Abstract
Dipeptidyl peptidase III (DPP III) is a zinc- dependent peptidase that cleaves dipeptides off of N-termini of its substrates. Previous studies on human DPP III reveal a reaction mechanism similar to that of thermolysin. Since the active site is conserved within the DPP III family, it is not surprising that the mechanism determined for Bacteroides thetaiotaomicron DPP III (BtDPP III) closely resembles that of hDPP III. However, the hydrogen bond network within the model differs slightly from that in the human ortholog, which results in two proposed pathways. The calculated Gibbs activation energy of 90.1 kJ mol–1 is larger than the one calculated from kinetic data for the preferred substrate Arg2-2-naphthylamide at room temperature (69 kJ mol–1), suggesting the importance of treating the whole DPP III enzyme in the calculations.
Highlights
D IPEPTIDYL peptidases III (DPPs III) are zinc-dependent peptidases that cleave dipeptides off of N-termini of their substrates, namely peptides consisting of 3–8 amino acid residues.[1]
Since the active site is conserved within the Dipeptidyl peptidase III (DPP III) family, it is not surprising that the mechanism determined for Bacteroides thetaiotaomicron DPP III (BtDPP III) closely resembles that of hDPP III
In the optimized structure of the enzyme-substrate complex model (ES), the zinc ion is coordinated by His448, His453, Glu476 and one water molecule (Figure 2), bringing its coordination to 4, which is in line with previous results of QM/MM calculations on the human DPP III.27
Summary
D IPEPTIDYL peptidases III (DPPs III) are zinc-dependent peptidases that cleave dipeptides off of N-termini of their substrates, namely peptides consisting of 3–8 amino acid residues.[1]. A mechanism of the peptide bond hydrolysis in the human ortholog has recently been proposed.[27] It is based on the similarity of the DPP III active site with that of the enzyme thermolysin,[28] whose catalytic mechanism had been studied earlier.[29] According to Tomić et al, the reaction rate is controlled by the first two steps, the glutamate-assisted water nucleophilic attack and the subsequent nitrogen inversion.[27] due to the lack of any crystal structure of BtDPP III – substrate complexes and the significantly different substrate affinity between hDPP III and BtDPP III (for example kcat values for the preferred synthetic substrate Arg2-2-naphthylamide are 21.8 and 5.0 s–1, respectively),[30,31] we felt prompted to investigate the BtDPP III reaction mechanism.
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