Lysyl oxidases (LOX) are copper-dependent enzymes that oxidize primary amine 
substrates to reactive aldehydes. The best-studied role of LOX enzymes is the 
remodeling of the extracellular matrix (ECM) in animals by cross-linking 
collagens and elastin, although intracellular functions have been reported as 
well. Five different LOX enzymes have been identified in mammals, LOX and 
LOX-like (LOXL) 1 to 4, showing a highly conserved catalytic carboxy terminal 
domain and more divergence in the rest of the sequence. Here we have surveyed a 
wide selection of genomes in order to infer the evolutionary history of LOX. We 
identified LOX proteins not only in animals, but also in many other eukaryotes, 
as well as in bacteria and archaea - which reveals a pre-metazoan origin for 
this gene family. LOX genes expanded during metazoan evolution resulting in two 
superfamilies, LOXL2/L3/L4 and LOX/L1/L5. Considering the current knowledge on 
the function of mammalian LOX isoforms in ECM remodeling, we propose that 
LOXL2/L3/L4 members might have preferentially been involved in making 
cross-linked collagen IV-based basement membrane, whereas the diversification of 
LOX/L1/L5 forms contributed to chordate/vertebrate-specific ECM innovations, 
such as elastin and fibronectin. Our work provides a novel view on the evolution 
of this family of enzymes.