We explore mechanistic problems at the intersection of biochemistry, cell biology, and human disease.
IDH as a driver of human cancer
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 biochemical, biophysical, cellular, microscopy, and -omics methods, we can understand how changes in enzyme catalysis occur in health and disease.
We seek to elucidate the catalytic and structural features of isocitrate dehydrogenase 1 (IDH1) and IDH2, focusing on tumor-driving mutations found in cancers of the brain (glioma), blood (acute myeloid leukemia), connective tissue (chondrosarcoma). Many IDH1 and IDH2 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.
Some of our recent contributions include: a comprehensive comparison of the catalytic efficiencies measured in all IDH1 mutants reported in tumors (1), with structural analysis to establish the mechanisms behind these differences (2, 3) establishing a connection between the catalytic efficiency of IDH1 mutants modulate D2HG levels in cellular and in vivo models (3); and multiple works that identify important features of mutant IDH1 inhibitor selectivity and potential resistance (2, 4, 5).
We are grateful for our funding sources: Current: NIH R35 (NIGMS), California Metabolic Research Foundation; Previous: American Cancer Society Research Scholar Grant, NIH K99/R00 (NCI), SDSU funding (Summer Undergraduate Research Program), U54 Cancer Partnership Pilot program (NIH),