It is widely believed that the steps in the major metabolic pathways are known and that the control of flux through these pathways occurs at a very limited number of """"""""rate limiting"""""""" steps. This concept has lead to the design of drugs to alter the kinetics of these """"""""rate limiting enzymes"""""""". It has also led to attempts to alter metabolic pathways by altering the amounts of rate limiting enzymes using the techniques of molecular biology. To the dismay of many, such interventions often fail to alter the rates of the pathways under study. These failures have led to an increased awareness that """"""""control"""""""" of pathway flux is distributed among many enzymes of a metabolic pathway and can vary from enzyme to enzyme depending upon conditions. Metabolic control theory predicts distribution of control among many enzymes of a pathway (Veech, R.L. & Fell, D.A. Cell Biochem. & Function 14: 229-236, 1996). However, actual demonstration and testing of such theories was technically difficult. We were the first laboratory to make the required measurements of flux, kinetic and thermodynamic constants of each step, and the levels of all substrates and products required to make such a formal analysis of flux control in a major metabolic pathway (Kashiwaya, Y. et al, J. Biol. Chem. 269: 25502-25514, 1994). We went on to show that ketone bodies can act in heart to overcome insulin resistance in heart (Kashiwaya, J. et al, Am J. Cardiol. 80: 50A 64A, 1997). Since Dr. Kashiwaya left this laboratory, I have continued to collaborate with him and he, with others at the Department of Neurology of Tottori University in Yonago, Japan, have applied these insights from our previous work to investigate the effects of ketone bodies upon two neuronal culture models of the two most common degenerative neurological diseases. Alzheimer's disease was modeled by adding amyloid beta 1-42 to embryonic rat hippocampal neuronal cultures and Parkinson's disease was modeled by adding MPP+ to mesencephalic neuronal cultures. In both case, ketone bodies protected neurons from death induced by these very different toxins. The ability of ketone bodies to protects neurons under these conditions offers the possibility of therapy of these very common diseases as well as other diseases resulting from failures in either glycolysis or mitochondrial energy generation. This work has now appeared in: Kashiwaya,Y., Takeshima,T., Mori,N., Nakashima,K., Clarke,K., Veech,R.L. Proc. Natl. Acad. Sci. (USA) 97: 5440-5444, 2000. Discussions of the uses of ketone bodies in the treatment of neurological diseases including refractory epilepsy and insulin resistance such as Leprechaunism was held in a Rare Disease Meeting at NIH on May 3, 2000. Work on metabolic control was done in collaboration with the Dept of Biochemistry, U of Barcelona and the Harbor UCLA Research Institute and was directed this year toward the hexosemonophosphate pathway and the role of thiamine in certain cancers and appeared in Cascante,M., Centelles,J.J., Veech, R.L., Lee, W-N.P., Boros, L.G. Nutrition and Cancer 36: 150-154, 2000.
| Masuda, R; Monahan, J W; Kashiwaya, Y (2005) D-beta-hydroxybutyrate is neuroprotective against hypoxia in serum-free hippocampal primary cultures. J Neurosci Res 80:501-9 |
| Koh, Ho-Jin; Lee, Su-Min; Son, Byung-Gap et al. (2004) Cytosolic NADP+-dependent isocitrate dehydrogenase plays a key role in lipid metabolism. J Biol Chem 279:39968-74 |
| Veech, Richard L (2004) The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids 70:309-19 |
| Hopkins, James C A; Radda, George K; Veech, Richard L et al. (2004) Accumulation of 2-deoxy-D-glucose-6-phosphate as a measure of glucose uptake in the isolated perfused heart: a 31P NMR study. Metab Eng 6:36-43 |
| Cahill Jr, George F; Veech, Richard L (2003) Ketoacids? Good medicine? Trans Am Clin Climatol Assoc 114:149-61; discussion 162-3 |
