We explore mechanistic problems at the intersection of biochemistry, cell biology, and human disease.
IDH as a driver of human disease
Altered catalytic activity can result from mutation, amplification, post-translational modification, and genetic- and microenvironmental-based regulation, representing creative ways to survive and thrive in rapidly changing cellular conditions, or as mechanisms of human disease. Using kinetic, structural, cellular, metabolomic, lipidomic, and mechanophenotypic based methods, we can understand how changes in enzyme catalysis occur in health and disease. One focus is elucidating the catalytic and structural features of isocitrate dehydrogenase (IDH), including mutations implicated in gliomas, chondrosarcomas, and leukemia. Many IDH mutations have the potential to confer both oncogenic and tumor suppressive properties, resulting in the neomorphic production of an oncometabolite. This hints that intriguing and complex molecular mechanisms must be at work. A mechanistic understanding of how these mutations change enzyme function provides a critical foundation for understanding cancer.
We are also interested in studying how changes in the local environment, particularly those relevant to the tumor microenviroment, play a role in regulating the activity of wild-type IDH. Changes in catalytic efficiency and catalytic partitioning of this enzyme drives reductive metabolism, an important strategy in the metabolic rewiring that drives many tumors.
MDH1 as a driver of human disease
Malate dehydrogenase 1 amplification has been implicated in ~10% of cases of squamous cell lung cancer, a type of non-small-cell lung cancer that has ~15% 5 year survival rate. Patients with this driver have a 50% reduction in survival. MDH1 is critical for supplying glycolysis with NAD+, and thus its amplification likely contributes to metabolic rerouting, including the Warburg effect. Like IDH, MDH1 appears to be regulated by environmental stress and other changes relevant to the tumor microenvironment.
Funding sources: American Cancer Society Research Scholar Grant, NIH K99/R00 (NCI), SDSU funding (Summer Undergraduate Research Program), U54 Cancer Partnership Pilot program (NIH), California Metabolic Research Foundation