Structural Investigation of an antibiotic-producing NRPS

Pacidamycins are group of peptide antibiotics which act against the Pseudomonas human pathogens by inhibiting cell wall biosynthesis. Pacidamycins are produced in Streptomyces coeruleorubidus by proteins of a nonribosomal peptide synthetase (NRPS) gene cluster. NRPS are a class of modular proteins that synthesize small peptide products with a wide variety of chemical and biological properties. Interestingly, one protein in the gene cluster, the transferase PacB, is not a typical NRPS protein, and has been shown to function by catalyzing the transfer of an alanine residue from alanyl-tRNA to the amino terminus of the NRPS-tethered peptide intermediate. Thus, PacB departs from normal NRPS logic to appropriate an amino acid substrate from the protein synthesis machinery. The aim of this project is to study how the unusual transferase PacB selects and adds alanine from tRNA to an NRPS peptide. Elucidating this mechanism has important implications in health sciences because it may enable the development of antibacterial drugs by producing pacidamycin derivatives, or using this PacB functionality in bioengineering of other peptide therapeutics.

Faculty Supervisor:

Martin Schmeing

Student:

Anantha Krishna Deepak Manuguri

Partner:

Discipline:

Biochemistry / Molecular biology

Sector:

University:

McGill University

Program:

Globalink