期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 54, 期 45, 页码 13457-13461出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201505282
关键词
biotechnology; CO2 fixation; crotonyl-CoA carboxylase; reductase; natural product engineering; polyketides
资金
- Gebert-Ruf-Stiftung [GRS 062-12]
- SNF-Ambizione program [PZ00P3_136828/1]
- Swiss National Science Foundation (SNF) [PZ00P3_136828] Funding Source: Swiss National Science Foundation (SNF)
Carboxylating enoyl-thioester reductases (ECRs) are a recently discovered class of enzymes. They catalyze the highly efficient addition of CO2 to the double bond of ,-unsaturated CoA-thioesters and serve two biological functions. In primary metabolism of many bacteria they produce ethylmalonyl-CoA during assimilation of the central metabolite acetyl-CoA. In secondary metabolism they provide distinct -carboxyl-acyl-thioesters to vary the backbone of numerous polyketide natural products. Different ECRs were systematically assessed with a diverse library of potential substrates. We identified three active site residues that distinguish ECRs restricted to C4 and C5-enoyl-CoAs from highly promiscuous ECRs and successfully engineered a selected ECR as proof-of-principle. This study defines the molecular basis of ECR reactivity, allowing for predicting and manipulating a key reaction in natural product diversification.
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