title: Effect of sulfonamides as carbonic anhydrase VA and VB inhibitors on mitochondrial metabolic energy conversion.
abstract: 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.
authors.affiliation: Department of Chemistry, Saint Louis University, St. Louis, MO 63103, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Arechederra
authors.forename: Abdul
authors.initials: A
authors.lastname: Waheed
authors.forename: William S
authors.initials: WS
authors.lastname: Sly
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Shelley D
authors.initials: SD
authors.lastname: Minteer
mesh_terms: D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D024404:Carbonic Anhydrase V / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055664:Electrochemical Techniques; D004566:Electrodes; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism; D019802:Succinic Acid / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D005227:Fatty Acids; D007527:Isoenzymes; D013449:Sulfonamides; D019289:Pyruvic Acid; D019802:Succinic Acid; D024404:Carbonic Anhydrase V