Three faculty members in the Department of Chemistry and Biochemistry at UC Santa Cruz—Assistant Professor Sarah Loerch, Assistant Professor Shaun McKinnie, and Professor Seth Rubin—have received major research grants from the National Institutes of Health through the Maximizing Investigators' Research Award (MIRA) program.
“These are prestigious grants, especially for new faculty like Sarah Loerch and Shaun McKinnie, who have each won Early Stage Investigator MIRA awards,” said department chair Glenn Millhauser, distinguished professor of chemistry and biochemistry.
The National Institute of General Medical Sciences MIRA program provides five-year grants intended to give investigators the stability and flexibility needed to enhance scientific productivity and the chances for important breakthroughs. The program also helps distribute funding more widely among the nation’s highly talented and promising investigators.
Protein synthesis
Loerch’s research focuses on how cells orchestrate the synthesis of proteins. “Something that we are just starting to appreciate is that protein synthesis at the right time and in the right place in a cell is crucial for the maintenance of functioning cells,” she said.
Every cell has millions of ribosomes, the molecular machines that build proteins, and ribosomes can switch between active and inactive states. Little is known, however, about how cells turn off protein synthesis and reactivate it when and where it’s needed. Loerch and others have identified a new mechanism used by a protein called eEF2K to shut off the protein synthesis machinery. The new grant will support her efforts to learn more about how this occurs and how cells resume protein expression.
“Because protein synthesis is such a fundamental process, eEF2K is likely involved in a range of diseases, such as neurological disorders, cancer, cardiovascular disease, and many others,” Loerch said. “Understanding this mechanism could help us think about strategies to correct errors in the many diseases it affects.”
Halogenation
McKinnie’s lab studies the biosynthesis of biologically significant natural products. His MIRA grant supports a project focusing on the incorporation of halogen atoms (fluorine, chlorine, bromine, and iodine) into small organic molecules. Conventional organic chemistry strategies for halogenation involve toxic reagents and generate undesirable byproducts, but natural microbial enzymes—called vanadium-dependent haloperoxidase (VHPO) enzymes—can incorporate halide ions into organic structures with negligible waste production.
“We're interested in understanding more about these unusual VHPO enzymes that nature uses to build bioactive natural product compounds,” McKinnie said.
There are hundreds of VHPO enzymes that catalyze specific halogenation reactions, but only a small fraction of them have been fully characterized. McKinnie will combine interdisciplinary chemical, biochemical, and genomic techniques to identify and characterize novel VHPO enzymes. The project aims to provide new biosynthetic tools for construction of biomedically relevant small molecules and biocatalytic alternatives to conventional organic chemistry halogenation strategies.
“We want to know how these enzymes work, what they can do, what kinds of molecules they make in nature, if any of these molecules have useful antibiotic or anticancer activities, and if we can use VHPOs as biocatalysts to make other halogenated molecules,” McKinnie said.
Cell cycle
Rubin studies the biochemical mechanisms that regulate the cell cycle of growth and division, and how this process goes awry in the uncontrolled proliferation of cancer cells.
“Tumor cells invariably have defects in the biochemical mechanisms that regulate cell growth and division, so understanding how these processes work is vital to understanding and inhibiting cancer,” he said.
The identification of proteins and pathways that regulate the cell’s decision to divide has led to the development of cell-cycle inhibitors to treat cancer. These drugs have significant shortcomings, however, highlighting the need for a better understanding of cell-cycle control, Rubin said.
“Our research is determining a molecular picture of how proteins control normal and cancer cell proliferation,” he said.
Rubin’s lab is studying the structure, function, and regulation of proteins that control the waves of gene expression involved in the cell cycle. The lab uses an integrated approach that combines structural biology with cell-based assays to determine how these proteins interact with each other and with the chromosomes to control gene expression.
The NIGMS MIRA grants for Loerch and McKinnie are both for about $1.9 million over five years; Rubin’s is for about $2.8 million over five years.
