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ERIC Number: ED526602
Record Type: Non-Journal
Publication Date: 2009
Pages: 230
Abstractor: As Provided
ISBN: ISBN-978-1-1096-4321-3
Biosynthesis of the Polycyclic Antimicrobial Peptides Lacticin 481, Haloduracin, and Cinnamycin
Cooper, Lisa E.
ProQuest LLC, Ph.D. Dissertation, University of Illinois at Urbana-Champaign
Lantibiotics are bacterial-derived polycyclic antimicrobial peptides. They are genetically encoded and ribosomally synthesized as precursor peptides containing a structural region that undergoes post-translational modification and a leader sequence that is not modified. Specific serine and threonine residues in the pre-lantibiotic structural region are dehydrated to dehydroalanine (Dha) and dehydrobutyrine (Dhb), respectively, and subsequently cyclized through intramolecular addition of cysteine thiol groups to these unsaturated amino acids. This process results in the formation of lanthionine (Lan; from Dha) and methyllanthionine (MeLan; from Dhb) rings. Removal of the leader peptide yields the mature biologically active compound. Class I lantibiotics are biosynthesized by a LanB dehydratase and a LanC cyclase while class II lantibiotics are generated by one bifunctional LanM enzyme. A previously developed "in vitro" production system for lacticin 481 was utilized in this study to investigate the molecular recognition elements involved in substrate binding for the lacticin 481 synthetase LctM. It was found that LctM could successfully process a series of substrate analogs, indicating that lantibiotics show promise for engineering novel therapeutic peptides. Using a bioinformatic approach, the two-peptide lantibiotic haloduracin was discovered and the activities of the haloduracin synthetases (HalM1 and HalM2) were reconstituted "in vitro". Site-directed mutagenesis of the two precursor peptides HalA1 and HalA2 was employed to generate substrate analogs that were used in structure-activity relationship studies. Efforts toward the "in vitro" biosynthesis of the lantibiotic cinnamycin have been initiated, resulting in the successful incorporation of three thioether rings by CinM and an unusual hydroxylated aspartic acid residue by CinX. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page:]
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Publication Type: Dissertations/Theses - Doctoral Dissertations
Education Level: N/A
Audience: N/A
Language: English
Sponsor: N/A
Authoring Institution: N/A