Chimeric Leader Peptides for the Generation of Non-Natural Hybrid RiPP Products

被引:90
作者
Burkhart, Brandon J. [1 ,2 ]
Kakkar, Nidhi [1 ]
Hudson, Graham A. [1 ]
van der Donk, Wilfred A. [1 ,2 ]
Mitchell, Douglas A. [1 ,2 ]
机构
[1] Univ Illinois, Dept Chem, 600 South Mathews Ave, Urbana, IL 61801 USA
[2] Univ Illinois, Carl R Woese Inst Genom Biol, 1206 West Gregory Dr, Urbana, IL 61801 USA
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
LANTHIPEPTIDE SYNTHETASE PROCM; NATURAL-PRODUCTS; COMBINATORIAL BIOSYNTHESIS; CATALYTIC PROMISCUITY; MODIFICATION ENZYMES; NISIN; MACROCYCLIZATION; CYCLODEHYDRATASE; IDENTIFICATION; SPECIFICITY;
D O I
10.1021/acscentsci.7b00141
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Combining biosynthetic enzymes from multiple pathways is an attractive approach for producing molecules with desired structural features; however, progress has been hampered by the incompatibility of enzymes from unrelated pathways and intolerance toward alternative substrates. Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are a diverse natural product class that employs a biosynthetic logic that is highly amenable to engineering new compounds. RiPP biosynthetic proteins modify their substrates by binding to a motif typically located in the N-terminal leader region of the precursor peptide. Here, we exploit this feature by designing leader peptides that enable recognition and processing by multiple enzymes from unrelated RiPP pathways. Using this broadly applicable strategy, a thiazoline-forming cyclodehydratase was combined with enzymes from the sactipeptide and lanthipeptide families to create new-to-nature hybrid RiPPs. We also provide insight into design features that enable control over the hybrid biosynthesis to optimize enzyme compatibility and establish a general platform for engineering additional hybrid RiPPs.
引用
收藏
页码:629 / 638
页数:10
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