Highly reactive cysteine residues are part of the substrate binding site of mammalian dipeptidyl peptidases III

Abramić, Marija; Šimaga, Šumski; Osmak, Maja; Čičin‐Šain, Lipa; Vukelić, Bojana; Vlahoviček, Kristian; Dolovčak, Ljerka

doi:10.1016/s1357-2725(03)00267-x

Cited by 35 publications

(40 citation statements)

References 35 publications

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“…Additional hydrogen bonds to the five-stranded β-core as well as to Tyr-318 suggest that the correct positioning of the P1 carbonyl group close to the catalytic zinc ion is the dominant basis of the dipeptidyl peptidase specificity of this enzyme. This is supported by the fact that all four of these catalytic residues are conserved among DPP IIIs (9,35) and that a 125-fold decrease of k cat /K m was observed in the Y318F variant of human DPP III (37).…”

Section: Resultsmentioning

confidence: 88%

“…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).…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 88%

mentioning

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.

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161

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“…Based on complete genome sequence data, orthologs have also been identified in Ͼ50 species, including lower eukaryotes (yeasts) and some specific bacteria (6). In rat, DPP III is found to be expressed in various tissues with high levels in brain, liver, small intestine, and kidney (7,8). It is generally found to be a cytosolic protein, but membrane-associated DPP III in rat brain has been reported as well (9).…”

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confidence: 99%

“…Mutagenesis data on the HEXXGH motif in the rat enzyme imply that the histidine residues coordinate the metal ion and that the glutamic acid acts as a general base in peptide hydrolysis (24). A second conserved linear motif within the DPP III family, EEXR(K)AE(D), is found 22-55 amino acids toward the C terminus from the first one (6,7), and the involvement of the second glutamic acid residue in the coordination of the active-site zinc was shown (24). Apart from that, little is known about the molecular mechanism of action of this hydrolase because no experimental three-dimensional structure of DPP III enzymes is available.…”

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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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“…DPP III is a monozinc exopeptidase that hydrolyzes dipeptides from the N-terminal of its substrates consisting of three or more amino acids [13]. In mammalian tissues, it is broadly distributed and thought to contribute in the final steps of normal intracellular protein catabolism [14]. There are strong indications of its role in the endogenous pain-modulation system [15] as well as in the endogenous defense against oxidative stress [16].…”

Section: Introductionmentioning

confidence: 99%

The effect of 17β-estradiol on the expression of dipeptidyl peptidase III and heme oxygenase 1 in liver of CBA/H mice

Šafranko

Sobočanec

Šarić

et al. 2014

J Endocrinol Invest

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Abstract:Background 17β-estradiol (E2) has well established cardioprotective, antioxidant and neuroprotective role and exerts a vast range of biological effects in both sexes. Dipeptidyl peptidase III (DPP III) is protease involved as activator in Keap1-Nrf2 signaling pathway, which is important in cellular defense to oxidative and electrophilic stress. It is generally accepted that oxidative stress is crucial in promoting liver diseases.Objective To examine the effect of E2 on the expression of DPP III and heme oxygenase 1 (HO-1) in liver of adult CBA/H mice of both sexes. We have corrected all the grammar and syntax errors throughout the Manuscript, according to the Reviewer's suggestions. Since there were many of the typographic errors and places where we had to omit/change/erase some words, we did not find relevant to specifically mark them, as they were only single letters or parts of the letters. This is the reason why Manuscript is without any underlined word/part of the sentence. We hope that the Reviewer will find this appropriate for the revised version of the Manuscript. But if the Reviewer wants us to mark all typo changes in the Manuscript, please let me know. Some of the "major" changes are also corrected, such as conclusion section of the abstract, and modification of the sentences regarding immunohistochemistry, according to the reviewer's suggestion. Also, the fold-change instead of f.c. is now on y axis of all the graphs. Please let me know if the reviewer is not able to see the corrected axis. Also, all the abbreviations are now next to each experimental group.Thank you very much in advance, Dr. Sandra Sobocanec 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 AbstractBackground 17β-estradiol (E 2 ) has well established cardioprotective, antioxidant and

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Highly reactive cysteine residues are part of the substrate binding site of mammalian dipeptidyl peptidases III

Cited by 35 publications

References 35 publications

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

The effect of 17β-estradiol on the expression of dipeptidyl peptidase III and heme oxygenase 1 in liver of CBA/H mice

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