Correlational networking guides the discovery of unclustered lanthipeptide protease-encoding genes

Author:

Xue Dan,Older Ethan A.,Zhong ZhengORCID,Shang Zhuo,Chen Nanzhu,Dittenhauser Nolan,Hou Lukuan,Cai Peiyan,Walla Michael D.,Dong Shi-HuiORCID,Tang XiaoyuORCID,Chen HexinORCID,Nagarkatti Prakash,Nagarkatti Mitzi,Li Yong-XinORCID,Li JieORCID

Abstract

AbstractBacterial natural product biosynthetic genes, canonically clustered, have been increasingly found to rely on hidden enzymes encoded elsewhere in the genome for completion of biosynthesis. The study and application of lanthipeptides are frequently hindered by unclustered protease genes required for final maturation. Here, we establish a global correlation network bridging the gap between lanthipeptide precursors and hidden proteases. Applying our analysis to 161,954 bacterial genomes, we establish 5209 correlations between precursors and hidden proteases, with 91 prioritized. We use network predictions and co-expression analysis to reveal a previously missing protease for the maturation of class I lanthipeptide paenilan. We further discover widely distributed bacterial M16B metallopeptidases of previously unclear biological function as a new family of lanthipeptide proteases. We show the involvement of a pair of bifunctional M16B proteases in the production of previously unreported class III lanthipeptides with high substrate specificity. Together, these results demonstrate the strength of our correlational networking approach to the discovery of hidden lanthipeptide proteases and potentially other missing enzymes for natural products biosynthesis.

Funder

Foundation for the National Institutes of Health

National Science Foundation

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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