Effect of sulfonamides as carbonic anhydrase VA and VB inhibitors on mitochondrial metabolic energy conversion

• Published in: Bioorganic & medicinal chemistry Vol. 21; no. 6; pp. 1544 - 1548
• Main Authors: Arechederra, Robert L., Waheed, Abdul, Sly, William S., Supuran, Claudiu T., Minteer, Shelley D.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.03.2013
• Subjects: acetates; Acetic acid; Animals; biochemical pathways; Carbonate dehydratase; Carbonic anhydrase inhibitors; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - metabolism; Carbonic Anhydrase V - antagonists & inhibitors; Carbonic Anhydrase V - metabolism; diabetes; Diabetes mellitus; Electrochemical Techniques; electrochemistry; Electrodes; energy conversion; Energy Metabolism; fatty acid metabolism; Fatty acids; Fatty Acids - metabolism; Isoenzymes; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; isozymes; Metabolic energy conversion; metabolic flux; Metabolic pathways; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - metabolism; Mitochondrial modified electrodes; Obesity; Pyruvic acid; Pyruvic Acid - metabolism; succinic acid; Succinic Acid - metabolism; Sulfonamides; Sulfonamides - chemistry; Sulfonamides - metabolism; Carbonic anhydrase inhibitors; Metabolic energy conversion; Sulfonamides; Mitochondrial modified electrodes
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.06.053

Obesity is quickly becoming an increasing problem in the developed world. One of the major fundamental causes of obesity and diabetes is mitochondria dysfunction due to faulty metabolic pathways which alter the metabolic substrate flux resulting in the development of these diseases. This paper examines the role of mitochondrial carbonic anhydrase (CA) isozymes in the metabolism of pyruvate, acetate, and succinate when specific isozyme inhibitors are present. Using a sensitive electrochemical approach of wired mitochondria to analytically measure metabolic energy conversion, we determine the resulting metabolic difference after addition of an inhibitory compound. We found that certain sulfonamide analogues displayed broad spectrum inhibition of metabolism, where others only had significant effect on some metabolic pathways. Pyruvate metabolism always displayed the most dramatically affected metabolism by the sulfonamides followed by fatty acid metabolism, and then finally succinate metabolism. This allows for the possibility of using designed sulfonamide analogues to target specific mitochondrial CA isozymes in order to subtly shift metabolism and glucogenesis flux to treat obesity and diabetes.