Tumor cytosol dipeptidyl peptidase III activity is increased with histological aggressiveness of ovarian primary carcinomas

Šimaga, Šumski; Babić, Damir; Osmak, Maja; Šprem, Marina; Abramić, Marija

doi:10.1016/s0090-8258(03)00462-1

Cited by 52 publications

(52 citation statements)

References 39 publications

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“…Recently it was revealed that human DPP III participates in the endogenous defense against oxidative stress, being an activator in the Keap1-Nrf2 signaling pathway 6,7 . Pathophysiological roles of human DPP III are indicated in cataractogenesis 8 , malignant growth 9,10 and influenza virus infection 11 . He et al reported that DPP III is a member of a six-gene signature that accurately predicts breast cancer patient survival 12 .…”

Section: Introductionmentioning

confidence: 99%

Novel dipeptidyl hydroxamic acids that inhibit human and bacterial dipeptidyl peptidase III

Cvitešić¹,

Sabljić

Makarević³

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Human dipeptidyl peptidase III (hDPP III), a zinc-metallopeptidase of the family M49, is an activator of the Keap1-Nrf2 cytoprotective pathway involved in defense against oxidative stress. Pathophysiological roles of DPP III have not been elucidated yet, partly due to the lack of specific inhibitors. We showed that substrate analog H-Tyr-Phe-NHOH is a strong competitive inhibitor of hDPP III, while H-Tyr-Gly-NHOH expresses much weaker inhibition. To investigate the effects of amino acid substitutions in inhibitor P1 position, we synthesized three new dipeptidyl hydroxamates and examined their influence on the activity of hDPP III and DPP III from the human gut symbiont Bacteroides thetaiotaomicron. The extent of inhibition of hDPP III, but not of bacterial enzyme, was dependent on the amino acid in P1. H-Phe-Phe-NHOH is recognized as one of the strongest inhibitors of hDPP III (K i ¼ 0.028 mM), and H-Phe-Leu-NHOH discriminated between human and bacterial ortholog of the M49 family.

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Section: Introductionmentioning

confidence: 99%

Novel dipeptidyl hydroxamic acids that inhibit human and bacterial dipeptidyl peptidase III

Cvitešić¹,

Sabljić

Makarević³

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…It is overexpressed in ovarian primary carcinomas, the aggressiveness of which is correlated with enhanced DPP III activity (21). In a recent genomic screen, it was also identified as a potential activator of the antioxidant response element by inducing nuclear translocation of NF-E2-related factor 2 (22).…”

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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.

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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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“…Recently, DPP III has also obtained much attention because of its overexpression in ovarian malignant tissues, and this property can be further exploited as a potential biomarker for carcinoma (20). Furthermore, a role for DPP III has been implied in cataractogenesis and endogenous defense mechanisms against oxidative stress (21,22).…”

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confidence: 99%

The First Structure of Dipeptidyl-peptidase III Provides Insight into the Catalytic Mechanism and Mode of Substrate Binding

Baral

Jajčanin-Jozić

Deller

et al. 2008

Journal of Biological Chemistry

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111

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Dipeptidyl-peptidases III (DPP III) are zinc-dependent enzymes that specifically cleave the first two amino acids from the N terminus of different length peptides. In mammals, DPP III is associated with important physiological functions and is a potential biomarker for certain types of cancer. Here, we present the 1.95-Å crystal structure of yeast DPP III representing the prototype for the M49 family of metallopeptidases. It shows a novel fold with two domains forming a wide cleft containing the catalytic metal ion. DPP III exhibits no overall similarity to other metallopeptidases, such as thermolysin and neprilysin, but zinc coordination and catalytically important residues are structurally conserved. Substrate recognition is accomplished by a binding site for the N terminus of the peptide at an appropriate distance from the metal center and by a series of conserved arginine residues anchoring the C termini of different length substrates.

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Tumor cytosol dipeptidyl peptidase III activity is increased with histological aggressiveness of ovarian primary carcinomas

Cited by 52 publications

References 39 publications

Novel dipeptidyl hydroxamic acids that inhibit human and bacterial dipeptidyl peptidase III

Novel dipeptidyl hydroxamic acids that inhibit human and bacterial dipeptidyl peptidase III

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

The First Structure of Dipeptidyl-peptidase III Provides Insight into the Catalytic Mechanism and Mode of Substrate Binding

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