The dead phosphatases society: a review of the emerging roles of pseudophosphatases

Abstract

Phosphatases are a diverse family of enzymes, comprising at least 10 distinct protein folds. Like most other enzyme families, many have sequence variations that predict an impairment or loss of catalytic activity classifying them as pseudophosphatases. Research on pseudoenzymes is an emerging area of interest, with new biological functions repurposed from catalytically active relatives. Here, we provide an overview of the pseudophosphatases identified to date in all major phosphatase families. We will highlight the degeneration of the various catalytic sequence motifs and discuss the challenges associated with the experimental determination of catalytic inactivity. We will also summarize the role of pseudophosphatases in various diseases and discuss the major challenges and future directions in this field.

The Roles of Pseudophosphatases in Disease

“…Pseudoenzymes' inability to perform catalysis categorizes them as atypical members within their superfamilies [1][2][3][4][5][6]. Over the past decade, the relevance of pseudoenzymes has been elevated and solidified as important signaling regulators.…”

“…Among these, pseudoenzymes, pseudokinases and pseudophosphatases provide the best examples of their molecular mechanisms. They serve as competitors, signal integrators, modulators, and anchors in cellular processes [5][6][7]. These modes of action and their roles in various cellular processes serve as an idea link for the roles of pseudoenzymes in pathologies and diseases.…”

The FEBS Journal in 2021: a sharp reminder that science really matters

“…We also published a Special Issue on 'Pseudoenzymes' (Fig. 2), edited by Colin Adrain (Queen's University, Belfast, N. Ireland) covering a diversity of topics highlighting the role of pseudoproteases, pseudokinases and pseudophosphatases, among other pseudoenzymes, in diverse biological processes ranging from cancer, inflammation, immunity and cell death [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. We are always very interested in hearing your proposals for Special Issues on cutting-edge topics of widespread interest; just email our editorial office with your proposal.…”

Pseudoenzymes: dead enzymes with a lively role in biology

“…Drug screening of catalytically active phosphatases—which possess these residues—frequently results in the preferential identification of negatively charged drugs that cannot cross the plasma membrane, making targeting difficult. This emphasizes that the study of dead enzymes is not simply an important discovery science pursuit, but also a potential conduit to pharmacologic modulation of currently undruggable pathways [9]. This theme is also emphasized in a review by Hinton [10]: that targeting pseudoenzymes, which often act as allosteric regulators of enzymes, may be a productive and novel way to block enzymatic activities during disease.…”

“…An overview of the major pseudophosphatase families and their biological functions is provided by Farhan et al . [9], who highlight a prevalent theme in the pseudoenzyme field: how to experimentally demonstrate catalytic inactivity. The authors also emphasize that pseudophosphatases may actually represent more effective drug targets than their catalytically active counterparts, owing to the frequent loss of positively charged residues associated with their catalytic sites.…”