Medical Research

University of Texas Southwestern Medical Center

Vincent S. Tagliabracci, Krzysztof Pawlowski, John Schoggins, Diana Tomchick
Dallas, TX
$1,000,000
December 2020

The human genome contains nearly 3,000 enzymes, biological machines that perform critical jobs in the cell by speeding up, or catalyzing, chemical reactions.  The genomes of all organisms also contain the instructions for making many pseudoenzymes, which are proteins that resemble other enzymes but appear to be inactive when tested using conventional methods for determining enzymatic activity.  An alternative explanation for the apparent lack of activity is that pseudoenzymes are being asked to perform the wrong reaction.  A team at the University of Texas Southwestern Medical Center discovered that the uncharacterized proteins, SelO and SidJ, which were predicted to be inactive “pseudokinases,” adopt the same shape as a kinase, but instead of transferring a phosphate to another protein, as kinases do, they instead transfer AMP and glutamate, respectively.  These discoveries were the first examples of kinase-like enzymes that can perform a different catalytic reaction.  The investigators suggest that some pseudoenzymes are active but performing different functions than the active enzymes they resemble.  Notably, an entire order of viruses, encompassing all coronaviruses, contains a SelO like pseudokinase domain of unknown function, which is essential for viral replication.  Thus, the goal of this grant is to discover new catalytic functions for pseudoenzymes, beginning with pseudokinases in mammals, bacteria, and viruses.

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