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Understanding the human DPP iii substrate specificity : QM/MM and MD calculations

Dipeptidyl-peptidase III (DPP III ; EC 3.4.14.4) is a two-domain monozinc exopeptidase of the peptidase family M49 that hydrolyzes dipeptides from the unsubstituted N-terminus of its substrates. Studies showed that tetrapeptides to octapeptides are the best substrates. Although assumed to be an enzyme with broad substrate specificity the exact kinetic parameters have been determined for only a few peptide substrates, such as: angiotensins, proctolin, α-melanocyte- stimulating hormone, dynorphin A(1-8), enkephalins and endomorphins, as well as some hemorphins and exorphins. All these findings suggest that DPP III may play physiological role in regulating the disposition of bioactive peptides. At the same time tynorphin (VVYPW), the truncated form of spinorphin, showed inhibitory activity toward DPP III isolated from monkey brain. Chiba et al. examined the inhibitory activities of various synthetic hemorphin-like peptides and found that the tynorphin analogs IVYPW and WVYPW showed even stronger inhibitory activity toward rat DPP III. Kumar et al. characterized tynorphin as a weak substrate of DPP III. One of the possible reasons why DPP III cleaves peptides with different sequences and sizes is its flexibility and thus adaptability of its binding site to accommodate molecules of different sizes. To better understand DPP III substrate specificity, we have investigated the catalytic performance of the enzyme in tynorphin hydrolysis by quantum mechanical – molecular mechanical calculations and molecular dynamics simulations, using the previously determined mechanism of hydrolysis in the DPP III – Leu-enkephalin complex as a starting point for these studies.

dipeptidyl peptides III ; tynorphin ; peptide hydrolysis ; QMMM calculations

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