Exploring the Role of Proline Metabolism in Helicobacter Pathogenicity

Abstract

Helicobacters have been associated with many diseases; including inflammatory bowel disease (Shomer, N et. al. 1997 Infec & Immun 65: 4858‐64). It is thought that the chronic inflammatory response experienced by the host in response to Helicobacter infection is the cause of subsequent host disease (Maggio‐Price L et. al. 2006 Cancer Research 66: 828‐38). One of the preferred respiratory substrates of Helicobacters is the amino acid proline. In some bacteria, proline is metabolized by proline utilization A (PutA). PutAs have been shown to utilize substrate channeling between two active site domains: a proline dehydrogenase, and a pyrroline‐5‐carboxylate dehydrogenase (Tanner, JJ. 2008 Amino Acids 35: 719‐30). The physiological importance of substrate channeling in any system is unknown. Though bioinformatical analysis indicates that Helicobacter PutAs have both domains, it is unknown if they exhibit substrate channeling, and what advantage channeling would confer. Previously, it has been shown that PutAs are required for H. pylori infection and that disrupting the putA gene in H. hepaticus leads to decreased host inflammation (Nakajima, K et. al. 2008 Biomedical Research 29: 9‐18; Krishnan, N et. al. 2008 Infec & Immun 76: 3037). Collagenase is also required for H. pylori infection (Kavermann, H et. al. (2003) J Exp Med 197:813‐22). Due to the high levels of proline in collagen, we hypothesize that collagenase is required for infection because it provides the pathogen with a steady source of proline, and the collagen breakdown leads to host inflammation. We therefore seek to explore the relationship between collagenase and proline metabolism, as well as the importance of substrate channeling, in H. bilis.