Naslov
Understanding h.DPP III mechanism – an aid in rationalization of the mutants (in)activity
(Understanding h.DPP III mechanism – an aid in rationalization of the mutants (in)activity)

Autori
Tomić, Sanja ; Kovačević, Borislav ; Tomić, Antonija ; Matovina, Mihaela ; Karačić, Zrinka ; Matić, Sara ; Abramić, Marija ; Agić, Dejan

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
19th IUPAB and 11th EBSA : Abstracts, European Biophysics Journal, Volume 46, Supplement 1 / - : Springer, 2017, S179-S179

Skup
19th IUPAB and 11th EBSA Congress

Mjesto i datum
Edinburgh, Ujedinjeno Kraljevstvo, 06.07.2017. - 20.07.2017

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
dipeptidyl peptidase III ; DPP III ; peptidase mechanism ; hydrolysis

Sažetak
Human dipeptidyl-peptidase III (h.DPP III) is a zinc-exopeptidase that hydrolysis dipeptides from the N-terminus of its substrates. Our study presents the first insight into the reaction mechanism of h.DPP III ; determined on the model and real systems. The Glu451-assisted water addition on amide carbon followed by nitrogen inversion are shown to be the rate- determine steps with the activation energies in a good agreement with the experimental results for the Leu-enkephalin hydrolysis. We found that precisely defined geometry of the enzyme binding site puts an additional restrains on the tetrahedral intermediate and stimulates the forward reaction towards final hydrolytic product. Namely, differently from the model, the N-inversion is in concerted fashion followed by favourable hydrogen bonding with Glu451 that immediately “locks” the system into the configuration where reversion to the enzyme-substrate complex is hardly achievable. Therefore we propose that the functional significance of DPP III is dual: to lower the energy barrier of the peptide hydrolysis and to suppress the reverse reaction. Based on the determined mechanism and protein dynamics we were able to rationalize the experimentally determined activity of several h.DPP III mutants detected in human cancers.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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