Mechanisms and Products of Lipid Oxidation and their Roles

in Cell Death Mechanisms and Degenerative Disease

Oxidation of the lipids that comprise our cell membranes, as well as the membranes of the various organelles and components of our cells, has long been implicated in the pathogenesis of a wide variety of degenerative diseases, as well as cancer and aging. To better understand the part lipid oxidation products play in these processes, we study the mechanisms by which lipids oxidize, as well as the mechanisms by which the oxidation products interact with other cellular constituents. Moreover, we synthesize what we believe to be particularly relevant oxidation products, and/or specifically-derivatized versions thereof, in order to probe their roles in cell and animal models of disease. Lipid classes currently under active investigation in the laboratory include plasmalogens, sterols and polyunsaturated fatty acids. Researchers pursuing projects in this area train in organic synthesis and kinetic and mechanistic studies, and may gain additional experience in the analysis of cell and tissue extracts with state-of-the-art UPLC with  tandem mass spectrometry, molecular and cell biology, and cell imaging.

 

Natural Product 'Antioxidants': What Do They Really Do, If Anything?

 

Ever wonder what all of those products in the herbal supplement aisles of the supermarket or drug store actually do? Or all of the additives to cosmetics and other personal care products? We do.

 

It has been well publicized that certain fruits, vegetables and other plants are excellent sources of 'antioxidants', which may counteract the damaging effects of 'free radicals' that are believed to contribute to aging and degenerative disease. In parallel with our efforts to understand the part lipid oxidation plays in these processes, we strive to elucidate the biological mechanisms of purported 'antioxidants'; either to put claims of their role in the maintenance of good health on solid molecular footing or to refute them. Thus, we synthesize the natural products, study their reactivity to radicals under a variety of settings, and determine whether they correlate (or not) with the biological activities of the compounds in cell models of degenerative disease. Moreover, we synthesize analogs of the natural products that have been derivatized in specific ways to enable identification of constituents of the cell with which they must react to elicit their biological activity. Purported 'antioxidants' under active investigation in the laboratory include the grape-derived polyphenol resveratrol and its higher oligomers, allicin and related organosulfur constituents of garlic, and curcumin, the essence of turmeric.

Are There Better Antioxidants Than What Nature Has Provided? 

 

Decades of research have shown that the gold-standard of naturally-occurring antioxidants, Vitamin E, has some drawbacks. Can we fix it?

 

While Vitamin E, the major lipid-soluble antioxidant in vivo, is essential to life it has disappointed in clinical trials designed to assess its preventive and/or therapeutic potential against degenerative disease. This has led researchers to question if lipid oxidation plays a significant role in these processes. Alternatively, some - like us - ask if Vitamin E is the optimally-designed compound to prevent lipid oxidation in vivo. Animals have evolved mechanisms to acquire Vitamin E from our diet and to ensure that it has good bioavailability, but the selection pressures that gave way to these mechanisms were unlikely to include subverting diseases that generally show up later in life, well after we have done our duty propagating the species. Our group makes use of what we learn about antioxidant mechanisms to design, synthesize and evaluate new compounds with increased potency compared to Vitamin E and other natural product antioxidants. Our motivation is two-fold: 1) to identify if and when lipid peroxidation plays a causal role in disease pathogenesis, and 2) to provide leads to strategies to slow its progression. Examples of the compounds we have developed are shown to the right; some of which are being evaluated in animal models of cardiovascular and neurodegenerative diseases.

Living in an Oxygenated Atmosphere Limits the Lifetime of All Hydrocarbons

 

The same reaction mechanisms that lead to the oxidation of cellular lipids are also responsible for the degradation of essentially all fossil-fuel derived products - from lubricating oils and rubber to jet fuels and plastics. Can we use what we learn from our studies of natural product 'antioxidants' to help develop new technology for preserving commercial products? You bet.

Phenols, amines and organosulfur compounds are among the most important additives to the myriad of fossil-fuel derived products that we make use of every day. In many cases, the molecular mechanisms that underpin the usefulness of these compounds are unknown or incomplete - which has stymied innovations in this important part of the chemical industry. Our group studies the mechanisms of additives currently used to preserve hydrocarbon-based products, and use what we learn to guide the design and synthesis of new technology. We are motivated to reduce fossil fuel consumption directly (by increasing the longevity of petroleum-derived products) and indirectly (by enabling the development of more efficient combustion engines), and work closely with industry partners in an effort to translate our discoveries to the real world.

Fundamental Radical Chemistry: The Kinetics, Thermodynamics and Mechanisms of Formal H-Atom Transfer Reactions

Arguably the simplest radical reaction is the transfer of a H-atom. Despite its similarity to a proton transfer, it is vastly more complex from a mechanistic perspective since the proton and electron of the H-atom can move in concert between the same atoms, in a step-wise fashion where the electron moves ahead of the proton or vice versa, or in a concerted fashion where the proton and electron end up in different spots on the acceptor molecule. Rationalizing and/or predicting the reactivity of potential H-atom donors in different contexts requires a thorough understanding of these mechanistic differences. Our current interests are focused on characterizing potent H-atom donors that are formed transiently in vivo, such as sulfenic acids, selenenic acids and hydropersulfides.