Effect of sulfonamides as carbonic anhydrase VA and VB inhibitors on mitochondrial metabolic energy conversion |
| |
Authors: | Robert L. Arechederra Abdul Waheed William S. Sly Claudiu T. Supuran Shelley D. Minteer |
| |
Affiliation: | 1. Department of Chemistry, Saint Louis University, St. Louis, MO 63103, United States;2. Edward Doisy Department of Biochemistry & Molecular Biology, Saint Louis University, St. Louis, MO 63104, United States;3. Polo Scientifico, Laboratorio di Chimica Bioinorganica, Rm. 188, Universit degli Studi di Firenze, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy;4. Department of Chemistry, University of Utah, Salt Lake City, UT 84112, United States;5. Department of Materials Science and Engineering, University of Utah, Salt Lake City, UT 84112, United States;1. Università degli Studi di Firenze, Polo Scientifico, NEUROFARBA Department, Pharmaceutical Sciences Section, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy |
| |
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. |
| |
Keywords: | |
本文献已被 ScienceDirect 等数据库收录! |
|