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Human carbonic anhydrase IX (CA IX) is a dimeric transmembrane zinc metalloenzyme catalyzing the extracellular conversion of CO2 and H2O into HCO3- and H+. CA IX expression in advanced tumors maintains optimal intracellular pH of cancer cells while acidifying the extracellular environment and promoting cancer cell survival, migration, and metastasis.[1] Extracellular CA IX consists of well-characterized catalytic domain and intrinsically disordered proteoglycan-like (PG) domain – a structural feature unique among other human CAs. Although the PG domain is functionally essential its structural and biophysical properties within CA IX are insufficiently investigated.[2, 3] We have determined biophysical properties of the extracellular part of CA IX which is crucial for subsequent inhibitor design. As structures of human CAs isoforms are highly conserved, it is important to design specific inhibitors that target solely to CAs upregulated in cancer cells (e.g., CA IX, CA XII) while not interacting with other CAs expressed in healthy cells.[4] Thus, the determination of CA IX biophysical properties will lead to specific inhibition of overexpressed CA IX and contribute to cancer cell elimination. [1] S. Pastorekova and R. J. Gillies, “The role of carbonic anhydrase IX in cancer development: links to hypoxia, acidosis, and beyond,” Cancer and Metastasis Reviews, vol. 38, no. 1–2. Springer New York LLC, pp. 65–77, Jun. 15, 2019, doi: 10.1007/s10555-019-09799-0. [2] V. Alterio et al., “Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX,” Proc. Natl. Acad. Sci. U. S. A., vol. 106, no. 38, pp. 16233–16238, 2009, doi: 10.1073/pnas.0908301106. [3] K. Koruza et al., “Biophysical characterization of cancer-related carbonic anhydrase ix,” Int. J. Mol. Sci., vol. 21, no. 15, pp. 1–20, Aug. 2020, doi: 10.3390/ijms21155277. [4] S. Singh, C. L. Lomelino, M. Y. Mboge, S. C. Frost, and R. McKenna, “Cancer Drug Development of Carbonic Anhydrase Inhibitors beyond the Active Site,” Molecules, vol. 23, no. 5, 2018, doi: 10.3390/molecules23051045.
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