Dipeptidyl peptidase III: a multifaceted oligopeptide N‐end cutter

Prajapati, Subhash C; Chauhan, Shyam S.

doi:10.1111/j.1742-4658.2011.08275.x

Cited by 87 publications

(107 citation statements)

References 126 publications

(251 reference statements)

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“…The recently resolved crystal structure of human DPP III (PDB ID: 3FVY) 3 shows close resemblance to the yeast DPP III (PDB ID: 3CSK). 2 DPP III has been implicated in intracellular protein catabolism, oxidative stress response, 4 and various physiological processes, such as blood pressure and pain regulation mechanism, 5,6 related to the hydrolysis of bioactive peptides, 1 as well as in some pathological processes -the cataractogenesis 7 and progression of ovarian cancer. 8 Due to its biological significance, human DPP III is interesting as a potential drug target.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, QSAR, and Molecular Dynamics Simulation of Amidino-substituted Benzimidazoles as Dipeptidyl Peptidase III Inhibitors

Rastija

Agić²,

Tomiš³

et al. 2015

ACSi

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A molecular modeling study has been performed on a series of 16 benzimidazole-based inhibitors of human dipeptidyl peptidase III (DPP III). Eight of these were novel compounds synthesized in excellent yields using green chemistry approach. This study aims at elucidating the structural features of benzimidazole derivatives required for the antagonism of human DPP III activity using Quantitative Structure-Activity Relationship (QSAR) analysis, and at understanding the mechanism of one of the most potent inhibitor bindings into the active site of this enzyme, namely by molecular dynamics (MD) simulations. The best model obtained includes S3K and RDF045m descriptors, which have explained 89.4% of inhibitory activity. The depicted moiety for the strong inhibition activity matches the structure of the most potent compound. MD simulation has revealed the importance of imidazolinyl and phenyl groups in the mechanism of binding into the active site of human DPP III.

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Section: Introductionmentioning

confidence: 99%

Synthesis, QSAR, and Molecular Dynamics Simulation of Amidino-substituted Benzimidazoles as Dipeptidyl Peptidase III Inhibitors

Rastija

Agić²,

Tomiš³

et al. 2015

ACSi

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“…22 As a metalloaminopeptidase, DPP III preferentially cleaves dipeptide residues (eg, Arg-Arg-, Ala-Arg-, Leu-Arg-, or Asp-Arg-) from the N terminus of oligopeptides ranging from 3 to 10 amino acid residues or proteins at physiological pH 6-8. 20,23,24 Endogenous DPP III has been detected in placenta, erythrocytes, and seminal plasma. [25][26][27] DPP III is implicated in various physiological and pathological processes through the breakdown of certain oligopeptides or their fragments, such as the angiotensins (Ang II, Ang III, and Ang IV) and opioid peptides (enkephalins and endorphins).…”

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confidence: 99%

Novel Therapeutic Role for Dipeptidyl Peptidase III in the Treatment of Hypertension

et al. 2016

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Abstract-Dipeptidyl peptidase III (DPP III) cleaves dipeptide residues from the N terminus of polypeptides ranging from 3 to 10 amino acids in length and is implicated in pathophysiological processes through the breakdown of certain oligopeptides or their fragments. In this study, we newly identified the biochemical properties of DPP III for angiotensin II (Ang II), which consists of 8 amino acids. DPP III quickly and effectively digested Ang II with K m = 3.7×10 −6 mol/L. In the in vivo experiments, DPP III remarkably reduced blood pressure in Ang II-infused hypertensive mice without alteration of heart rate. DPP III did not affect hemodynamics in noradrenalin-induced hypertensive mice or normotensive mice, suggesting specificity for Ang II. When DPP III was intravenously injected every other day for 4 weeks after Ang II osmotic minipump implantation in mice, Ang II-induced cardiac fibrosis and hypertrophy were significantly attenuated. This DPP III effect was at least similar to that caused by an angiotensin receptor blocker candesartan. Furthermore, administration of DPP III dramatically reduced the increase in urine albumin excretion and kidney injury and inflammation markers caused by Ang II infusion. Both DPP III and candesartan administration showed slight additive inhibition in the albumin excretion. These results reveal a novel potential use of DPP III in the treatment of hypertension and its protective effects on hypertension-sensitive organs, such as the heart and kidneys.

