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Exploring the substrate profile of CFTR Inhibitory Factor
Author(s) -
Hvorecny Kelli L,
Bahl Christopher D,
Morisseau Christophe H,
Bomberger Jennifer M,
Stanton Bruce A,
Hammock Bruce D,
Madden Dean R
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.559.7
Subject(s) - epoxide hydrolase , chemistry , enzyme , virulence factor , hydrolase , epoxide hydrolase 2 , pseudomonas aeruginosa , biochemistry , secretion , microbiology and biotechnology , cystic fibrosis transmembrane conductance regulator , biology , virulence , bacteria , genetics , gene , microsome
Chronic obstructive pulmonary disease (COPD), the third leading cause of death in the US, results in poor mucociliary clearance and increased lung colonization by opportunistic pathogens, such as Pseudomonas aeruginosa ( PA ). Previous work has shown that the ion channel CFTR, which regulates the fluid balance at the air‐liquid interface of the lungs, is downregulated in the presence of PA , through the secretion of an epoxide hydrolase virulence factor, CFTR Inhibitory Factor (Cif). Further, the Cif protein alone elicits a decrease in apical CFTR. Studies on other epoxide hydrolases, like the human soluble epoxide hydrolase, demonstrate that these enzymes act as regulators of signaling pathways. Cif's hydrolysis activity, therefore, may function in Cif's ability to alter CFTR regulation. In order to develop a better understanding of Cif's method of action in vivo, we have delineated a hydrolysis profile for xenobiotic substrates of Cif. Our enzymatic assays indicate that Cif has clear substrate preferences in terms of enantiomeric and substituent specificity and processivity. Using X‐ray crystallography, we are also able to describe how Cif accommodates various substrates. We hypothesize that these preferences contribute to Cif's ability to disrupt normal CFTR regulation. Funding from the NIH and the CFF.