Biosynthesis of the Angiogenesis Inhibitor Borrelidin by Streptomyces parvulus Tü4055

Olano, Carlos; Wilkinson, Barrie; Sánchez, César; Moss, Steven J.; Sheridan, Rose; Math, Vidya; Weston, Alison J.; Braña, Alfredo F.; Martin, Christine; Oliynyk, Markiyan; Méndez, Cármen; Leadlay, Peter F.; Salas, José A.

doi:10.1016/j.chembiol.2003.12.018

Cited by 105 publications

(112 citation statements)

References 42 publications

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“…Gene expression profiling of S. cerevisiae revealed that borrelidin up-regulated GCN4 leucine zipper mRNA synthesis (13), and this in turn induced the expression of amino acid biosynthetic enzymes. Because of its intriguing biological activities, the chemical synthesis (14,15) and biosynthesis (16) of borrelidin have been explored.…”

mentioning

confidence: 99%

A Unique Hydrophobic Cluster Near the Active Site Contributes to Differences in Borrelidin Inhibition among Threonyl-tRNA Synthetases

Ruan

Bovee

Sacher

et al. 2005

Journal of Biological Chemistry

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Borrelidin, a compound with anti-microbial and antiangiogenic properties, is a known inhibitor of bacterial and eukaryal threonyl-tRNA synthetase (ThrRS). The inhibition mechanism of borrelidin is not well understood. Archaea contain archaeal and bacterial genre ThrRS enzymes that can be distinguished by their sequence. We explored species-specific borrelidin inhibition of ThrRSs. The activity of ThrRS from Sulfolobus solfataricus and Halobacterium sp. NRC-1 was inhibited by borrelidin, whereas ThrRS enzymes from Methanocaldococcus jannaschii and Archaeoglobus fulgidus were not. In Escherichia coli ThrRS, borrelidin binding induced a conformational change, and threonine was not activated as shown by ATP-PP i exchange and a transient kinetic assay measuring intrinsic tryptophan fluorescence changes. These assays further showed that borrelidin is a noncompetitive tight binding inhibitor of E. coli ThrRS with respect to threonine and ATP. Genetic selection of borrelidin-resistant mutants showed that borrelidin binds to a hydrophobic region (Thr-307, His-309, Cys-334, Pro-335, Leu-489, Leu-493) proximal to the zinc ion at the active site of the E. coli ThrRS. Mutating residue Leu-489 3 Trp reduced the space of the hydrophobic cluster and resulted in a 1500-fold increase of the K i value from 4 nM to 6 M. An alignment of ThrRS sequences showed that this cluster is conserved in most organisms except for some Archaea (e.g. M. jannaschii, A. fulgidus) and some pathogens (e.g. Helicobacter pylori). This study illustrates how one class of natural product inhibitors affects aminoacyl-tRNA synthetase function, providing potentially useful information for structure-based inhibitor design.Aminoacyl-tRNA synthetases (aaRSs) 1 catalyze the acylation of transfer RNAs with their cognate amino acids and are therefore essential enzymes for protein synthesis in all organisms (1). They display exquisite specificity in discriminating between similar amino acid or tRNA substrates. Even though the core architectures of the active sites of individual aaRSs are relatively conserved, protein sequence alignments showed significant divergence among the three domains of life. However, finely tuned structural differences between aaRS orthologs provide ample opportunities for the evolution of species-specific inhibitors of any given tRNA synthetase. For example, mupirocin, an antibiotic produced by Pseudomonas fluorescens, selectively inhibits the prokaryotic isoleucyl-tRNA synthetases but has little or no effect on the eukaryotic enzymes (2, 3). Indolmycin, a secondary metabolite of Streptomyces griseus and analogue of tryptophan, inhibits only one of the two tryptophanyl-tRNA synthetases in Streptomyces coelicolor (4).ThrRS is a class II aaRS containing an N-terminal editing domain, a C-terminal tRNA binding domain, and a zinc-binding catalytic domain with the class II conserved motifs 1, 2, and 3 that provide critical ATP binding determinants (5). ThrRSs from Chinese hamster ovary cells, Saccharomyces cerevisiae and Escherichia coli (revie...

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confidence: 99%

A Unique Hydrophobic Cluster Near the Active Site Contributes to Differences in Borrelidin Inhibition among Threonyl-tRNA Synthetases

Ruan

Bovee

Sacher

et al. 2005

Journal of Biological Chemistry

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“…To accomplish adipic acid biosynthesis through PKS engineering, we focused on the borrelidin PKS because it contains the only known loading AT domain that initiates polyketide biosynthesis with a carboxylated substrate (Figure 2a). 13 The proposed natural substrate based on the isolated borrelidin structure is trans-1,2-cyclopentanedicarboxylic acid (trans-1,2-CPDA) activated to its cognate CoA. Our studies indicated not only a requirement of the loading AT for substrates containing a terminal carboxyl moiety, but also that this loading didomain could use additional acidic substrates beyond trans-1,2-CPDA.…”

Section: Substrate Specificities Of Pks Domainsmentioning

confidence: 86%

Insights into polyketide biosynthesis gained from repurposing antibiotic-producing polyketide synthases to produce fuels and chemicals

2016

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“…25 The presumed natural substrate of the loading AT is trans-1,2-cyclopentanedicarboxylic acid (trans-1,2-CPDA) activated to its cognate CoA. 26 We have also demonstrated that the downstream protein BorA2 (KS-AT-KR-ACP) could accept the succinyl starter and extend with malonyl-CoA to produce 3-hydroxyadipic, attached to the ACP in BorA2. 25 This enzyme-bound product was released as a 3-hydroxyadipic acid by linking the erythromycin PKS TE domain immediately downstream of BorA2.…”

Section: Diacidsmentioning

confidence: 94%

Bio-based production of fuels and industrial chemicals by repurposing antibiotic-producing type I modular polyketide synthases: opportunities and challenges

2016

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Complex polyketides comprise a large number of natural products that have broad application in medicine and agriculture. They are produced in bacteria and fungi from large enzyme complexes named type I modular polyketide synthases (PKSs) that are composed of multifunctional polypeptides containing discrete enzymatic domains organized into modules. The modular nature of PKSs has enabled a multitude of efforts to engineer the PKS genes to produce novel polyketides of predicted structure. We have repurposed PKSs to produce a number of short-chain mono-and di-carboxylic acids and ketones that could have applications as fuels or industrial chemicals.

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Biosynthesis of the Angiogenesis Inhibitor Borrelidin by Streptomyces parvulus Tü4055

Cited by 105 publications

References 42 publications

A Unique Hydrophobic Cluster Near the Active Site Contributes to Differences in Borrelidin Inhibition among Threonyl-tRNA Synthetases

A Unique Hydrophobic Cluster Near the Active Site Contributes to Differences in Borrelidin Inhibition among Threonyl-tRNA Synthetases

Insights into polyketide biosynthesis gained from repurposing antibiotic-producing polyketide synthases to produce fuels and chemicals

Bio-based production of fuels and industrial chemicals by repurposing antibiotic-producing type I modular polyketide synthases: opportunities and challenges

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