Rational generation of lasso peptides based on biosynthetic gene mutations and site-selective chemical modifications

Liu, Tan; Ma, Xiaojie; Yu, Jiahui; Yang, Wensheng; Wang, Guiyang; Wang, Zhengdong; Ge, Yuanjie; Song, Juan; Han, Hua; Zhang, Wen; Yang, Donghui; Li, Xuehui; Ma, Ming

doi:10.1039/d1sc02695j

Cited by 14 publications

(19 citation statements)

References 61 publications

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“…Natural stlassin is a class II lasso peptide without any extra PTMs (Figure 2a). Double cysteine mutant variants Val2Cys/Ala11Cys and Val3Cys/Pro12Cys produced two stlassin derivatives with disulfide bonds positioned between the macrolactam ring and the Cterminal loop, creating a type of lasso fold that is outside the traditional four classes [24]. Notably, these derivatives support that disulfide bonds in lasso peptides might form spontaneously, consistent with the findings from class I and IV lasso peptides.…”

Section: Disulfurationsupporting

confidence: 76%

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Unusual Post-Translational Modifications in the Biosynthesis of Lasso Peptides

Duan

Niu

Pang

et al. 2022

IJMS

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Lasso peptides are a subclass of ribosomally synthesized and post-translationally modified peptides (RiPPs) and feature the threaded, lariat knot-like topology. The basic post-translational modifications (PTMs) of lasso peptide contain two steps, including the leader peptide removal of the ribosome-derived linear precursor peptide by an ATP-dependent cysteine protease, and the macrolactam cyclization by an ATP-dependent macrolactam synthetase. Recently, advanced bioinformatic tools combined with genome mining have paved the way to uncover a rapidly growing number of lasso peptides as well as a series of PTMs other than the general class-defining processes. Despite abundant reviews focusing on lasso peptide discoveries, structures, properties, and physiological functionalities, few summaries concerned their unique PTMs. In this review, we summarized all the unique PTMs of lasso peptides uncovered to date, shedding light on the related investigations in the future.

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Section: Disulfurationsupporting

confidence: 76%

“…), antiviral activities (e.g., MS-271, specialicin [14], etc.) and receptor antagonistic activity (e.g., stlassin [24]), lasso peptides have attracted much attention during the past few years with a notably increasing number of RiPPs of this subclass.…”

Section: Discussionmentioning

confidence: 99%

Unusual Post-Translational Modifications in the Biosynthesis of Lasso Peptides

Duan

Niu

Pang

et al. 2022

IJMS

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“…While changes to the isopeptide-bonded residues are generally not tolerated for lasso peptides, , several reports demonstrated that certain biosynthetic enzymes could tolerate variations at these positions. ,, For cloacaenodin, G1A and E9D variants were not produced, as the variants could not be detected in the supernatant or the cell pellet.…”

Section: Resultsmentioning

confidence: 99%

Cloacaenodin, an Antimicrobial Lasso Peptide with Activity against Enterobacter

et al. 2022

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Using genome mining and heterologous expression, we report the discovery and production of a new antimicrobial lasso peptide from species related to the Enterobacter cloacae complex. Using NMR and mass spectrometric analysis, we show that this lasso peptide, named cloacaenodin, employs a threaded lasso fold which imparts proteolytic resistance that its unthreaded counterpart lacks. Cloacaenodin has selective, low micromolar, antimicrobial activity against species related to the E. cloacae complex, including species implicated in nosocomial infections and against clinical isolates of carbapenem-resistant Enterobacterales. We further used site-directed mutagenesis to probe the importance of specific residues to the peptide's biosynthesis, stability, and bioactivity.

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“…Several mutantvariants of stlassin, including I4A, I4C, F15Y, and the chemically modified I4C and F15Y (I4C−III and F15Y−I) exert comparable inhibitory activities, in which F15Y and F15Y−I display smaller IC 50 values than the native peptide. 168 Atropopeptides (atropitides) are a new family RiPPs with only four members identified up to now: tryptorubin A and B from Streptomyces sp. CLI2509 and amyxirubin A and B from Amycolatopsis xylanica (Figure 25).…”

Section: Ripps With Other Biological Activitiesmentioning

confidence: 99%

“…PKUMA01240 shows no antimicrobial, antitumor, or antivirus activity but antagonistic activity against the binding of lipopolysaccharides (LPS) to toll-like receptor 4 (TLR4), which may be used for preventing or treating inflammatory diseases. Several mutant-variants of stlassin, including I4A, I4C, F15Y, and the chemically modified I4C and F15Y (I4C–III and F15Y–I) exert comparable inhibitory activities, in which F15Y and F15Y–I display smaller IC 50 values than the native peptide …”

Section: Ripps With Other Biological Activitiesmentioning

confidence: 99%

Recent Advances in Discovery, Bioengineering, and Bioactivity-Evaluation of Ribosomally Synthesized and Post-translationally Modified Peptides

Zhong

Wang

Yan

et al. 2022

ACS Bio Med Chem Au

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Ribosomally synthesized and post-translationally modified peptides (RiPPs) are of increasing interest in natural products as well as drug discovery. This empowers not only the unique chemical structures and topologies in natural products but also the excellent bioactivities such as antibacteria, antifungi, antiviruses, and so on. Advances in genomics, bioinformatics, and chemical analytics have promoted the exponential increase of RiPPs as well as the evaluation of biological activities thereof. Furthermore, benefiting from their relatively simple and conserved biosynthetic logic, RiPPs are prone to be engineered to obtain diverse analogues that exhibit distinct physiological activities and are difficult to synthesize. This Review aims to systematically address the variety of biological activities and/or the mode of mechanisms of novel RiPPs discovered in the past decade, albeit the characteristics of selective structures and biosynthetic mechanisms are briefly covered as well. Almost one-half of the cases are involved in anti-Gram-positive bacteria. Meanwhile, an increasing number of RiPPs related to anti-Gram-negative bacteria, antitumor, antivirus, etc., are also discussed in detail. Last but not least, we sum up some disciplines of the RiPPs' biological activities to guide genome mining as well as drug discovery and optimization in the future.

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Rational generation of lasso peptides based on biosynthetic gene mutations and site-selective chemical modifications

Abstract: Lasso peptides are a unique family of natural products whose structures feature a specific threaded fold, which confers these peptides the resistance to thermal and proteolytic degradation. This stability gives...

Cited by 14 publications

References 61 publications

Unusual Post-Translational Modifications in the Biosynthesis of Lasso Peptides

Unusual Post-Translational Modifications in the Biosynthesis of Lasso Peptides

Cloacaenodin, an Antimicrobial Lasso Peptide with Activity against Enterobacter

Recent Advances in Discovery, Bioengineering, and Bioactivity-Evaluation of Ribosomally Synthesized and Post-translationally Modified Peptides

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