Demystifying DPP III Catalyzed Peptide Hydrolysis—Computational Study of the Complete Catalytic Cycle of Human DPP III Catalyzed Tynorphin Hydrolysis

Tomić, Antonija; Tomić, Sanja

doi:10.3390/ijms23031858

Cited by 5 publications

(5 citation statements)

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“…This stronger interaction of the substrate with a catalytically important metal center and a larger deviation from the Bürgi–Dunitz angle [ 23 ] defining the direction of attack of the hydroxide ion, could explain the somewhat lower K M and decrease in turnover (lower k cat ), respectively, determined for the R669A–Arg 2 -2NA complex compared to the WT–Arg 2 -2NA complex ( Figure 6 and Figure S9 , Table 3 ). It is important to note that the QM/MM calculations [ 17 ] showed tighter binding with the catalytically important metal center in the Michaelis complex of the good Leu-enkephalin substrate bound with DPP III (2.45 Å) compared to the slow tynorphin (3.00 Å), suggesting a good relationship to the measured k cat values.…”

Section: Resultsmentioning

confidence: 99%

“…As a result, the hydrogen bonding between these residues decreased ( Figure 3 ). Moreover, the mutation resulted in the loss of hydrogen bonds between the tynorphin P1 residue and the highly conserved residues H568 and Y318, which are important for stabilizing the substrate during hydrolysis ( Figure 3 and Figure S6 ) [ 4 , 17 , 21 , 22 ]. The less favorable binding of the P2, P1, and P1′ subsites of tynorphin to the R669A mutant compared to the WT enzyme was also confirmed via the MM/GBSA analysis ( Figure 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, the available crystal structures of human DPP III are mostly complexes with natural peptides, mainly neuropeptides (PDB: 5EGY, 3T6B, 3T6J, 5E2Q, 5E33, 5E3A, 5E3C, and 5EHH) [ 15 , 16 ]. These structures provided better insight into the accommodation of natural peptides in the active site of DPP III and enabled a detailed QM/MM study that we recently performed for another neuropeptide, tynorphin [ 17 ], to explain the different behaviors of tynorphin and Leu-enkephalin. Unlike Leu-enkephalin, which is a good substrate for DPP III, tynorphin is considered a DPP III inhibitor or slow substrate.…”

Section: Introductionmentioning

confidence: 99%

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Influence of Mutations of Conserved Arginines on Neuropeptide Binding in the DPP III Active Site

2023

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Dipeptidyl peptidase III (DPP III), a zinc exopeptidase, is involved in the final steps of intercellular protein degradation and has a marked affinity for opioid peptides such as enkephalins and endomorphins. Recently, we characterized a number of neuropeptides as potential substrates and inhibitors of human DPP III and provided an explanation for their differential behavior. These studies prompted us to investigate the influence of the conserved R399 and R669 on neuropeptides binding to DPP III. Measuring kinetic parameters in inhibitory assays, we found that mutation of R669 to Ala or Met significantly reduced the inhibitory properties of the slow substrates tynorphin and valorphin, whereas the effects on binding of the good substrates Arg2-2NA and Leu-enkephalin were small. Molecular dynamics simulations of wild-type (WT) and mutant DPP III complexes with Leu-enkephalin, tynorphin, valorphin, and Arg2-2NA in conjunction with calculations of binding free energies revealed that the lower inhibitory potency of slow substrates in the R669A mutant can be explained by the lower binding affinity of tynorphin and the higher propensity of valorphin to hydrolyze in the mutant than in WT. The R399A mutation was shown to affect the binding and/or hydrolysis of both good and slow substrates, with the effects on Leu-enkephalin being the most pronounced.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influence of Mutations of Conserved Arginines on Neuropeptide Binding in the DPP III Active Site

2023

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“…The binding mode of peptides observed in the available crystal structures does not allow a clear distinction between the peptides which are good substrates of DPP III and those which are reported as substrate "inhibitors" or "slow" substrates. However, most recently, by using quantum molecular mechanics calculations and various molecular dynamics techniques, Tomić and Tomić [53] described the entire catalytic cycle of human DPP III and explained why tynorphin is a poor substrate compared to Leu-enkephalin. They did not find a difference in the reaction mechanism, but in significantly higher stabilization of the intermediate structure and of the products of tynorphin hydrolysis in the active site, which hinder regeneration of the enzyme [53].…”

