Role of small molecule interactions and multiprotein assemblies in CYP1B1 disease-associated function and dysfunction

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Abstract CYP1B1 is absent or expressed at very low levels in the liver and healthy tissues while being overexpressed in tumors, giving it the title of “universal tumor antigen”. Evidence from basic science, clinical, and epidemiological studies demonstrate that CYP1B1 is involved in cancer initiation, progression, and resistance to a wide range of chemotherapeutics. In addition, several point mutations have been discovered within CYP1B1 that are associated with other disease states, particularly hereditary congenital glaucoma and metabolic disorders. However, there is currently no known molecular mechanism that explains how mutations, altered protein levels, and environmental conditions impact the function and dysfunction of this enzyme. We hypothesize that CYP1B1 subcellular localization, oligomerization, protein:protein assembly, degradation, and small molecule binding are altered in cancer cells as a result of specific single nucleotide polymorphisms or environmental features. Trafficking of CYP1B1 from the ER to the mitochondria, association into multimeric states, or generation of abnormal protein:protein assemblies could result in damaging levels of the protein and, consequently, metabolic products including ROS and mutagens that facilitate malignant progression. This work will demonstrate how the protein:protein interactions of a cytochrome P450 enzyme impacts enzyme activity and protein lifecycle. Single molecule microscopy methods and fluorescence lifetime microscopy imaging will be used to gain high resolution information on protein assembly and activity in live cells. Additionally, paradigm-shifting inhibitors of this enzyme will be developed that act though two distinct mechanisms: long-residence-time coordinative inhibition, and activation of CYP1B1 degradation. Reduction of CYP1B1 protein levels and activity should suppress its role in cancer progression, and is anticipated to facilitate restoration of efficacy for a variety of chemotherapeutics.