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Simultaneous and independent vs. antagonistic inhibition of muscle carbonic anhydrase iii by acetazolamide and cyanate

Biochemical Pharmacology 33(16): 2641-2646

Simultaneous and independent vs. antagonistic inhibition of muscle carbonic anhydrase iii by acetazolamide and cyanate

The inhibition by cyanate and acetazolamide of pig muscle carbonic anhydrase III (CA III) CO2 hydratase activity was studied in order to explore mechanistic features possibly unique to the muscle isoenzyme. The turnover number of CO2 hydration was found to be 6000 s-1 with a Km of 83 mM for CO2. Cyanate inhibition (Ki, 3 .mu.M) and acetazolamide inhibition (Ki, 44 .mu.M) were both found to be noncompetitive with respect to CO2. Significantly, acetazolamid and cyanate displayed non-exclusive binding to pig muscle carbonic anhydrase. The similarity of mode and degree of inhibition of muscle carbonic anhydrase by cyanate as compared with the inhibition of the erythrocyte isoenzymes suggests the existence of a similar metal environment. That cyanate and acetazolamide bind simultaneously to CA III and the comparatively large Ki for acetazolamide per se appear to be more compatible with a different mode of coordination of the Zn with the sulfonamide, supporting a 5-coordinant Zn in the catalytic mechanism of CO2 hydration for CA III.

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Accession: 006418987

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