Exp Mol Med.  2003 Aug;35(4):228-242.

A model for the reaction mechanism of the transglutaminase 3 enzyme

• Ahvazi B
• Steinert P

Abstract

Transglutaminase enzymes (TGases) catalyze the calcium dependent formation of an isopeptide bond between protein-bound glutamine and lysine substrates. Previously we have shown that activated TGase 3 acquires two additional calcium ions at site two and three. The calcium ion at site three results in the opening of a channel. At this site, the channel opening and closing could modulate, depending on which metal is bound. Here we propose that the front of the channel could be used by the two substrates for enzyme reaction. We propose that the glutamine substrate is directed from Trp236 into the enzyme, shown by molecular docking. Then a lysine substrate approaches the opened active site to engage Trp327, leading to formation of the isopeptide bond. Further, direct comparisons of the structures of TGase 3 with other TGases have allowed us to identify several residues that might potentially be involved in generic and specific recognition of the glutamine and lysine substrates.

Keyword

calcium ions; protein structure; residue specificity; TGase; TGase mechanism; X-ray crystallography

MeSH Terms

Animals
Binding Sites
Calcium/metabolism
Calcium-Binding Proteins/*metabolism
Glutamine/metabolism
Human
Lysine/metabolism
Models, Chemical
Models, Molecular
Protein Binding
Protein Structure, Tertiary
Transglutaminases/*metabolism