5S Clavam Biosynthetic Genes Are Located in Both the Clavam and Paralog Gene Clusters in Streptomyces clavuligerus

Tahlan, Kapil; Anders, Cecilia L.; Wong, Amy; Mosher, Roy H.; Beatty, Perrin H.; Brumlik, Michael J.; Griffin, A.; Hughes, Claire E.; Griffin, John J.; Barton, Barry; Jensen, Susan E.

doi:10.1016/j.chembiol.2006.11.012

Cited by 34 publications

(50 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Both the CA supercluster and the clavam cluster lie on the chromosome, whereas the paralog cluster is located on the pSCL4 plasmid (37). The complexity of CA-clavam biosynthesis is also reflected at the level of regulation, and at least 6 regulatory genes (ccaR [45,52], claR [43], cvm7P [59], and orf21 to orf23 [25,55]) were identified among the three gene clusters. Intricate cross-regulation between the arginine and CA (12, 51), cephamycin C and CA (44,45), and CA and holomycin (11) pathways were also reported.…”

mentioning

confidence: 99%

Induction of Holomycin Production and Complex Metabolic Changes by the argR Mutation in Streptomyces clavuligerus NP1

Yin¹,

Xiang²,

Zheng³

et al. 2012

Appl Environ Microbiol

View full text Add to dashboard Cite

ABSTRACTIn bacteria, arginine biosynthesis is tightly regulated by a universally conserved regulator, ArgR, which regulates the expression of arginine biosynthetic genes, as well as other important genes. Disruption ofargRinStreptomyces clavuligerusNP1 resulted in complex phenotypic changes in growth and antibiotic production levels. To understand the metabolic changes underlying the phenotypes, comparative proteomic studies were carried out between NP1 and itsargRdisruption mutant (designated CZR). In CZR, enzymes involved in holomycin biosynthesis were overexpressed; this is consistent with its holomycin overproduction phenotype. The effects on clavulanic acid (CA) biosynthesis are more complex. Several proteins from the CA cluster were moderately overexpressed, whereas several proteins from the 5S clavam biosynthetic cluster and from the paralog cluster of CA and 5S clavam biosynthesis were severely downregulated. Obvious changes were also detected in primary metabolism, which are mainly reflected in the altered expression levels of proteins involved in acetyl-coenzyme A (CoA) and cysteine biosynthesis. Since acetyl-CoA and cysteine are precursors for holomycin synthesis, overexpression of these proteins is consistent with the holomycin overproduction phenotype. The complex interplay between primary and secondary metabolism and between secondary metabolic pathways were revealed by these analyses, and the insights will guide further efforts to improve production levels of CA and holomycin inS. clavuligerus.

show abstract

mentioning

confidence: 99%

Induction of Holomycin Production and Complex Metabolic Changes by the argR Mutation in Streptomyces clavuligerus NP1

Yin¹,

Xiang²,

Zheng³

et al. 2012

Appl Environ Microbiol

View full text Add to dashboard Cite

show abstract

“…Except for cas1, paralogues for all of the other early biosynthetic genes of the clavulanic acid gene cluster are found in the paralogue gene cluster (22,53). The paralogue gene cluster also contains genes involved specifically in the late steps of 5S clavam biosynthesis (22,51,53).…”

mentioning

confidence: 99%

“…1). Two reactions from the late stages of the pathway leading to clavulanic acid have been characterized (2,21,35), while only one intermediate leading specifically to the 5S clavams, 2-carboxymethylideneclavam, has been identified (51).…”

mentioning

confidence: 99%

“…The roles of these three genes in 5S clavam biosynthesis are uncertain, but Cvm5 may catalyze a Baeyer-Villiger-type oxidation leading to 2-formyloxymethylclavam production. Two other genes, c6p and c7p, are found in the paralogue gene cluster and are also required for the production of all the 5S clavams (51). c6p encodes an aminotransferase that is predicted to catalyze the first step from clavaminic acid toward the 5S clavams, while c7p encodes a probable transcriptional regulator of 5S clavam biosynthesis.…”

mentioning

confidence: 99%

“…In the clavam gene cluster, cvm1, cvm2, and cvm5 are necessary for the production of all 5S clavams (34,51). cvm1 encodes a putative aldo-keto reductase, cvm2 shows similarity to isomerases, and cvm5 encodes a predicted monooxygenase.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Alanylclavam Biosynthetic Genes Are Clustered Together with One Group of Clavulanic Acid Biosynthetic Genes inStreptomyces clavuligerus

et al. 2008

Self Cite

View full text Add to dashboard Cite

Streptomyces clavuligerus produces at least five different clavam metabolites, including clavulanic acid and the methionine antimetabolite, alanylclavam. In vitro transposon mutagenesis was used to analyze a 13-kb region upstream of the known paralogue gene cluster. The paralogue cluster includes one group of clavulanic acid biosynthetic genes in S. clavuligerus. Twelve open reading frames (ORFs) were found in this area, and mutants were generated in each using either in vitro transposon or PCR-targeted mutagenesis. Mutants with defects in any of the genes orfA, orfB, orfC, or orfD were unable to produce alanylclavam but could produce all of the other clavams, including clavulanic acid. orfA encodes a predicted hydroxymethyltransferase, orfB encodes a YjgF/ YER057c/UK114-family regulatory protein, orfC encodes an aminotransferase, and orfD encodes a dehydratase. All of these types of proteins are normally involved in amino acid metabolism. Mutants in orfC or orfD also accumulated a novel clavam metabolite instead of alanylclavam, and a complemented orfC mutant was able to produce trace amounts of alanylclavam while still producing the novel clavam. Mass spectrometric analyses, together with consideration of the enzymes involved in its production, led to tentative identification of the novel clavam as 8-OH-alanylclavam, an intermediate in the proposed alanylclavam biosynthetic pathway.

show abstract

β‐Lactam Antibiotics

Testero

Fisher

Mobashery

2010

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

The β‐lactam classes of antibacterials are preeminent in the treatment of bacterial infection due to their unparalleled clinical efficacy and clinical safety. Following the discovery of the penicillins, successive β‐lactam drug discovery has added the cephalosporin, penem cephamycin, clavulanate, monobactam, nocardicin, and carbapenem subclasses. The driving force behind much of this era of discovery is the staggering ability of pathogenic bacteria to adapt previous generations of the β‐lactam by the acquisition and expression of resistance mechanisms. Although many factors contribute to β‐lactam resistance, alterations to the molecular targets of the β‐lactams (the penicillin binding proteins) and the use of enzymes (the β‐lactamases) capable of the hydrolytic deactivation of the β‐lactams are paramount. This review traces the historical development of β‐lactam drug discovery, with emphasis on the most recent progress in the medicinal chemistry, biochemistry, and microbiology of the β‐lactams leading to the discovery of new generation β‐lactam antibacterials effective against the Gram‐negative and ‐positive bacterial pathogens of current medical concern.

show abstract

5S Clavam Biosynthetic Genes Are Located in Both the Clavam and Paralog Gene Clusters in Streptomyces clavuligerus

Cited by 34 publications

References 42 publications

Induction of Holomycin Production and Complex Metabolic Changes by the argR Mutation in Streptomyces clavuligerus NP1

Induction of Holomycin Production and Complex Metabolic Changes by the argR Mutation in Streptomyces clavuligerus NP1

Alanylclavam Biosynthetic Genes Are Clustered Together with One Group of Clavulanic Acid Biosynthetic Genes inStreptomyces clavuligerus

β‐Lactam Antibiotics

Contact Info

Product

Resources

About