Lysyl Oxidase LOXL2 Selectively Oxidizes Primary, α-Unbranched Amines and Prefers Cationic Substrates

Lysyl oxidases (LOXs) initiate the posttranslational cross-linking of collagen by oxidizing lysine to allysine residues, a process crucial for the mechanical properties of the extracellular matrix. However, dysregulated LOX levels─particularly those of the LOXL2 isoform─have been implicated in numerous fibrotic diseases and cancers. Accordingly, considerable effort has been devoted to understanding the biological role of LOXL2. Despite this interest, little is known about how the type, structure, and neighboring groups of the amine influence LOXL2 activity. Here, we determined Michaelis-Menten kinetics for a panel of lysine-based model substrates to assess the structural determinants of LOXL2-catalyzed oxidation. We show that LOXL2 oxidizes exclusively primary, α-unbranched amines. In addition, our studies revealed that an additional positively charged group enhances LOXL2 activity.