The evolution of family 1 glycoside hydrolases: How humble prokaryotic enzymes became goddesses

Glycoside hydrolase family 1 (GH1) comprises a large group of retaining glycosidic enzymes found in all types of living organisms across the phylogenetic spectrum. These enzymes exhibit diverse activities, including β-glucosidase, β-galactosidase, phospho-β-galactosidase, β-mannosidase and β-glucuronidase. From an evolutionary perspective, GH1 enzymes emerged as tools for carbon recycling, and most members of this family still play a fundamental role in carbohydrate metabolism in both prokaryotic and eukaryotic organisms. Nevertheless, some GH1 enzymes have evolved highly specialised functions. For instance, in plants, GH1-encoding genes are often present in very high copy numbers, and GH1 enzymes are involved in numerous processes, including resistance to microbial infection, defence against insects and grazing herbivores, lignification, phytohormone activation, signalling mechanisms, fruit ripening, and pigment metabolism. Among animals, GH1 proteins reach a high level of evolutionary sophistication in mammals. Two notable examples are intestinal lactase-phlorizin hydrolase (LPH) and klotho. These two proteins arose through the fusion of repeated GH1 domains into a single polypeptide. LPH is the enzyme responsible for lactose digestion in suckling mammals and its deficiency leads to lactose intolerance in adults. Klotho was identified as a key factor in human ageing. It has demonstrated senotherapeutic properties and has emerged as a promising agent capable of reversing cellular senescence.