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ARS Home » Midwest Area » Ames, Iowa » National Animal Disease Center » Infectious Bacterial Diseases Research » Research » Publications at this Location » Publication #181780

Title: THE VITAMIN K-DEPENDENT CARBOXYLASE HAS BEEN ACQUIRED AND ADAPTED BY LEPTOSPIRA PATHOGENS FOR A ROLE OTHER THAN PROTEIN CARBOXYLATION

Author
item Rishavy, Mark
item Hallgren, Kevin
item Yakubenko, Anna
item Zuerner, Richard
item Runge, Kurt
item Berkner, Kathleen

Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/29/2005
Publication Date: 10/14/2005
Citation: Rishavy, M.A., Hallgren, K.W., Yakubenko, A.V., Zuerner, R.L., Runge, K.W., Berkner, K.L. 2005. The vitamin k-dependent carboxylase has been acquired and adapted by Leptospira pathogens for a role other than protein carboxylation. Journal of Biological Chemistry. 280(41):34870-7.

Interpretive Summary: Leptospirosis is one of the most widespread diseases in the world that is transmitted from animals to humans. Pathogenic bacteria in the genus Leptospira cause leptospirosis, and in humans, Leptospira infection can range in severity from a mild-flu like infection to a severe, acute infection ending in death. One of the more serious complications of leptospirosis is the development of hemorrhage, or escaping of blood from vessels into tissue. The cause of hemorrhage during leptospirosis is unknown, but in this report, we provide evidence that Leptospira has acquired a host gene that influences blood clotting (hemostasis). The activity of the Leptospira version of this protein is different from its eukaryotic counterpart, such that it may interfere with hemostasis, thereby promoting the development of hemorrhage.

Technical Abstract: Leptospirosis is an emerging infectious disease whose pathology includes a hemorraghic response, and recent sequencing of the Leptospira interrogans genome revealed an ortholog of the vitamin K-dependent (VKD) carboxylase as one of several hemostatic proteins present in the bacterium. Until now, the VKD carboxylase was known to be present only in metazoans, and the restricted distribution and high sequence similarity between metazoan and Leptospira orthologs strongly suggests that Leptospira acquired the VKD carboxylase ortholog by horizontal transfer. In metazoans, the VKD carboxylase is bifunctional, acting as an epoxidase that oxygenates vitamin K to a strong base and a carboxylase that uses the base to convert Glu's to Gla's in VKD proteins, rendering them active in hemostasis and other physiologies. In contrast, the Leptospira ortholog showed epoxidase activity but not detectable carboxylase activity, and a region of identity in all known metazoan VKD carboxylases important to Glu-interaction is divergent in the Leptospira VKD epoxidase. Furthermore, while the human carboxylase is regulated so that vitamin K epoxidation does not occur when Glu-substrate is absent, the Leptospira VKD epoxidase showed unfettered epoxidation even in the absence of Glu-substrate. Finally, human VKD protein orthologs were not detected in the L. interrogans genome. The combined data, then, indicate that Leptospira exapted the metazoan VKD carboxylase for some other use than VKD protein carboxylation, such as using the strong vitamin K base for a new reaction or to promote oxidative damage, or depleting vitamin K to indirectly inhibit host VKD protein carboxylation.