Interactions of Synthetic Metal Porphyrinates with PhuS, a Cytoplasmic Heme Trafficking Protein from Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa is an opportunistic, Gram negative, bacterial pathogen that commonly establishes infection in immunocompromised individuals. It contains protein-based, iron uptake pathways that target both heme and nonheme iron sources in the host. When the Pseudomonas heme uptake system is compromised by genetic knockout of the cytoplasmic heme trafficking protein, PhuS, the ability to establish infection is lost. PhuS functions to transfer heme to a heme oxygenase, an 02 dependent heme metabolizing enzyme, so that it can be degraded to a usable form for the organism. Within the long-term goal of developing pharmaceutical agents to inhibit heme uptake by bacterial pathogens, this study aims to evaluate the general thermodynamic parameters of metalloporphyrin binding to PhuS. Two synthetic iron porphyrinates and the Ni(II) complex of protoporphyrin IX have been investigated and their binding constants have been determined. The implications of these results for inhibiting heme uptake will be discussed.