Recent Advances in the High-throughput Engineering of Lanthipeptides

doi:10.13523/j.cb.2011007

China Biotechnology

2021, Vol. 41

Issue (1): 30-41 DOI: 10.13523/j.cb.2011007

Recent Advances in the High-throughput Engineering of Lanthipeptides

GUO Er-peng,ZHANG Jian-zhi(

),SI Tong(

)

Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen Institute of Synthetic Biology, Shenzhen 518055, China

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Abstract

Lanthipeptides are a major class of ribosomally synthesized and posttranslationally modified peptides (RiPPs) with diverse molecular structures and biological activities. New lanthipeptides obtained by genome mining and engineering are an important source of drug leads. Lanthipeptides are particularly amenable to bioengineering because their precursor peptides are encoded by genes and biosynthetic enzymes often exhibit high promiscuity, which is helpful for the efficient construction of lanthipeptides derivatives. This paper reviews the recent advances in high-throughput creation and screening of lanthipeptide derivatives. For mutant library creation, we discuss the introduction of noncanonical amino acids (ncAAs), combinatorial biosynthesis, and chimeric-leader approach for creating hybrid RiPPs. Then, we introduce large-scale structural and activity screening of lanthipeptide mutants assisted by cell surface display, reverse two-hybrid system, cellular autolysis, cell-free system, and microfluidics. Finally, we present future perspectives on the use of synthetic biology automation to streamline lanthipeptide bioengineering.

Key words： Lanthipeptide Biosynthesis High-throughout screening Synthetic biology Cell surface-display

Received: 02 November 2020 Published: 09 February 2021

ZTFLH:

Q819

Corresponding Authors: Jian-zhi ZHANG,Tong SI E-mail: zhangjz@siat.ac.cn;tong.si@siat.ac.cn

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	GUO Er-peng
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Cite this article:

GUO Er-peng, ZHANG Jian-zhi, SI Tong. Recent Advances in the High-throughput Engineering of Lanthipeptides. China Biotechnology, 2021, 41(1): 30-41.

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https://manu60.magtech.com.cn/biotech/10.13523/j.cb.2011007 OR https://manu60.magtech.com.cn/biotech/Y2021/V41/I1/30

Fig.1 Biosynthetic mechanisms for lanthipeptides (a)Four classes of lanthipeptides synthetases. Lanthipeptides were divided into four different classes according to the characteristics of the synthetases that produced thioether crosslinks. The dehydration and cyclization of class I lanthipeptides were driven by two enzymes. The dehydration cyclization of the other three classes of lanthipeptides was driven by a multi-domain enzyme. The cyclase domain of class III lanthipeptides exhibits sequence homology with the other three classes but contains no zinc ligands (b)Dehydration processes for Ser/Thr residuals. Two mechanisms are discovered for Dha/Dhb formation utilizing either Glu-tRNA or NTP for activating the side-chain hydroxyl group of Ser/Thr (c)Biosynthesis of lanthipeptides. Precursor peptides usually consist of a leader peptide and a core peptide. In some cases, a follower peptide is present. The leader/follower peptide is recognized by biosynthetic enzymes that install post-translational modifications on the core peptide and then removed to obtain a mature lanthipeptide product (d)Chemical structure of nisin A. Atoms derived from Cys, Ser, and Thr residues are shown in red, blue, and green, respectively

Fig.2 Modular construction and characterization of lanthipeptide derivatives (a)Scheme of combinatorial biosynthesis of lanthipeptide variants via modular domain assembly. Lanthipeptide derivatives were produced in L. lactis NZ9000 harboring the natural biosynthetic machinery for nisin (b)The plug and play system for genome mining. Potential core peptide sequences revealed by computational genome mining were fused to the C-terminus of the nisin leader peptide. Synthetic precursor peptides were expressed in the abovementioned L. lactis chassis for structural and bioactivity-based screening

Fig.3 Bioengineering of lanthipeptides using surface display approaches (a) Scheme of yeast surface display of lanthipeptides. The precursor peptide was fused to the C-terminus of Aga2 and modified by LctM, which was fused with an endoplasmic reticulum (ER)-retaining signal peptide fused at its C-terminus. The modified lantipeptide-Aga2 fusion was then secreted and attached to the surface-anchored Aga1 via disulfide bonds (b)Phage display of lanthipeptide. On the left:an N-to-C configuration of ompA-pIII-LP-CP fusion was slowly transported through the Sec pathway, so that sufficient interaction was permitted in the cytosol between the C-terminus of pIII and ProcM for PTM installation. On the right:an N-to-C configuration of ompA-LP-CP-pIII fusion was rapidly transported to the periplasm before modifications by cytosolic ProcM, so that unmodified lanthipeptide precursors was mostly displayed on phage surface. (Orange triangle:ompA signal peptide,LP:leader peptide,CP:core peptide)(c)Scheme of mRNA display of lanthipeptides. Photo-crosslinking and puromycin-peptide interactions mediates the formation of an mRNA-DNA-peptides complex, which was enriched by iterative rounds of affinity selection, reverse transcription, PCR amplification, and in vitro transcription and translation. Enrichment processed can be monitored using next-generation sequencing (NGS)


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