a) the structure and catalytic mechanism of ASNS, and (b) the role that ASNS may play in the onset of drug-resistant childhood ALL. In addition, the first successful, mechanism-based efforts to prepare and characterize nanomolar ASNS inhibitors are discussed, together with the implications of these studies for future efforts to develop useful drugs.

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Section: Using Structural Homology and Chemical Constraints To Model mentioning

confidence: 99%

Asparagine Synthetase Chemotherapy

Richards

Kilberg

2006

Annu. Rev. Biochem.

201

221

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“…In the first step, L-arginine and D-glyceraldehyde-3-phosphate react to give N 2 -(2-carboxyethyl)arginine in a thiamin diphosphate-dependent reaction catalyzed by N 2 -(2-carboxyethyl)arginine synthase (CEAS) 2 (14). ␤-Lactam formation is catalyzed by ␤-lactam synthetase (BLS) (15,16), to give deoxyguanidinoproclavaminic acid (17), which is then converted in four steps to (3S,5S)-clavaminic acid. Three of these steps are catalyzed by a single 2-oxoglutarate (2-OG)-dependent oxygenase, clavaminic acid synthase (CAS2) (10, 18 -20), and one is catalyzed by proclavaminate amidinohydrolase (PAH) (21), to give the bicyclic clavam ring system (22)(23)(24).…”

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confidence: 99%

ORF17 from the Clavulanic Acid Biosynthesis Gene Cluster Catalyzes the ATP-dependent Formation of N-Glycyl-clavaminic Acid

Arulanantham

Kershaw

Hewitson

et al. 2006

Journal of Biological Chemistry

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“…Genes located in this region include ceaS (encoding carboxyethylarginine synthase) (14), bls (␤-lactam synthetase) (3,18), pah (proclavaminate amidinohydrolase) (2,11,34), cas2 (clavaminate synthase) (4,17,26,27), and cad (clavulanic acid dehydrogenase) (21), all enzymes for recognized steps in the biosynthetic pathway. In addition, oat, a gene encoding a protein with ornithine acetyltransferase activity, has been identified (13), but its role in clavulanic acid is not yet understood, and claR, a gene encoding a transcriptional regulator that controls the late steps in clavulanic acid biosynthesis, is also located in this region (22,24).…”

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confidence: 99%

Five Additional Genes Are Involved in Clavulanic Acid Biosynthesis in Streptomyces clavuligerus

Jensen

Paradkar

Mosher

et al. 2004

Antimicrob Agents Chemother

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An approximately 12.5-kbp region of DNA sequence from beyond the end of the previously described clavulanic acid gene cluster was analyzed and found to encode nine possible open reading frames (ORFs). Involvement of these ORFs in clavulanic acid biosynthesis was assessed by creating mutants with defects in each of the ORFs. orf12 and orf14 had been previously reported to be involved in clavulanic acid biosynthesis. Now five additional ORFs are shown to play a role, since their mutation results in a significant decrease or total absence of clavulanic acid production. Most of these newly described ORFs encode proteins with little similarity to others in the databases, and so their roles in clavulanic acid biosynthesis are unclear. Mutation of two of the ORFs, orf15 and orf16, results in the accumulation of a new metabolite, N-acetylglycylclavaminic acid, in place of clavulanic acid. orf18 and orf19 encode apparent penicillin binding proteins, and while mutations in these genes have minimal effects on clavulanic acid production, their normal roles as cell wall biosynthetic enzymes and as targets for ␤-lactam antibiotics, together with their clustered location, suggest that they are part of the clavulanic acid gene cluster.

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β-Lactam synthetase: implications for β-lactamase evolution

Cited by 38 publications

References 18 publications

Asparagine Synthetase Chemotherapy

Asparagine Synthetase Chemotherapy

ORF17 from the Clavulanic Acid Biosynthesis Gene Cluster Catalyzes the ATP-dependent Formation of N-Glycyl-clavaminic Acid

Five Additional Genes Are Involved in Clavulanic Acid Biosynthesis in Streptomyces clavuligerus

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