Microbial O-carbamylation of novobiocin.

Kuo, M. S.; Yurek, David A.; Chirby, D. G.; Cialdella, J. I.; Marshall, Vincent P.

doi:10.7164/antibiotics.44.1096

Cited by 12 publications

(7 citation statements)

References 8 publications

(1 reference statement)

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“…This is at variance with results obtained with novobiocin derivatives. Isonovobiocin, the result of a migration of the carbamyl group from 3''-to 2''-OH, [23] and 2''-O-carbamylnovobiocin, the result of carbamylation both of 2''-OH and of 3''-OH, [24] both show much less antibacterial activity than novobiocin.…”

Section: Discussionmentioning

confidence: 97%

CloN6, a Novel Methyltransferase Catalysing the Methylation of the Pyrrole‐2‐carboxyl Moiety of Clorobiocin

Westrich

Heide

2003

ChemBioChem

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The aminocoumarin antibiotic clorobiocin contains a 5-methylpyrrole-2-carboxylic acid unit. This pyrrole unit is derived from L-proline, and it would be expected that its 5-methyl group should be introduced by a methylation reaction. However, sequence analysis of the clorobiocin biosynthetic gene cluster did not reveal a gene with sequence similarity to the SAM-dependent methyltransferases that could be assigned to this reaction. This study, however, has provided evidence that the gene cloN6 is involved in this methylation reaction. Its gene product CloN6 shares conserved sequence motifs with the recently identified radical SAM protein superfamily, and it has been suggested that members of this family can catalyse methylcobalamin-dependent methylation reactions. cloN6 was inactivated in the clorobiocin producer Streptomyces roseochromogenes var. oscitans DS 12.976 by use of the PCR-targeting method. The cloN6(-) mutants accumulated, instead of clorobiocin, a derivative lacking the 5"'-methyl group of the pyrrole moiety (termed novclobiocin 109). A structural isomer carrying the pyrrole-2-carboxyl moiety at 2"-OH rather than at the 3"-OH of the deoxysugar (novclobiocin 110), and a derivative completely lacking the pyrrole unit (novclobiocin 104) were also identified. The structures of the metabolites were confirmed by NMR and MS analysis. Antibacterial activity tests against Bacillus subtilis showed that novclobiocin 109 and novclobiocin 110 have antibacterial activities about eight times less than that of clorobiocin, whereas novclobiocin 104 showed no activity under the test conditions.

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Section: Discussionmentioning

confidence: 97%

CloN6, a Novel Methyltransferase Catalysing the Methylation of the Pyrrole‐2‐carboxyl Moiety of Clorobiocin

Westrich

Heide

2003

ChemBioChem

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“…Modifications at the carbamoyl of novobiose result in a drastic reduction in the effectiveness of the drug (Kuo et al, 1991). Thrl65 forms a water-mediated hydrogen bond to the adenine ring of ADPNP, therefore it is possible that a mutation at this residue would have an affect on the ATPase and supercoiling activities of DNA gyrase.…”

Section: Discussionmentioning

confidence: 99%

“…The 2'-hydroxyl of novobiose forms a hydrogen bond to the carbonyl oxygen of Asn46, and the 4'-methoxyl oxygen forms a hydrogen bond to the side chain of Asn46. Transfer of the carbamoyl from position 3' of novobiose to position 2' (isonovobiocin) has been implicated in one mechanism for resistance to novobiocin (Kuo et al, 1991). Isonovobiocin has a dramatically reduced affinity for DNA gyrase.…”

Section: Interactions Between P24 and Gr122222xmentioning

confidence: 99%

“…One mechanism for this acquired coumarin resistance is believed to be due to the ability of some prokaryotes to chemically modify novobiocin, transferring the carbamoyl at position 3' of the novobiose sugar moiety to position 2' (Kuo et al, 1991). These include poor oral absorption, low activity versus certain Gram-negative bacteria, and a tendency for coumarin-sensitive organisms readily to become novobiocin-resistant.…”

Section: Introductionmentioning

confidence: 99%

“…These include poor oral absorption, low activity versus certain Gram-negative bacteria, and a tendency for coumarin-sensitive organisms readily to become novobiocin-resistant. One mechanism for this acquired coumarin resistance is believed to be due to the ability of some prokaryotes to chemically modify novobiocin, transferring the carbamoyl at position 3' of the novobiose sugar moiety to position 2' (Kuo et al, 1991). In order to determine the binding sites of the coumarins and the cyclothialidines, we have solved the crystal structures of complexes of these compounds with a 24 kDa N-terminal fragment of DNA gyrase B protein (p24).…”

Section: Introductionmentioning

confidence: 99%

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The nature of inhibition of DNA gyrase by the coumarins and the cyclothialidines revealed by X-ray crystallography.

et al. 1996

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This study describes the first crystal structures of a complex between a DNA topoisomerase and a drug. We present the structures of a 24 kDa N‐terminal fragment of the Escherichia coli DNA gyrase B protein in complexes with two different inhibitors of the ATPase activity of DNA gyrase, namely the coumarin antibiotic, novobiocin, and GR122222X, a member of the cyclothialidine family. These structures are compared with the crystal structure of the complex with an ATP analogue, adenylyl‐beta‐gamma‐imidodiphosphate (ADPNP). The likely mechanism, by which mutant gyrase B proteins become resistant to inhibition by novobiocin are discussed in light of these comparisons. The three ligands are quite dissimilar in chemical structure and bind to the protein in very different ways, but their binding is competitive because of a small degree of overlap of their binding sites. These crystal structures consequently describe a chemically well characterized ligand binding surface and provide useful information to assist in the design of novel ligands.

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Molecular mechanisms of durg inhibition of DNA gyrase

1996

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SummaryDNA gyrase, an enzyme unique to prokaryotes, has been implicated in almost all processes that involve DNA. Although efficient inhibitors of this protein have been known for more than 20 years, none of them have enjoyed prolonged pharmaceutical success. It is only recently that the mechanisms of inhibition for some of these classes of drugs have been established unequivocally by X-ray crystallography. It is hoped that this detailed structural information will assist the Accepted design of novel, effective inhibitors of DNA gyrase.

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Microbial O-carbamylation of novobiocin.

Cited by 12 publications

References 8 publications

CloN6, a Novel Methyltransferase Catalysing the Methylation of the Pyrrole‐2‐carboxyl Moiety of Clorobiocin

CloN6, a Novel Methyltransferase Catalysing the Methylation of the Pyrrole‐2‐carboxyl Moiety of Clorobiocin

The nature of inhibition of DNA gyrase by the coumarins and the cyclothialidines revealed by X-ray crystallography.

Molecular mechanisms of durg inhibition of DNA gyrase

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