Investigation of Penicillin Binding Protein (PBP)-like Peptide Cyclase and Hydrolase in Surugamide Non-ribosomal Peptide Biosynthesis. Issue 5 (16th May 2019)

• Record Type: Journal Article
• Authors: Zhou, Yongjun; Lin, Xiao; Xu, Chunmin; Shen, Yaoyao; Wang, Shu-Ping; Liao, Hongze; Li, Lei; Deng, Hai; Lin, Hou-Wen
• Is Part Of: Cell chemical biology. Volume 26:Issue 5(2019)
• Page Start: 737
• Page End: 744.e4
• Publication Date: 2019-05-16
• Subjects: penicillin binding protein -- non-ribosomal peptide biosynthesis -- cyclase and hydrolase -- surugamides; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2019.02.010
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Non-ribosomal peptides (NRPs) are biosynthesized on non-ribosomal peptides synthetase (NRPS) complexes, of which a C-terminal releasing domain commonly offloads the products. Interestingly, a dedicated releasing domain is absent in surugamides (SGM) NRPS, which directs the biosynthesis of cyclic octapeptides, SGM-A to -E, and the linear decapeptide, SGM-F. Here, we confirmed that sur E is essential for the production of SGMs via genetic experiments. Biochemical characterization demonstrated that the recombinant enzyme, SurE, can generate the main products SGM-A and -F from the corresponding SNAC substrates, indicating that SurE is a standalone thioesterase-like enzyme. SurE also displays considerable substrate plasticity with expanded ring or different amino acid compositions to produce different cyclopeptides, highlighting the potential of chemoenzymatic applications. Site-directed mutagenesis allowed identification of the key residues of SurE. Finally, bioinformatics analysis suggested that SurE homologs are widely distributed in bacteria, suggesting a general mechanism of NRP release in Nature. Graphical Abstract: Highlights: An unusual PBP-like thioesterase, SurE, is identified from an NRP biosynthetic pathway SurE shows considerable substrate tolerance for generating new cyclopeptides Site-directed mutagenesis allowed the identification of the key residues of SurE The PBP-like thioesterases are widely discovered in NRP biosynthetic gene clusters Abstract : Zhou et al. reported a penicillin binding protein (PBP)-like thioesterase catalyzing peptide chain termination in surugamide non-ribosomal peptide (NRP) biosynthesis. The family of enzymes is widely distributed in NRP biosynthetic pathways in bacteria, either as standalones or C-terminal domains of multidomain NRPSs, suggesting a general mechanism in Nature.