Audrey Lamb

Structural and functional analysis of enzymes associated with iron uptake.

With the exception of a few microbial organisms, iron is required for life on earth.  Iron serves as an important cofactor for a variety of enzymes that perform crucial reactions, including roles in cellular respiration, nucleic acid synthesis, and resistance to reactive oxygen intermediates.  Fe(III) is very insoluble and frequently biologically inaccessible such that the concentration of available iron in the human host is ~10^-9 mM.  Since a typical pathogenic bacterium requires ~1 mM iron for optimal growth, these organisms have developed elaborate systems to scavenge iron from the host.  The pathogens that we study use low molecular weight iron chelators called siderophores.  The bacteria synthesize, secrete, and then selectively take up the iron-loaded siderophore to colonize human tissues.  Non-ribosomal peptide synthetases (NRPSs) and their accessory proteins are a fascinating collection of enzymes required for the production of these bioactive peptides.  Siderophore biosynthetic enzymes are found in plants, fungi and bacteria, frequently having no human homologues, making them attractive targets for the development of new antimicrobial compounds.  The goal of the lab is to understand the structure-function relationships that drive the biosynthesis of siderophores, compounds linked to virulence and pathogenesis in a variety of deadly bacteria.  The ultimate outcome of the work will be the structural biology and mechanistic enzymology required for the development of new antibiotics to fight many bacterial infections, including P. aeruginosa, an opportunistic pathogen that is problematic for cystic fibrosis and other susceptible patients, as well as for bacteria that generate chemically-related siderophores such as Yersinia pestis (plague), Vibrio cholera (cholera) and Mycobacterium tuberculosis (tuberculosis).  The enzymes we study are also of interest to the protein engineering community, as many bioactive peptides contain similar chemical moieties and homologous enzymes are found in biosynthetic pathways of a variety of natural products.  Two examples are epothilone and cyclosporin.  Therefore, our work may also impact the design of new anti-cancer and immunosuppressive therapeutics.