A promiscuous ancestral enzyme´s structure unveils protein variable regions of the highly diverse metallo-β-lactamase family.

The metallo-β-lactamase fold is an ancient protein structure present in numerous enzyme families responsible for diverse biological processes. The crystal structure of the hyperthermostable crenarchaeal enzyme Igni18 from Ignicoccus hospitalis was solved at 2.3 A and could resemble a possible first archetype of a multifunctional metallo-β-lactamase. Ancestral enzymes at the evolutionary origin are believed to be promiscuous all-rounders. Consistently, Igni18´s activity can be cofactor-dependently directed from β-lactamase to lactonase, lipase, phosphodiesterase, phosphotriesterase or phospholipase. Its core-domain is highly conserved within metallo-β-lactamases from Bacteria, Archaea and Eukarya and gives insights into evolution and function of enzymes from this superfamily. Structural alignments with diverse metallo-β-lactamase-fold-containing enzymes allowed the identification of Protein Variable Regions accounting for modulation of activity, specificity and oligomerization patterns. Docking of different substrates within the active sites revealed the basis for the crucial cofactor dependency of this enzyme superfamily. The structure of Igni18, ancient enzyme from the Crenarchaean species Ignicoccus hospitalis, is solved and characterized by Perez-Garcia, Chow and colleagues. This structure provides insight as to the evolution of metallo-beta-lactamases and their functions.