Protein Acylation is a General Regulatory Mechanism in Biosynthetic Pathway of Acyl-CoA-Derived Natural Products

Jun-Yu Xu; Ya Xu; Zhen Xu; Lin-Hui Zhai; Yang Ye; Yingming Zhao; Xiaohe Chu; Minjia Tan; Bang-Ce Ye

doi:10.1016/j.chembiol.2018.05.005

Protein Acylation is a General Regulatory Mechanism in Biosynthetic Pathway of Acyl-CoA-Derived Natural Products

Cell Chem Biol. 2018 Aug 16;25(8):984-995.e6. doi: 10.1016/j.chembiol.2018.05.005. Epub 2018 Jun 7.

Authors

Jun-Yu Xu¹, Ya Xu², Zhen Xu², Lin-Hui Zhai³, Yang Ye³, Yingming Zhao⁴, Xiaohe Chu⁵, Minjia Tan⁶, Bang-Ce Ye⁷

Affiliations

¹ Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; Lab of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China.
² Lab of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China; Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
⁵ Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China.
⁶ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: mjtan@simm.ac.cn.
⁷ Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China; Lab of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China. Electronic address: bcye@ecust.edu.cn.

PMID: 29887264
DOI: 10.1016/j.chembiol.2018.05.005

Abstract

Coenzyme A (CoA) esters of short fatty acids (acyl-CoAs) function as key precursors for the biosynthesis of various natural products and the dominant donors for lysine acylation. Herein, we investigated the functional interplay between beneficial and adverse effects of acyl-CoA supplements on the production of acyl-CoA-derived natural products in microorganisms by using erythromycin-biosynthesized Saccharopolyspora erythraea as a model: accumulation of propionyl-CoA benefited erythromycin biosynthesis, but lysine propionylation inhibited the activities of important enzymes involved in biosynthetic pathways of erythromycin. The results showed that the overexpression of NAD⁺-dependent deacylase could circumvent the inhibitory effects of high acyl-CoA concentrations. In addition, we demonstrated the similar lysine acylation mechanism in other acyl-CoA-derived natural product biosynthesis, such as malonyl-CoA-derived alkaloid and butyryl-CoA-derived bioalcohol. These observations systematically uncovered the important role of protein acylation on interaction between the accumulation of high concentrations of acyl-CoAs and the efficiency of their use in metabolic pathways.

Keywords: acyl-CoA; biosynthetic pathway; mass spectrometer; metabolic engineering; natural product biosynthesis; post-translational modification; protein acylation; quantitative acylomics; synthetic biology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acyl Coenzyme A / metabolism*
Acylation
Amino Acid Sequence
Bacterial Proteins / chemistry
Bacterial Proteins / metabolism
Biological Products / metabolism*
Biosynthetic Pathways*
Erythromycin / metabolism*
Lysine / metabolism
Protein Processing, Post-Translational
Saccharopolyspora / chemistry
Saccharopolyspora / enzymology*
Saccharopolyspora / metabolism*
Secondary Metabolism

Substances

Acyl Coenzyme A
Bacterial Proteins
Biological Products
propionyl-coenzyme A
Erythromycin
Lysine