Approaching transglutaminase from Streptomyces bacteria over three decades

Transglutaminases are protein cross‐linking and protein‐modifying enzymes that have attracted considerable interest due to their causal involvement in various diseases and versatility in industrial applications. In particular, microbial transglutaminases (MTG) from Streptomyces bacteria have managed in recent years to evolve from simple food additives to specialized enzymes for the site‐directed modification of therapeutic proteins. The review summarizes relevant studies from the beginning dealing with the occurrence, production, structure, catalysis, and substrate molecules of MTG enzymes. It also addresses biotechnological procedures with MTG from S. mobaraensis ( Sm MTG) as the most prominent representative in focus. Reassessment of the available data revealed unexpected insights into catalysis of Sm MTG and other transglutaminases, suggesting selection of glutamine donor proteins by subsites at the front vestibule and the existence of distinct lysine pockets. Flexibility of the Sm MTG‐accessible glutamine donor substrate regions seems to be more important than the glutamine environment. Nevertheless, residues in close vicinity to glutamines also determine interaction with the Sm MTG subsites. The apparent lack of subsites for lysine donor proteins suggests self‐assembly of the substrate proteins prior to enzymatic cross‐linking. The study of natural substrate proteins, especially their mutual interaction, is proposed to further illuminate catalysis of Sm MTG. To this end, structure and function of the characterized substrate proteins from S. mobaraensis are discussed in conclusion.