Identification and characterization of gamma-glutamylamine cyclotransferase, an enzyme responsible for gamma-glutamyl-epsilon-lysine catabolism.
Gamma-glutamylamine cyclotransferase (GGACT) is an enzyme that converts gamma-glutamylamines to free amines and 5-oxoproline. GGACT shows high activity toward gamma-glutamyl-epsilon-lysine, derived from the breakdown of fibrin and other proteins cross-linked by transglutaminases. The enzyme adopts the newly identified cyclotransferase fold, observed in gamma-glutamylcyclotransferase (GGCT), an enzyme with activity toward gamma-glutamyl-alpha-amino acids (Oakley, A. J., Yamada, T., Liu, D., Coggan, M., Clark, A. G., and Board, P. G. (2008) J. Biol. Chem. 283, 22031-22042). Despite the absence of significant sequence identity, several residues are conserved in the active sites of GGCT and GGACT, including a putative catalytic acid/base residue (GGACT Glu(82)). The structure of GGACT in complex with the reaction product 5-oxoproline provides evidence for a common catalytic mechanism in both enzymes. The proposed mechanism, combined with the three-dimensional structures, also explains the different substrate specificities of these enzymes. Despite significant sequence divergence, there are at least three subfamilies in prokaryotes and eukaryotes that have conserved the GGCT fold and GGCT enzymatic activity.
Oakley
Aaron J
AJ
Division of Molecular and Health Technologies, Commonwealth Scientific and Industrial Research Organization, Parkville, Victoria 3052.
Coggan
Marjorie
M
John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 2601, Australia.
Board
Philip G
PG
John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 2601, Australia. Electronic address: Philip.Board@anu.edu.au.
D000595:Amino Acid Sequence; D002384:Catalysis; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D003432:Cross-Linking Reagents / Q000737:chemistry; D018360:Crystallography, X-Ray / Q000379:methods; D004151:Dipeptides / Q000737:chemistry*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D005722:gamma-Glutamylcyclotransferase / Q000737:chemistry* / Q000235:genetics*
D003432:Cross-Linking Reagents; D004151:Dipeptides; C001299:epsilon-(gamma-glutamyl)-lysine; D005722:gamma-Glutamylcyclotransferase; D011761:Pyrrolidonecarboxylic Acid