Section: Oligopeptidesmentioning

confidence: 99%

Survey of Dipeptidyl Peptidase III Inhibitors: From Small Molecules of Microbial or Synthetic Origin to Aprotinin

Abramić

Agić

2022

Molecules

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Dipeptidyl peptidase III (DPP III) was originally thought to be a housekeeping enzyme that contributes to intracellular peptide catabolism. More specific roles for this cytosolic metallopeptidase, in the renin-angiotensin system and oxidative stress regulation, were confirmed, or recognized, only recently. To prove indicated (patho)physiological functions of DPP III in cancer progression, cataract formation and endogenous pain modulation, or to reveal new ones, selective and potent inhibitors are needed. This review encompasses natural and synthetic compounds with experimentally proven inhibitory activity toward mammalian DPP III. Except for the polypeptide aprotinin, all others are small molecules and include flavonoids, coumarin and benzimidazole derivatives. Presented are current strategies for the discovery or development of DPP III inhibitors, and mechanisms of inhibitory actions. The most potent inhibitors yet reported (propioxatin A and B, Tyr-Phe- and Phe-Phe-NHOH, and JMV-390) are active in low nanomolar range and contain hydroxamic acid moiety. High inhibitory potential possesses oligopeptides from the hemorphin group, valorphin and tynorphin, which are poor substrates of DPP III. The crystal structure of human DPP III-tynorphin complex enabled the design of the transition-state peptidomimetics inhibitors, effective in low micromolar concentrations. A new direction in the field is the development of fluorescent inhibitor for monitoring DPP III activity.

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“…Tyrosine (valine-valine-tyrosine-proline-tryptophan), a derivative of rotorphanin ( 95 ), has been shown to inhibit the activity of purified DPP3 in the brain of monkey ( 96 ). By synthesizing orphanoid pentapeptides containing aliphatic or aromatic amino acids at the N-terminus, such as VVYPW, LVYPW, IVYPW, YVYPW, FVYPW, and WVYPW, it was found that among these pentapeptides, IVYPW is a stronger inhibitor than casomorphin agent, and inhibits the activity of rat DPP3 with nanomolar affinity ( 42 , 97 ).…”

Section: Biological Propertiesmentioning

confidence: 99%

DPP3: From biomarker to therapeutic target of cardiovascular diseases

Duan²,

Leng³

et al. 2022

Front. Cardiovasc. Med.

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Cardiovascular disease is the leading cause of death globally among non-communicable diseases, which imposes a serious socioeconomic burden on patients and the healthcare system. Therefore, finding new strategies for preventing and treating cardiovascular diseases is of great significance in reducing the number of deaths and disabilities worldwide. Dipeptidyl peptidase 3 (DPP3) is the first zinc-dependent peptidase found among DPPs, mainly distributes within the cytoplasm. With the unique HEXXGH catalytic sequence, it is associated with the degradation of oligopeptides with 4 to 10 amino acids residues. Accumulating evidences have demonstrated that DPP3 plays a significant role in almost all cellular activities and pathophysiological mechanisms. Regarding the role of DPP3 in cardiovascular diseases, it is currently mainly used as a biomarker for poor prognosis in patients with cardiovascular diseases, suggesting that the level of DPP3 concentration in plasma is closely linked to the mortality of diseases such as cardiogenic shock and heart failure. Interestingly, it has been reported recently that DPP3 regulates blood pressure by interacting with the renin-angiotensin system. In addition, DPP3 also participates in the processes of pain signaling, inflammation, and oxidative stress. But the exact mechanism by which DPP3 affects cardiovascular function is not clear. Hence, this review summarizes the recent advances in the structure and catalytic activity of DPP3 and its extensive biological functions, especially its role as a therapeutic target in cardiovascular diseases. It will provide a theoretical basis for exploring the potential value of DPP3 as a therapeutic target for cardiovascular diseases.

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Demystifying DPP III Catalyzed Peptide Hydrolysis—Computational Study of the Complete Catalytic Cycle of Human DPP III Catalyzed Tynorphin Hydrolysis

Cited by 5 publications

References 58 publications

Influence of Mutations of Conserved Arginines on Neuropeptide Binding in the DPP III Active Site

Influence of Mutations of Conserved Arginines on Neuropeptide Binding in the DPP III Active Site

Survey of Dipeptidyl Peptidase III Inhibitors: From Small Molecules of Microbial or Synthetic Origin to Aprotinin

DPP3: From biomarker to therapeutic target of cardiovascular diseases

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