The opportunistic pathogen P. aeruginosa encodes two extracellular heme uptake systems, the Pseudomonas heme uptake (phu) and the heme assimilation systems (has).1 Consistent with recent studies indicating PhuR as the primary heme receptor in clinical infection, our laboratory has shown Phu system is the major heme transporter with the hemophore dependent Has system acting primarily in heme sensing.2 13C-heme isotopic labeling and bacterial genetics combined with biochemical and biophysical studies further show the intracellular heme chaperone PhuS is critical in linking heme flux through the biliverdin IXβ and IXδ regioselective HemO to post-transcriptional regulation of heme utilization.3,4 Complementation of the ΔhemO deletion strain with a BVIX-α selective (hemOα) or a catalytically inactive (hemOin) hemO mutant down regulates expression of the hemophore HasA and its cognate receptor HasR. Mechanistic aspects of the BVIX-dependent regulation at the transcriptional and post-transcriptional level will be discussed. Coupling the regioselective metabolic flux of heme through PhuS-HemO with the heme sensing and regulatory network, provides a novel mechanism for the cell to rapidly respond and adapt to changes in extracellular heme availability. (1) Ochsner, U. A.; Vasil, M. L. Gene repression by the ferric uptake regulator in Pseudomonas aeruginosa: cycle selection of iron-regulated genes. Proc Natl Acad Sci U S A 1996, 93, 4409-4414. (2) Smith, A. D.; Wilks, A. Differential Contributions of the Outer Membrane Receptors PhuR and HasR to Heme Acquisition in Pseudomonas aeruginosa. J Biol Chem 2015, 290, 7756-7766. (3) O'Neill, M. J.; Bhakta, M. N.; Fleming, K. G.; Wilks, A. Induced fit on heme binding to the Pseudomonas aeruginosa cytoplasmic protein (PhuS) drives interaction with heme oxygenase (HemO). Proc Natl Acad Sci U S A 2012, 109, 5639-5644. (4) O'Neill, M. J.; Wilks, A. The P. aeruginosa heme binding protein PhuS is a heme oxygenase titratable regulator of heme uptake. ACS chemical biology 2013, 8, 1794-1802.

Biliverdin dependent regulation of extracellular heme uptake in Pseudomonas aeruginosa

251st National Meeting (2016)

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