Elucidating the Biosynthetic Pathway for the Polyketide-Nonribosomal Peptide Collismycin A: Mechanism for Formation of the 2,2′-bipyridyl Ring

García, Ignacio; Vior, Natalia M.; Braña, Alfredo F.; González‐Sabín, Javier; Rohr, Jürgen; Morís, Francisco; Méndez, Cármen; Salas, José A.

doi:10.1016/j.chembiol.2012.01.014

Cited by 50 publications

(68 citation statements)

References 63 publications

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“…ity, short aligned region, and predicted catalytic motif missing one of the two histidines of canonical condensation domains (HHXXXDG) (41,42). Furthermore, the NRPS gene and formyltransferase homologue were located at a six-gene operon, here named lst for putative lipstatin biosynthesis.…”

Section: ϫ2mentioning

confidence: 99%

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Operon for Biosynthesis of Lipstatin, the Beta-Lactone Inhibitor of Human Pancreatic Lipase

Bai

Zhang

Lin

et al. 2014

Appl Environ Microbiol

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c Lipstatin, isolated from Streptomyces toxytricini as a potent and selective inhibitor of human pancreatic lipase, is a precursor for tetrahydrolipstatin (also known as orlistat, Xenical, and Alli), the only FDA-approved antiobesity medication for long-term use. Lipstatin features a 2-hexyl-3,5-dihydroxy-7,10-hexadecadienoic-␤-lactone structure with an N-formyl-L-leucine group attached as an ester to the 5-hydroxy group. It has been suggested that the ␣-branched 3,5-dihydroxy fatty acid ␤-lactone moiety of lipstatin in S. toxytricini is derived from Claisen condensation between two fatty acid substrates, which are derived from incomplete oxidative degradation of linoleic acid based on feeding experiments. In this study, we identified a six-gene operon (lst) that was essential for the biosynthesis of lipstatin by large-deletion, complementation, and single-gene knockout experiments. lstA, lstB, and lstC, which encode two ␤-ketoacyl-acyl carrier protein synthase III homologues and an acyl coenzyme A (acyl-CoA) synthetase homologue, were indicated to be responsible for the generation of the ␣-branched 3,5-dihydroxy fatty acid backbone. Subsequently, the nonribosomal peptide synthetase (NRPS) gene lstE and the putative formyltransferase gene lstF were involved in decoration of the ␣-branched 3,5-dihydroxy fatty acid chain with an N-formylated leucine residue. Finally, the 3␤-hydroxysteroid dehydrogenase-homologous gene lstD might be responsible for the reduction of the ␤-keto group of the biosynthetic intermediate, thereby facilitating the formation of the unique ␤-lactone ring.

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Section: ϫ2mentioning

confidence: 99%

“…However, it is worth noting that an HXXXDG catalytic motif, which was reported previously to be essential for the condensation reaction (41,42), present in this short aligned region. We therefore named this unknown domain the condensationlike domain (C # domain), on the basis of its low-level similar- …”

Section: ϫ2mentioning

confidence: 99%

Operon for Biosynthesis of Lipstatin, the Beta-Lactone Inhibitor of Human Pancreatic Lipase

Bai

Zhang

Lin

et al. 2014

Appl Environ Microbiol

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“…15−19 Interestingly, the PKS/NRPS system in 1 was able to synthesize a bipyridyl product CRM L 2 ( Figure 1) with an L-leucine attached at C-7, 15 and a similar product was also identified in the collismycin A pathway. 16 However, the exact mechanism to form the bipyridine core in 1 and collismycin A remains unclear. 15−19 Nevertheless, several modification steps in the biosynthesis of 1 and collismycin A have been well established by in vivo characterizing metabolites from gene knockout mutants and in vitro elucidating the enzyme functions, 15−19 which lead to a proposal of the biosynthetic pathway of 1 ( Figure 1).…”

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confidence: 99%

Biochemical and Structural Insights into the Aminotransferase CrmG in Caerulomycin Biosynthesis

Zhu

Mei

et al. 2016

ACS Chem. Biol.

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“…The collismycin A cluster of Streptomyces sp. CS40 contains two regulatory genes, clmR1 and clmR2, and a set of membrane-transporter-coding genes that could be involved in metabolite import and/or export (García et al, 2012). Here we report the characterization of clmR1 and clmR2 through insertional inactivation, gene expression and transcriptional analysis and we propose a model for regulation of the biosynthesis of collismycin A that includes iron levels as a core element in the regulatory process.…”

Section: Introductionmentioning

confidence: 99%

“…Both the collismycin A (Fig. 1b) and the caerulomycin gene clusters have been isolated and characterized (García et al, 2012;Qu et al, 2012;Zhu et al, 2012). In addition, several derivatives of collismycin A have been generated by insertional inactivation, biocatalysis and mutasynthesis Sialer et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Collismycin A biosynthesis in Streptomyces sp. CS40 is regulated by iron levels through two pathway-specific regulators

et al. 2014

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Two putative pathway-specific regulators have been identified in the collismycin A gene cluster: ClmR1, belonging to the TetR-family, and the LuxR-family transcriptional regulator ClmR2. Inactivation of clmR1 led to a moderate increase of collismycin A yields along with an early onset of its production, suggesting an inhibitory role for the product of this gene. Inactivation of clmR2 abolished collismycin A biosynthesis, whereas overexpression of ClmR2 led to a fourfold increase in production yields, indicating that ClmR2 is an activator of collismycin A biosynthesis. Expression analyses of the collismycin gene cluster in the wild-type strain and in DclmR1 and DclmR2 mutants confirmed the role proposed for both regulatory genes, revealing that ClmR2 positively controls the expression of most of the genes in the cluster and ClmR1 negatively regulates both its own expression and that of clmR2. Additionally, production assays and further transcription analyses confirmed the existence of a higher regulatory level modulating collismycin A biosynthesis in response to iron concentrations in the culture medium. Thus, high iron levels inhibit collismycin A biosynthesis through the repression of clmR2 transcription. These results have allowed us to propose a regulatory model that integrates the effect of iron as the main environmental stimulus controlling collismycin A biosynthesis.

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Elucidating the Biosynthetic Pathway for the Polyketide-Nonribosomal Peptide Collismycin A: Mechanism for Formation of the 2,2′-bipyridyl Ring

Cited by 50 publications

References 63 publications

Operon for Biosynthesis of Lipstatin, the Beta-Lactone Inhibitor of Human Pancreatic Lipase

Operon for Biosynthesis of Lipstatin, the Beta-Lactone Inhibitor of Human Pancreatic Lipase

Biochemical and Structural Insights into the Aminotransferase CrmG in Caerulomycin Biosynthesis

Collismycin A biosynthesis in Streptomyces sp. CS40 is regulated by iron levels through two pathway-specific regulators

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