Abstract

Lantibiotics are ribosomally synthesized and post-translationally modified peptide natural products. The biosynthetic enzymes that convert peptide substrates into constrained antibiotics are not well understood, especially with regards to substrate recognition. Here, we seek to carry out biochemical, and structural biological studies on several of these enzymes and address questions regarding substrate recognition, and substrate tolerance. We anticipate that this work will be of use not only towards the discovery of new compounds but to enable the production of peptide-based compounds of any structure.

Public Health Relevance

This research plan focuses on understanding how potent antibiotics and antivirals are made from simple peptides. Knowledge gained from this proposal will allow the production of drugs and therapeutics with improved functions and properties.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM079038-10A1
Application #
10145473
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Bond, Michelle Rueffer
Project Start
2006-02-01
Project End
2024-06-30
Budget Start
2020-09-15
Budget End
2021-06-30
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
University of Illinois Urbana-Champaign
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820

  Publications

An, Linna; Cogan, Dillon P; Navo, Claudio D et al. (2018) Substrate-assisted enzymatic formation of lysinoalanine in duramycin. Nat Chem Biol 14:928-933
Morita, Maho; Hao, Yue; Jokela, Jouni K et al. (2018) Post-Translational Tyrosine Geranylation in Cyanobactin Biosynthesis. J Am Chem Soc 140:6044-6048
Ortega, Manuel A; Cogan, Dillon P; Mukherjee, Subha et al. (2017) Two Flavoenzymes Catalyze the Post-Translational Generation of 5-Chlorotryptophan and 2-Aminovinyl-Cysteine during NAI-107 Biosynthesis. ACS Chem Biol 12:548-557
Sardar, Debosmita; Hao, Yue; Lin, Zhenjian et al. (2017) Enzymatic N- and C-Protection in Cyanobactin RiPP Natural Products. J Am Chem Soc 139:2884-2887
Repka, Lindsay M; Chekan, Jonathan R; Nair, Satish K et al. (2017) Mechanistic Understanding of Lanthipeptide Biosynthetic Enzymes. Chem Rev 117:5457-5520
Hao, Yue; Pierce, Elizabeth; Roe, Daniel et al. (2016) Molecular basis for the broad substrate selectivity of a peptide prenyltransferase. Proc Natl Acad Sci U S A 113:14037-14042
Ortega, Manuel A; Hao, Yue; Walker, Mark C et al. (2016) Structure and tRNA Specificity of MibB, a Lantibiotic Dehydratase from Actinobacteria Involved in NAI-107 Biosynthesis. Cell Chem Biol 23:370-380
Tang, Weixin; Dong, Shi-Hui; Repka, Lindsay M et al. (2015) Applications of the class II lanthipeptide protease LicP for sequence-specific, traceless peptide bond cleavage. Chem Sci 6:6270-6279
Dong, Shi-Hui; Tang, Weixin; Lukk, Tiit et al. (2015) The enterococcal cytolysin synthetase has an unanticipated lipid kinase fold. Elife 4:
Ortega, Manuel A; Hao, Yue; Zhang, Qi et al. (2015) Structure and mechanism of the tRNA-dependent lantibiotic dehydratase NisB. Nature 517:509-12

Showing the most recent 10 out of 16 publications