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Structure and inhibition of the CO2-sensing carbonic anhydrase Can2 from the pathogenic fungus Cryptococcus neoformans.

Title data

Schlicker, Christine ; Hall, Rebecca A. ; Vullo, Daniela ; Middelhaufe, Sabine ; Gertz, Melanie ; Supuran, Claudiu T. ; Mühlschlegel, Fritz A. ; Steegborn, Clemens:
Structure and inhibition of the CO2-sensing carbonic anhydrase Can2 from the pathogenic fungus Cryptococcus neoformans.
In: Journal of Molecular Biology. Vol. 385 (30 January 2009) Issue 4 . - pp. 1207-1220.
ISSN 0022-2836
DOI: https://doi.org/10.1016/j.jmb.2008.11.037

Abstract in another language

In the pathogenic fungus Cryptococcus neoformans, a CO(2)-sensing system is essential for survival in the natural environment (approximately 0.03% CO(2)) and mediates the switch to virulent growth in the human host (approximately 5% CO(2)). This system is composed of the carbonic anhydrase (CA) Can2, which catalyzes formation of bicarbonate, and the fungal, bicarbonate-stimulated adenylyl cyclase Cac1. The critical role of these enzymes for fungal metabolism and pathogenesis identifies them as targets for antifungal drugs. Here, we prove functional similarity of Can2 to the CA Nce103 from Candida albicans and describe its biochemical and structural characterization. The crystal structure of Can2 reveals that the enzyme belongs to the "plant-type" beta-CAs but carries a unique N-terminal extension that can interact with the active-site entrance of the dimer. We further tested a panel of compounds, identifying nanomolar Can2 inhibitors, and present the structure of a Can2 complex with the inhibitor and product analog acetate, revealing insights into interactions with physiological ligands and inhibitors.

Further data

Item Type: Article in a journal
Refereed: Yes
Additional notes: PubMed-ID: 19071134
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry > Chair Biochemistry - Univ.-Prof. Dr. Clemens Steegborn
Faculties
Faculties > Faculty of Biology, Chemistry and Earth Sciences
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry
Result of work at the UBT: No
DDC Subjects: 500 Science > 540 Chemistry
Date Deposited: 16 Apr 2015 12:16
Last Modified: 16 Apr 2015 12:16
URI: https://eref.uni-bayreuth.de/id/eprint/10309