Office of the Chief

Section of Molecular Pharmacology and Toxicology

Section on Nuclear Magnetic Resonance

Section on Nutritional Neuroscience
 

The Section of Molecular Pharmacology and Toxicology specializes on the biochemical properties of ethanol-inducible cytochrome P450 2E1 (CYP2E1) and mitochondrial aldehyde dehydrogenase (ALDH2). These enzymes play important roles in the metabolism of ethanol and other toxins, they mitigate oxidative damage, and they are involved in cell death signaling. The Section is currently trying to determine which proteins are oxidatively modified in oxidative environments, and how this affects protein function. The Section believes that oxidative modification and inactivation of proteins in the mitochondria and endoplasmic reticulum (ER) precede tissue pathologies. Specifically, the Section’s work suggests that tissue damage is attributable to ER stress and mitochondrial dysfunctions, which are mediated by oxidized proteins involved in chaperone activities, anti-oxidant defense, and intermediary ethanol metabolism. Based on these results, the Section is evaluating therapeutic compounds that prevent protein oxidation, such as a diet rich in PUFAs. Other lines of investigation show that toxic compounds (such as ethanol and CYP2E1 substrates) are involved cell death signaling. The Section is building on these insights with experiments that show that this process is likely mediated by c-Jun N-terminal protein kinase (JNK) and p38 kinase.

The Section on Nuclear Magnetic Resonance focuses on structural and functional studies of reconstituted G protein-coupled membrane receptors (GPCRs) and their biophysical properties in polyunsaturated fatty acids (PUFAs). Much of the Section’s work involves the cannabinoid receptor 2 (CB2). CB2 is thought to be an important therapeutic target for substance related disorders. However, the rational design of molecules that interact with CB2 has been hampered by a lack of structural and functional information about the receptor. In order to obtain this information, the Section has crystallized CB2 by fusing it with a maltose-binding protein, expressed the fusion protein in E. coli cells, and reconstituted it in lipid matrix. The Section has also examined the properties of rhodopsin (a GPCR) in a lipid matrix with high concentrations of docosahexaenoic acid (DHA). These studies suggest that there are weak and transient interactions that take place at the interface between DHA and rhodopsin. Further experiments on the function of rhodopsin in lipid bilayers suggest that the high conformational flexibility and rapid structural conversions of DHA chains account for the low molecular order of lipid bilayers with high DHA contents. This likely eases the conformational transitions of rhodopsin when the receptor is activated.

The Section on Nutritional Neuroscience focuses on the impact of omega-3 highly unsaturated fatty acid (n-3 HUFA) deficiencies. These deficiencies are important because they are both caused by, and contribute to, substance abuse. The Section’s research has shown that the benefits of n-3 HUFAs derived from eating fish and seafood during pregnancy far outweigh the risks of trace levels of heavy metals. These findings led directly to the modification of national and international nutritional recommendations. The Section continues to conduct quantitative risk-benefit analyses to inform recommendations, and it has shown that children of mothers who eat seafood score higher on IQ tests than children of mothers who eat no seafood. The Section’s research has demonstrated that excessive alcohol use leads to the degradation of n-3 HUFA in the brain, and that low plasma levels of n-3 HUFA is predictive of relapse following treatment for substance abuse. These finds have led to successful clinical trials on the efficacy of n-3 HUFA for substance abuse and major depression. The Section has conducted other research, which suggests that massive increases in the consumption of omega 6 polyunsaturated fatty acids in the United States have contributed to n-3 HUFA deficiencies. And the Section is working with the military to modify soldiers’ rations to eliminate n-3 PUFA deficiencies, in the hope of reducing suicides.