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“…Dipeptidyl peptidase III (DPP III), also known as enkephalinase B, is an enkephalin-degrading enzyme that cleaves dipeptides sequentially from the N termini of substrates (6). All DPP IIIs described thus far contain the unique zinc-binding motif HEXXGH characteristic of metallopeptidase family M49 (7).…”

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confidence: 99%

Entropy-driven binding of opioid peptides induces a large domain motion in human dipeptidyl peptidase III

Bezerra

Dobrovetsky

Viertlmayr

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

161

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Opioid peptides are involved in various essential physiological processes, most notably nociception. Dipeptidyl peptidase III (DPP III) is one of the most important enkephalin-degrading enzymes associated with the mammalian pain modulatory system. Here we describe the X-ray structures of human DPP III and its complex with the opioid peptide tynorphin, which rationalize the enzyme's substrate specificity and reveal an exceptionally large domain motion upon ligand binding. Microcalorimetric analyses point at an entropy-dominated process, with the release of water molecules from the binding cleft ("entropy reservoir") as the major thermodynamic driving force. Our results provide the basis for the design of specific inhibitors that enable the elucidation of the exact role of DPP III and the exploration of its potential as a target of pain intervention strategies.isothermal titration calorimetry | metallopeptidase | peptide binding | X-ray crystallography T he endogenous opioid system, composed of opioid peptides and their receptors, modulates a large number of physiological processes, such as endocrine and immune function, gastrointestinal motility, respiration, reward, stress, complex social behavior (e.g., sexual activity), vulnerability to drug addiction, and most notably the procession and transmission of pain stimuli (nociception) (1, 2). Two major types of endogenous opioid peptides are those containing enkephalin sequences at the N terminus (TyrGly-Gly-Phe-Met/Leu) (3) and, more recently identified, endomorphins 1 and 2 (Tyr-Pro-Trp/Phe-Phe-NH 2 ) (4, 5). Knowledge and control over synthesis and degradation pathways of this class of molecules is prerequisite for the development of new therapies that target pertinent physiological processes.Dipeptidyl peptidase III (DPP III), also known as enkephalinase B, is an enkephalin-degrading enzyme that cleaves dipeptides sequentially from the N termini of substrates (6). All DPP IIIs described thus far contain the unique zinc-binding motif HEXXGH characteristic of metallopeptidase family M49 (7). Enzymes from several human and animal tissues, as well as from lower eukaryotes, were purified and biochemically characterized (8, 9). DPP III is largely found as a cytosolic protein, although membrane association in rat brain and Drosophila melanogaster has been described (10, 11). The 3D structure of the yeast ortholog has recently been determined, revealing a unique protein fold with two lobes forming a wide-open substrate-binding cleft (12). The lack of structural information on peptide complexes, however, left the question of substrate specificity largely unanswered.DPP III purified from monkey brain microsomes is strongly inhibited by the neuropeptide spinorphin (Leu-Val-Val-Tyr-ProTrp-Thr), an endogenous factor isolated from bovine spinal cord that also inhibits other enkephalin-degrading enzymes, such as neutral endopeptidase (NEP, neprilysin), aminopeptidase, and angiotensin-converting enzyme (13). Because of a different mode of action compared with morphine, spinorp...

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Dipeptidyl peptidase III: a multifaceted oligopeptide N‐end cutter

Cited by 87 publications

References 126 publications

Synthesis, QSAR, and Molecular Dynamics Simulation of Amidino-substituted Benzimidazoles as Dipeptidyl Peptidase III Inhibitors

Synthesis, QSAR, and Molecular Dynamics Simulation of Amidino-substituted Benzimidazoles as Dipeptidyl Peptidase III Inhibitors

Novel Therapeutic Role for Dipeptidyl Peptidase III in the Treatment of Hypertension

Entropy-driven binding of opioid peptides induces a large domain motion in human dipeptidyl peptidase III

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