Dr. David Giedroc
Indiana University – Department of Chemistry
Friday, March 12, 2021
HOST: Dr. Aaron Smith
“Metals, molecules and metabolism: Molecular mechanisms of bacterial metallostasis”
Late d-block first-row transition metals from manganese (Mn) to zinc (Zn) function as catalytic and structural cofactors in ≈30% of proteins in a typical bacterial proteome, and thus are broadly integrated into metabolism. Proper metalation of the metalloproteome is therefore crucial and is thought to be acutely impacted by transition metal bioavailability inside the cell. A major unresolved issue is how host transition metal restriction impacts the metalation status of the pathogen proteome. Using the Gram-negative opportunistic pathogen Acinetobacter baumannii as a model system, we have begun to explore the hypothesis that metabolic adaptation by A. baumannii to host-mediated restriction involves re-routing or prioritization of metabolism when there is insufficient Zn or Fe to metalate all sites in the proteome. We propose that a poorly understood Zur (Zn uptake repressor)-regulated COG0523-family GTPase metallochaperone ZigA functions in prioritization in Ab, allocating Zn to specific metalloenzyme clients to sustain certain metabolic processes. Ab mutants lacking ZigA struggle to synthesize flavins, and thus flavodoxins, when Fe levels are insufficient to metalate ferredoxins. Zn restriction also appears to impact translational integrity. Our proteomics analysis in Ab suggests that queuosine (Q) biosynthesis, which harbors seven metalloenzymes, is prioritized under these conditions as previously shown in plants. Q is a ubiquitous 7-deazaguanosine modification installed the wobble position of anticodon loops of four tRNAs. Placing this work in the context of other studies in other bacteria leads us to propose that Zn restriction is a specific example of nutritional stress that directly impacts GTP-centered catabolism.