Gabrielle Alli's notes on peusdoenzyme analysis, an emerging field on a special enzyme.
Like many of us on a day to day basis, life itself is always looking for ways to be more efficient. One example of this is a group of special proteins called enzymes, which are used to catalyze chemical reactions. The functionality of enzymes is dependent on what amino acids they are made up of. So what happens when there is something different about an enzyme’s amino acids? This is where pseudoenzyme analysis comes in.
Discovering pseudoenzymes occurred as sequencing methods became more advanced. Researchers were able to determine general amino acid “signatures” commonly seen in polypeptides that would reveal their functions. Polypeptides with the same signatures were placed into families of enzymes. However, within each of these families, some molecules diverged from the rest. This is because part of their sequencing patterns suggests that their basic function as enzymes is inactive, meaning they cannot speed up chemical reactions. Researchers are still working to determine the enzymes which fall into this category, as it can be difficult to determine lack of catalytic activity from no catalytic activity at all.
Understanding how pseudoenzymes form can be made simpler by understanding the central dogma of biology. DNA is used to create RNA which is used to create protein. Therefore, the way a protein forms is determined by an RNA template. This explains why enzymes (and pseudoenzymes) have variability. Their structure is slightly different, causing their functions to be different.In simple terms, pseudoenzymes are structurally similar to enzymes but have mutations within their amino acids. This results in little to no catalysis, which is integral to a molecule’s classification as an enzyme. However, these molecules maintain other functions. Pseudoenzyme analysis aims to identify these functions and how they affect biological processes.
STYX is a specific type of pseudoenzyme known as a pseudophosphatase. Pseudophosphatases have alternative signaling functions, such as regulation of complex assembly, which can lead to disease. STYX binds with a protein known as FBXW7, associated with preventing the overgrowth of cells. This protein-protein interaction prevents FBXW7 from binding with the SCF complex which assists it in performing its normal function. If FBXW7 cannot control cell proliferation, tumors can develop. This has been shown to be the case in studies on breast cancer and endometrial cancer, presenting STYX-FBXW7 interactions as a potential target for drug therapies.
Other pseudoenzymes are encoded by large DNA viruses. These are known as viral pseudoenzymes. One example is vaccinia viral B12 pseudokinase, which interacts with cellular BAF (barrier to autointegration factor). Cellular BAF binds to viral DNA and induces replication. Its activity is reduced by phosphorylation. Vaccinia viral B12 pseudokinase has the ability to reduce cellular BAF phosphorylation levels. In one study, B12 pseudokinase was seen to interrupt cellular kinase VRK1’s ability to inactive cellular BAF. This suggests that this pseudoenzyme plays a role in the regulation of viral DNA replication.
Pseudoenzyme analysis remains a fairly new concept in biology research. Despite studies already being done to understand these molecules’ alternative functions, many are still working to solidify what defines a molecule as a pseudoenzyme. Regardless of what the future holds, it has become clear that understanding pseudoenzymes will allow us to understand problems faced in many scientific fields: cancer biology, virology, and beyond.
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