Selenium and its Unique Biochemistry in Cellular and Human Health

  The element selenium plays an important role in cellular and human health. In the chemistry of life, selenium expands the chemical mechanisms for proteins to execute enzymatic reactions. In contrast to metals or organic co-factors, however, selenium is covalently incorporated into these proteins in the form of the rare amino acid selenocysteine (Sec, U). The resulting selenoproteins play important roles in diverse pathways such as reactive oxygen species (ROS) mediated signaling and detoxification, regulation of redox pathways, hormone synthesis, calcium signaling and the cellular response to dysfunctional proteins.

  A part of our team studies selenoproteins particularly in the context of oxidative stress –an imbalance between cellular oxidants such as free radicals and antioxidants. Prolonged oxidative stress caused by environmental factors or improper cellular response, not only leads to impaired signaling but to the actual damage of proteins, lipids and DNA. Accumulation of such damages over time can severely compromise human health and lead, for example, to diabetes, cardiovascular diseases, cancer and aging.

  We work on understanding the function of individual selenoproteins in the management and clearance of oxidative stress in cells. For this important biological function, the noncanonical amino acid selenocysteine plays a central role and its differences and similarities to the “normal” cysteine in the context of protein functions is of great interest to us. Our desire to thoroughly study selenoproteins and the unique biochemistry of selenium has naturally led us to the development of novel biochemical and biophysical tools, such as the efficient preparation of selenoproteins by expressed chemical ligation or the advancement of ⁷⁷Se-NMR spectroscopy methods to study selenium containing proteins. An overview of these related research topics is given below. 

While selenoproteins are low in number in any given genome, their contribution is often disproportionally important if not critical for survival when an organism is under oxidative stress. However, we currently know the precise physiological function for only a small fraction of the selenoproteome and still have yet to fully capture and describe the chemical diversity of reactivities within the selenoprotein family. To that end, we pursuing the following fundamental questions regarding selenoproteins:

  The wide gap in our knowledge regarding selenoproteins is primarily caused by the difficulty of obtaining selenoproteins in sufficient quantities for meaningful biochemical and biophysical characterization. This supply challenge has a biomolecular cause:  Unlike the 20 canonical amino acids with their individual codons, selenocysteine (Sec, U) is genetically encoded by an UGA codon, which is unfortunately also used as signal to stop translation. Nature provided a workaround this ambiguity by employing dedicated ancillary proteins to aid the incorporation of Sec into the polypeptide chain during translational. To overcome the limitation this process puts on selenoprotein production, we have developed new and innovative ways to increase the amount of selenoproteins we can produce to levels that enable us to conduct biochemical and biophysical characterizations in the laboratory. In a particularly efficient approach, we were able to exploit the high chemical reactivity of selenocysteine to join two separately expressed protein fragments to form the final protein. This technique enables us also to introduce selenocysteine in a protein at any position. Because of selenium’s chemical properties, this selenocysteine represents a unique, bioorthogonal, chemical handle that expands the utility of this method beyond protein production.