CAREER: Mechanistic Studies of Tyrosine Derived Cofactors

University Of Kansas Center For Research Inc, Lawrence KS

Investigators

Abstract

Copper amine oxidase (CAO) and lysyl oxidase (LOX) belong to a family of proteins that contain quinone cofactors that are formed post-translationally from tyrosine, 2,4,5-trihydroxy-phenylalanine quinone (TPQ), and lysine tyrosylquinone (LTQ), respectively. These enzymes catalyze the modification of biogenic amines and play roles in cell signaling and collagen formation. The structure/function study of these quinone cofactors is essential to characterize the differences in their chemical properties. Although the chemical function of TPQ in CAO catalysis has been well studied, very little is known about LTQ. Further, the role of copper in catalysis in both enzymes remains unclear. The research project will further define the chemical properties of TPQ and LTQ and the role of copper in CAO catalysis, as well as develop a model system to understand the chemical function of LTQ in LOX. The research utilizes the tools and techniques of biochemistry, molecular biology, bioinorganic and synthetic organic chemistry. The results of this research will not only broaden understanding of quinoproteins but also impact fundamental understanding of other cross-linked quinones that are widely found in nature. This will aid in understanding the evolutionary advantage of selecting one quinone cofactor over the other in biological systems. Broader Impact: This multidisciplinary project provides an excellent opportunity for graduate and undergraduate students to study at the interface of chemistry and biology and participate in an international collaboration. An outreach program will be initiated to invite female students from local high schools to spend two weeks in the Chemistry department at the University of Kansas. The students will work in the laboratory and meet with female faculty and graduate students to discuss both science and the issues facing women in chemistry. These experiences are intended to encourage more women to follow careers in chemistry by demonstrating at the outset that the academic environment can be supportive to women. The workshop will also show that chemistry is a diverse subject that is much broader in scope than what would typically be taught in high school. In concert, a chemical biology course targeting upper level undergraduate and graduate students will be developed to demonstrate how chemical methods are used to understand fundamental aspects of biological systems. The course will include protein chemistry, especially post-translational modifications as well as a survey of cutting edge discoveries, intended to show students that chemists can make important contributions at the cutting-edge of biological science. Students participating in the Initiative for Minority Student Development (IMSD)-Bioscience Initiative program at the University of Kansas will be encouraged to enroll in this course. The principal investigator will actively recruit minority undergraduate students through this program into her laboratory to help them in pursuing graduate studies and a research career in the field of chemical biology.