Graz University of Technology Austria Institute of Biochemistry ...

plant genes that apparently encode flavin-dependent oxidases. These genes are currently
expressed in our laboratory in order to characterize the role of the enzymes in alkaloid
biosynthesis (thesis project of Silvia Wallner).
Dipeptidylpeptidase III
Dipeptidyl-peptidases III (DPPIII; EC 3.4.14.4) are Zn-dependent enzymes with molecular
masses of ca. 80-85 kDa that specifically cleave the first two amino acids from the N-
terminus of different length peptides. All known DPPIII sequences contain the unique motif
HEXXGH, which enabled the recognition of the dipeptidyl-peptidase III family as a distinct
evolutionary metallopeptidase family (M49). In mammals, DPPIII is associated with
important physiological functions such as pain regulation, and hence the enzyme is a potential
drug target. Previously, Sigrid Deller and Nina Jajcanin-Jozic have successfully expressed,
purified and characterized the recombinant yeast enzyme, and Pravas Baral in Karl Gruber’s
laboratory at the Karl-Franzens-University has elucidated the crystal structure of the yeast
protein. This work revealed that yeast DPPIII features a novel protein topology.
Structure of human DPPIII in its open form (right) and peptide liganded (closed) form
In collaboration with a structural genomics group in Toronto led by Dr. Sirano Dhe-Paganon,
Gustavo Arruda has solved the structure of the human enzyme both in its open (right, above)
and closed conformation (left, above). The latter structure was obtained by co-crystallization
of a tightly binding peptide to an inactive variant of human DPPIII. These two new structures
constitute a major breakthrough in our effort to understand the physiological role of the
enzyme and pave the way for the development of potentially useful inhibitors of the enzyme
(Gustavo Arruda’s thesis project in Prof. Gruber’s laboratory supported by Alexandra Binter).
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