Areas of interest:
Enzyme mechanisms; metabolism in general; cerebral energy metabolism in particular; toxification reactions; biochemical mechanisms involved in neurodegenerative diseases.

Ongoing projects:
1. Many halogenated, electrophilic xenobiotics (foreign compounds) are detoxified through the mercapturate pathway. In this pathway, the xenobiotic is successively converted to the corresponding glutathione S-conjugate, cysteine S-conjugate and mercapturate (N-acetyl-L-cysteine S-conjugate), and excreted. The pathway, however, can sometimes lead to bioactification (toxification). In this case, the cysteine S-conjugate is irreversibly converted to pyruvate, ammonia and a sulfhydryl-containing fragment by cysteine S-conjugate b-lyases. If the fragment is chemically reactive, the parent xenobiotic may be nephrotoxic and neurotoxic. We are interested in characterizing the various cysteine S-conjugate b-lyases, including a high-molecular-weight lyase recently discovered in our laboratory. We have recently uncovered evidence that toxicants can be channeled from the active site of the lyases to susceptible enzymes in the mitochondria, resulting in loss of TCA cycle function. It is possible that lifetime exposure to low levels of electrophilic toxicants in the environment, coupled with endogenous cysteine S-conjugate b-lyase activity, may contribute to mitochondrial dysfunctions associated with neurodegenerative disease in susceptible individuals.
2. At least ten neurodegenerative diseases, including Huntington disease (HD), are caused by (CAG)n/Qn expansions in the affected gene/expressed protein. As first proposed by Green (Cell 74, 955-956, 1993), we believe that transglutaminases (TGases) may be an important factor in (CAG)n/Qn-expansion diseases. TGases catalyze the Ca2+-dependent covalent attachment of a protein lysyl (K) residue, an amine, diamine, or polyamine to the carboxamide moiety of a protein/peptide Q residue. The resulting bond (an isopeptide bond) is resistant to proteolytic digestion, and proteins cross linked by these bonds are often highly insoluble. We and others have shown that Qn doamins are excellent substrates of TGases. We have also shown that cystamine - an in vitro inhibitor of TGases - prolongs the lives of HD-transgenic mice. These findings may provide a basis for understanding the mechanism of "selective vulnerability" of various brain regions in the different (CAG)n/Qn-expansion diseases. We are in the process of characterizing the various TGases in the human brain. Our eventual goal is to design selective inhibitors of these enzymes as potential therapeutic agents.