Overview of the Properties of Glutamic Peptidases That Are Present in Plant and Bacterial Pathogens and Play a Role in Celiac Disease and Cancer

Abstract

Seven peptidase (proteinase) families─aspartic, cysteine, metallo, serine, glutamic, threonine, and asparagine─are in the peptidase database MEROPS, version 12.4 (https://www.ebi.ac.uk/merops/). The glutamic peptidase family is assigned two clans, GA and GB, and comprises six subfamilies. This perspective summarizes the unique features of their representatives. (1) G1, scytalidoglutamic peptidase, has a β-sandwich structure containing catalytic residues glutamic acid (E) and glutamine (Q), thus the name eqolisin. Most family members are pepstatin-insensitive and act as plant pathogens. (2) G2, preneck appendage protein, originates in phages, is a transmembrane protein, and its catalytic residues consist of glutamic and aspartic acids. (3) G3, strawberry mottle virus glutamic peptidase, originates in viruses and has a β-sandwich structure with catalytic residues E and Q. Neprosin has propyl endopeptidase activity, is associated with celiac disease, has a β-sandwich structure, and contains catalytic residues E-E and Q-tryptophan. (4) G4, Tiki peptidase, of the erythromycin esterase family, is a transmembrane protein, and its catalytic residues are E-histidine pairs. (5) G5, RCE1 peptidase, is associated with cancer, is a transmembrane protein, and its catalytic residues are E-histidine and asparagine-histidine. Microcystinase, a bacterial toxin, is a transmembrane protein with catalytic residues E-histidine and asparagine-histidine. (6) G6, Ras/Rap1-specific peptidase, is a bacterial pathogen, a transmembrane protein, and its catalytic residues are E-histidine pairs. This family's common features are that their catalytic residues consist of a glutamic acid and another (variable) amino acid and that they exhibit a diversity of biological functions─plant and bacterial pathogens and involvement in celiac disease and cancer─that suggests they are viable drug targets.