"Seriously Sweet": Acesulfame K Exhibits Selective Inhibition Using Alternative Binding Modes in Carbonic Anhydrase Isoforms

Human carbonic anhydrase IX (CA IX) is upregulated in neoplastic tissues; as such, it is studied as a drug target for anticancer chemotherapy. Inhibition of CA IX has been shown to be therapeutically favorable in terms of reducing tumor growth. Previously, saccharin, a commonly used artificial sweetener, has been observed to selectively inhibit CA IX over other CA isoforms. In this study, X-ray crystallography showed acesulfame potassium (Ace K) binding directly to the catalytic zinc in CA IX (mimic) and through a bridging water in CA II. This modulation in binding is reflected in the binding constants, with Ace K inhibiting CA IX but not other CA isoforms. Hence, this study establishes the potential of Ace K (an FDA approved food additive) as a lead compound in the design and development of CA IX specific inhibitors.