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Dipeptidyl Peptidase III: Physiological Role, Monitoring and Inhibition
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Dipeptidyl Peptidase III: Physiological Role, Monitoring and Inhibition

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Macromolecular Chemistry".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 7449

Special Issue Editor

Prof. Dr. Sanja Tomić

E-Mail Website
Guest Editor
Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institut, Bijnička 54, HR-10000 Zagreb, Croatia
Interests: protein interactions; medicinal chemistry; chemical biology; computational chemistry; reaction mechanisms; enzymology; drug design; thermodynamics

Special Issue Information

Dear Colleagues,

Dipeptidyl peptidase III (DPP III; EC 3.4.14.4) is a zinc peptidase of the M49 family and the only metalloenzyme among the dipeptidyl peptidases. It is defined by five evolutionarily conserved regions, including two characteristic motifs, HEXXGH and EEXR(K) AE (D), that are critical for zinc binding and catalytic activity. This cytosolic enzyme, widely distributed in various species and tissues, cleaves dipeptides from the unsubstituted amino end of its substrate. DPP III shows a marked affinity for several bioactive peptides (angiotensins II, III, IV and opioid peptides) as well as flavonoids and various peptidomimetics, many of which contain a large aromatic moiety. The broad substrate specificity of human DPP III may be due to the high flexibility of its 3D structure and the plasticity of its ligand-binding site. In addition to its role in the final stages of protein turnover, it is also involved in a number of physiological and pathophysiological processes, such as defense against oxidative stress, apoptosis, and inflammation, but the details of its biological effects are still unknown. Moreover, the increased amount and activity of DPP III compared to normal tissues suggest that it is involved in the development of some cancers. Therefore, the new search for effective inhibitors and fluorescent ligands of human DPP III would be of great importance to define its physiological role and therapeutic potential.

This Special Issue will focus on new findings revealing these biological functions and researchers are invited to contribute with their high quality research articles from all research areas to elucidate the physiological role of DPP III and search for its inhibitors and ligands.

Prof. Dr. Sanja Tomić
Guest Editor

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Keywords

  • dipeptidyl peptidase III
  • metalloenzyme
  • inhibition
  • peptides
  • oxidative stress
  • fluorescent probes
  • enzymatic mechanism
  • biopeptides

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Published Papers (3 papers)

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Research

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17 pages, 3426 KiB  
Article
Influence of Mutations of Conserved Arginines on Neuropeptide Binding in the DPP III Active Site
by Antonija Tomić, Zrinka Karačić and Sanja Tomić
Molecules 2023, 28(4), 1976; https://doi.org/10.3390/molecules28041976 - 19 Feb 2023
Cited by 1 | Viewed by 1867
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Dipeptidyl Peptidase III: Physiological Role, Monitoring and Inhibition)
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10 pages, 1477 KiB  
Article
Dipeptidyl Peptidase 3 Activity as a Promising Biomarker of Bone Fragility in Postmenopausal Women
by Ciro Menale, Gaia Tabacco, Anda Mihaela Naciu, Maria Lucia Schiavone, Francesca Cannata, Emanuela Morenghi, Cristina Sobacchi and Andrea Palermo
Molecules 2022, 27(12), 3929; https://doi.org/10.3390/molecules27123929 - 19 Jun 2022
Cited by 4 | Viewed by 2298
Abstract
The dipeptidyl peptidase 3 (Dpp3) is a ubiquitous zinc-dependent aminopeptidase, participating in the activation or degradation of signaling peptides and in the Keap1–Nrf2 antioxidant pathway. The absence of Dpp3 in the Dpp3 knockout mouse model causes increased osteoclast activity, altered osteogenic [...] Read more.
The dipeptidyl peptidase 3 (Dpp3) is a ubiquitous zinc-dependent aminopeptidase, participating in the activation or degradation of signaling peptides and in the Keap1–Nrf2 antioxidant pathway. The absence of Dpp3 in the Dpp3 knockout mouse model causes increased osteoclast activity, altered osteogenic function, sustained oxidative stress in the bone tissue, and bone loss. We aimed to assess the association of Dpp3 activity with bone fragility in postmenopausal osteoporosis and the impact of denosumab on enzymatic activity. We conducted a two-phase study including 69 postmenopausal women with severe osteoporosis and 36 postmenopausal women without osteometabolic conditions, as controls (cross-sectional phase). Subjects with severe osteoporosis were assessed at baseline and 14 days after the first denosumab administration (prospective phase). The results showed significant reduction in serum Dpp3 activity (expressed as nmoles of formed product/mg proteins/min) in patients vs. controls (0.791 ± 0.232 vs. 1.195 ± 0.338; p < 0.001), and significant association with bone mass at the femoral neck (r = 0.28, p = 0.02) in patients prior to treatment. We found a negative correlation between C-terminal telopeptide (CTX) or N-terminal pro-peptide of type 1 procollagen (P1NP) levels and Dpp3 activity (respectively, r = −0.29, p = 0.012; and r = −0.2572, p = 0.033). Dpp3 activity did not change after denosumab injection. Our findings support a critical role played by Dpp3 in bone homeostasis as a potential bone protective factor. Additional clinical studies in larger cohorts might explore the implementation of Dpp3 assessment as a biomarker of bone health status. Full article
(This article belongs to the Special Issue Dipeptidyl Peptidase III: Physiological Role, Monitoring and Inhibition)
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Review

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23 pages, 7142 KiB  
Review
Survey of Dipeptidyl Peptidase III Inhibitors: From Small Molecules of Microbial or Synthetic Origin to Aprotinin
by Marija Abramić and Dejan Agić
Molecules 2022, 27(9), 3006; https://doi.org/10.3390/molecules27093006 - 7 May 2022
Cited by 13 | Viewed by 2603
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Dipeptidyl Peptidase III: Physiological Role, Monitoring and Inhibition)
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