To be or not to be an enzyme: pseudoenzymes in UniProt

Enzymes are essential for many biological processes. Without them, common tasks such as digesting food or replicating DNA would not be possible.

In recent years, and in part triggered by the expansion of the analysis and annotation of complete genomes, it has become apparent that several enzyme families in a wide range of species contain members that look like enzymes but fail to behave like enzymes. For example, in human, several of these families have between 5 to 10% of these enzyme-like proteins. Whilst these proteins have sequences and 3D structure features similar to active enzymes, they tend to lack essential amino acid residues such as those involved in catalytic reactions and/or binding substrates, making them incapable of catalysing chemical reactions. Based on these characteristics, scientists decided to call them pseudoenzymes.

Why are genes coding for pseudoenzymes maintained in the genome? It turns out that, despite their lack of enzymatic activity, this group of proteins carries out essential functions in cells. For example, they help assemble signalling cascades by acting as scaffolds, they regulate the activity of other enzymes and ensure that proteins are localized to the right cellular compartment. Consequently, they have become potential targets for the design of therapeutic treatments.

To support the growing interest in pseudoenzyme biology, UniProt recently revisited this important group of proteins. In collaboration with the pseudoenzyme community, we implemented changes to enhance their identification and discoverability. The outcome of this project was published in two articles in Science signalling and FEBS journal .

Ultimately, this effort will provide the scientific community with a comprehensive resource for pseudoenzymes, which in turn will lead to a better understanding of the evolution of these molecules and their active counterparts and the aetiology of related diseases. It will also support the ongoing quest to target pseudoenzymes for therapeutic treatments and offer some insight into the expanding field of enzyme engineering.