Transcriptional organization of ThnI-regulated thienamycin biosynthetic genes in Streptomyces cattleya

Rodríguez, Martín González; Méndez, Cármen; Salas, José A.; Blanco, Gloria

doi:10.1038/ja.2009.133

Cited by 3 publications

(5 citation statements)

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“…These enzymes have been proposed to be responsible for the coupled C-5 epimerization and C-2/C-3 desaturation of (2S,5S)-carbapenam to (5R)-carbapenem-3-carboxylate (13,30). Recent studies of the genetics of thienamycin regulation in S. cattleya have revealed that the thn genes display a different expression pattern (27,28). Interestingly, genes encoding the carbapenem ring assembly enzymes (ThnE, ThnM, and ThnG/ThnQ) show a completely different organization than those of their homologues in P. carotovorum, as they are not adjacent and not transcriptionally coupled (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…It is involved in the regulation of a subgroup of 10 genes in the thn cluster, which constitute the ThnI regulon (27,28). A putative model for the mechanism of ThnI regulation has been proposed, in which ThnI appears to in part positively autoregulate its own expression (28).…”

Section: Vol 55 2011mentioning

confidence: 99%

“…The thnT gene is adjacent to the cephamycin regulatory gene cphU. thnR is adjacent to thnQ, the distal gene in this side of the cluster involved in thienamycin biosynthesis, since it belongs to the ThnI regulon (27,28).…”

Section: Identification Of Genes Not Essential For Thienamycin Biosynmentioning

confidence: 99%

“…ThnI is a LysR-type transcriptional regulator which constitutes a key factor in controlling thien- Arrows indicate the order and direction of the transcription of the previously described thn gene cluster (25). Among them, gray arrows represent the ThnI-dependent genes integrating the ThnI regulon (27,28). The cross-hatched arrow indicates a gene not required for thienamycin biosynthesis but essential for cephamycin biosynthesis (27), here named cphU (formerly thnU).…”

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Mutational Analysis of the Thienamycin Biosynthetic Gene Cluster from Streptomyces cattleya

Rodríguez

Núñez

Braña

et al. 2011

Antimicrob Agents Chemother

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The generation of non-thienamycin-producing mutants with mutations in the thnL, thnN, thnO, and thnI genes within the thn gene cluster from Streptomyces cattleya and their involvement in thienamycin biosynthesis and regulation were previously reported. Four additional mutations were independently generated in the thnP, thnG, thnR, and thnT genes by insertional inactivation. Only the first two genes were found to play a role in thienamycin biosynthesis, since these mutations negatively or positively affect antibiotic production. A mutation of thnP results in the absence of thienamycin production, whereas a 2-to 3-fold increase in thienamycin production was observed for the thnG mutant. On the other hand, mutations in thnR and thnT showed that although these genes were previously reported to participate in this pathway, they seem to be nonessential for thienamycin biosynthesis, as thienamycin production was not affected in these mutants. High-performance liquid chromatography (HPLC)-mass spectrometry (MS) analysis of all available mutants revealed some putative intermediates in the thienamycin biosynthetic pathway. A compound with a mass corresponding to carbapenam-3-carboxylic acid was detected in some of the mutants, suggesting that the assembly of the bicyclic nucleus of thienamycin might proceed in a way analogous to that of the simplest natural carbapenem, 1-carbapen-2-em-3-carboxylic acid biosynthesis. The accumulation of a compound with a mass corresponding to 2,3-dihydrothienamycin in the thnG mutant suggests that it might be the last intermediate in the biosynthetic pathway. These data, together with the establishment of cross-feeding relationships by the cosynthesis analysis of the non-thienamycin-producing mutants, lead to a proposal for some enzymatic steps during thienamycin assembly.

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Section: Discussionmentioning

confidence: 99%

Section: Vol 55 2011mentioning

confidence: 99%

Section: Identification Of Genes Not Essential For Thienamycin Biosynmentioning

confidence: 99%

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confidence: 99%

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Mutational Analysis of the Thienamycin Biosynthetic Gene Cluster from Streptomyces cattleya

Rodríguez

Núñez

Braña

et al. 2011

Antimicrob Agents Chemother

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“…250Three regulatory genes present in the thn cluster: thnI, cphU and thnB, 251 are the main candidates for the phenomenon observed,(Fig.1). The LysR-type 252 transcriptional activator ThnI, a key factor in activating thienamycin 253 biosynthesis, involved in the regulation of 10 genes within the thn cluster 254 including the regulator itself in a complex regulatory network(Rodríguez et al 255 2008;Rodríguez et al 2010). ThnI was the most obvious candidate to be 256 involved in heterologous activation since it was the only one present in all 257 cosmids displaying a positive phenotype(Fig.1).…”

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Activation and silencing of secondary metabolites in Streptomyces albus and Streptomyces lividans after transformation with cosmids containing the thienamycin gene cluster from Streptomyces cattleya

et al. 2014

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Activation and silencing of secondary metabolites in Streptomyces albus after 1 transformation with cosmids containing the thienamycin gene cluster from 2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Streptomyces cattleya

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Comparative analysis of a cryptic thienamycin-like gene cluster identified in Streptomyces flavogriseus by genome mining

Blanco

2011

Arch Microbiol

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In silico database searches allowed the identification in the S. flavogriseus ATCC 33331 genome of a carbapenem gene cluster highly related to the S. cattleya thienamycin one. This is the second cluster found for a complex highly substituted carbapenem. Comparative analysis revealed that both gene clusters display a high degree of synteny in gene organization and in protein conservation. Although the cluster appears to be silent under our laboratory conditions, the putative metabolic product was predicted from bioinformatics analyses using sequence comparison tools. These data, together with previous reports concerning epithienamycins production by S. flavogriseus strains, suggest that the cluster metabolic product might be a thienamycin-like carbapenem, possibly the epimeric epithienamycin. This finding might help in understanding the biosynthetic pathway to thienamycin and other highly substituted carbapenems. It also provides another example of genome mining in Streptomyces sequenced genomes as a powerful approach for novel antibiotic discovery.

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Transcriptional organization of ThnI-regulated thienamycin biosynthetic genes in Streptomyces cattleya

Cited by 3 publications

References 21 publications

Mutational Analysis of the Thienamycin Biosynthetic Gene Cluster from Streptomyces cattleya

Mutational Analysis of the Thienamycin Biosynthetic Gene Cluster from Streptomyces cattleya

Activation and silencing of secondary metabolites in Streptomyces albus and Streptomyces lividans after transformation with cosmids containing the thienamycin gene cluster from Streptomyces cattleya

Comparative analysis of a cryptic thienamycin-like gene cluster identified in Streptomyces flavogriseus by genome mining

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