Lassomycin, a Ribosomally Synthesized Cyclic Peptide, Kills Mycobacterium tuberculosis by Targeting the ATP-Dependent Protease ClpC1P1P2

Gavrish, Ekaterina; Sit, Clarissa S.; Cao, Shugeng; Kandror, Olga; Spoering, Amy L.; Peoples, Aaron J.; Ling, Losee L; Fetterman, Ashley; Hughes, Dallas E.; Bissell, Anthony; Torrey, Heather L.; Akopian, Tatos; Müller, Andreas U.; Epstein, Slava S.; Goldberg, Alfred L.; Clardy, Jon; Lewis, Kim

doi:10.1016/j.chembiol.2014.01.014

Cited by 358 publications

(422 citation statements)

References 39 publications

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“…Herein, we identified and thoroughly characterized the responsible enzyme. Descriptions of lasso peptide tailoring in the literature are notably rare (the only examples are C-terminal methylation of lassomycin (20) and Trp hydroxylation of some RES-701 family lasso peptides).…”

Section: Discussionmentioning

confidence: 99%

“…The PadeA (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) peptide consisting of the last 11 residues of the precursor peptide is converted with moderate efficiency and can be quickly and easily accessed by chemical synthesis. It was therefore selected as a scaffold for more intricate exchanges of the C-terminal Ser.…”

Section: Mutational Analysis Of the Precursor Peptide Provides Insighmentioning

confidence: 99%

“…First, an optimized modification assay was performed on a large scale on PadeA (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) to obtain pure phosphorylated peptide. Additionally, a version of the 11-residue peptide already carrying a phosphorylated Ser side chain (PadeA(13-23)-Ser-23-OPO 3 2Ϫ ) was chemically synthesized as a reference.…”

Section: Mutational Analysis Of the Precursor Peptide Provides Insighmentioning

confidence: 99%

“…The sample was lyophilized and redissolved in 100 l of 20% MeCN and employed for LC-MS analysis. The unmodified PadeA (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) 15 N probe with z-gradient. The temperature effect on the spectra was surveyed by recording 1 H spectra in a range of 283-308 K. Consequently, all two-dimensional spectra were recorded at 298 K. TOCSY spectra were recorded with a mixing time of 80 ms, whereas for NOESY measurements mixing times of 150 and 300 ms were applied.…”

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confidence: 99%

“…Determination of Kinetic Parameters for ThcoK-For time course measurements, a standard in vitro reaction (50 l) in assay buffer containing 5 M enzyme was run for varying durations (10,20,30,45,60,120,240, and 480 min) in triplicate. Reactions were quenched by addition of TFA (final concentration of 5% (v/v)) and subjected to LC-MS analysis.…”

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confidence: 99%

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Insights into the Unique Phosphorylation of the Lasso Peptide Paeninodin

Zhu¹,

Hegemann

Fage

et al. 2016

Journal of Biological Chemistry

122

199

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Lasso peptides are a new class of ribosomally synthesized and post-translationally modified peptides and thus far are only isolated from proteo-and actinobacterial sources. Typically, lasso peptide biosynthetic gene clusters encode enzymes for biosynthesis and export but not for tailoring. Here, we describe the isolation of the novel lasso peptide paeninodin from the firmicute Paenibacillus dendritiformis C454 and reveal within its biosynthetic cluster a gene encoding a kinase, which we have characterized as a member of a new class of lasso peptide-tailoring kinases. By employing a wide variety of peptide substrates, it was shown that this novel type of kinase specifically phosphorylates the C-terminal serine residue while ignoring those located elsewhere. These experiments also reveal that no other recognition motif is needed for efficient enzymatic phosphorylation of the C-terminal serine. Furthermore, through comparison with homologous HPr kinases and subsequent mutational analysis, we confirmed the essential catalytic residues. Our study reveals how lasso peptides are chemically diversified and sets the foundation for rational engineering of these intriguing natural products.

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Section: Discussionmentioning

confidence: 99%

Section: Mutational Analysis Of the Precursor Peptide Provides Insighmentioning

confidence: 99%

Section: Mutational Analysis Of the Precursor Peptide Provides Insighmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Insights into the Unique Phosphorylation of the Lasso Peptide Paeninodin

Zhu¹,

Hegemann

Fage

et al. 2016

Journal of Biological Chemistry

122

199

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Dual substrate‐controlled kinase activity leads to polyphosphorylated lasso peptides

et al. 2016

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Edited by Alfonso ValenciaLasso peptides are characterized by their peculiar lariat knot-like structure. Except for maturation of this fold, post-translational modifications of lasso peptides are rare. However, we recently delineated the biosynthetic pathway of a post-translationally phosphorylated lasso peptide, paeninodin. In this study, further investigation of two kinases revealed their ability to transfer multiple phosphate groups onto precursor peptide substrates, ultimately leading to polyphosphorylated lasso peptides. We found that this polyphosphorylating activity depended on the identity of the phosphate donor and the sequence of the precursor peptide. Our investigations provide new insight into the remarkable strategies for chemical diversification employed by the lasso peptide biosynthetic machinery.

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Efficient computational model for identification of antitubercular peptides by integrating amino acid patterns and properties

2019

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Tuberculosis (TB) is a leading killer caused by Mycobacterium tuberculosis. Recently, anti‐TB peptides have provided an alternative approach to combat antibiotic tolerance. We have developed an effective computational predictor, identification of antitubercular peptides (iAntiTB), by the integration of multiple feature vectors deriving from the amino acid sequences via random forest (RF) and support vector machine (SVM) classifiers. The iAntiTB combines the RF and SVM scores via linear regression to enhance the prediction accuracy. To make a robust and accurate predictor, we prepared the two datasets with different types of negative samples. The iAntiTB achieved area under the ROC curve values of 0.896 and 0.946 on the training datasets of the first and second datasets, respectively. The iAntiTB outperformed the other existing predictors.

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Lassomycin, a Ribosomally Synthesized Cyclic Peptide, Kills Mycobacterium tuberculosis by Targeting the ATP-Dependent Protease ClpC1P1P2

Cited by 358 publications

References 39 publications

Insights into the Unique Phosphorylation of the Lasso Peptide Paeninodin

Insights into the Unique Phosphorylation of the Lasso Peptide Paeninodin

Dual substrate‐controlled kinase activity leads to polyphosphorylated lasso peptides

Efficient computational model for identification of antitubercular peptides by integrating amino acid patterns and properties

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