Thioxo amino acid pyrrolidides and thiazolidides: new inhibitors of proline specific peptidases

Stöckel-Maschek, Angela; Mrestani-Klaus, Carmen; Stiebitz, B.; Demuth, Hans‐Ulrich; Neubert, Klaus

doi:10.1016/s0167-4838(00)00054-6

Cited by 41 publications

(32 citation statements)

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“…The inhibition constants reported clearly indicate the effect of the compounds on DPIV-like activity and correlates with previous reports [34].…”

Section: Discussionsupporting

confidence: 91%

“…This correlates well with what has been reported for DPIV in the literature [31,33]. Similarly, Ile-Thiazolidide and IlePyrrolidide have both been reported as specific DPIV inhibitors, which provides an important tool in elucidating the structure and function of the proteolytic enzyme [34]. Both compounds proved to be very specific inhibitors of the purified activity.…”

Section: Discussionsupporting

confidence: 89%

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The purification and characterisation of novel dipeptidyl peptidase IV-like activity from bovine serum

Buckley

Collins

O’Connor

2004

The International Journal of Biochemistry & Cell Biology

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“…The inhibition constants reported clearly indicate the effect of the compounds on DPIV-like activity and correlates with previous reports [34].…”

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 89%

The purification and characterisation of novel dipeptidyl peptidase IV-like activity from bovine serum

Buckley

Collins

O’Connor

2004

The International Journal of Biochemistry & Cell Biology

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“…#P Ͻ 0.05, P32/98 ϩ forskolin/IBMX vs. forskolin/IBMX alone. structural similarity of thiazolidine to proline, P32/98 (isoleucine-thiazolidine) is a dipeptide product analog with high affinity for binding to the active site and inhibiting DPPIV (38,41). Diprotin A and P32/98 are respectively 10 and 80 times more potent for inhibiting DPPIV than for inhibiting the functionally related proline-specific protease DPPII (29,41).…”

Section: Discussionmentioning

confidence: 99%

Role of dipeptidyl peptidase IV in regulating activity of Na⁺/H⁺exchanger isoform NHE3 in proximal tubule cells

Girardi¹,

Knauf²,

Demuth³

et al. 2004

American Journal of Physiology-Cell Physiology

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103

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We recently reported that NHE3 exists in multimeric complexes with dipeptidyl peptidase IV (DPPIV) in renal brush-border membranes. To examine the possible role of DPPIV in modulating NHE3 activity, we evaluated whether specific competitive inhibitors that bind to the active site of DPPIV affect NHE3 activity in the OKP line of opossum kidney proximal tubule cells. The DPPIV inhibitors diprotin A and P32/98 significantly reduced NHE3 activity, whereas the inactive isomer P34/98 had no effect. DPPIV inhibitors did not reduce the activity of another brush-border transport process, Na-phosphate cotransport. Effects of DPPIV inhibitors on NHE3 activity were not associated with detectable changes in amount or apparent molecular weight of NHE3 or in NHE3 surface expression. To investigate the signaling mechanisms involved in modulation of NHE3 activity by DPPIV, we used inhibitors of protein kinase pathways known to regulate NHE3. Whereas the PKA inhibitor H-89 failed to block the effect of DPPIV inhibitors, the tyrosine kinase inhibitor genistein alone caused a decrement in NHE3 activity very similar in magnitude to that caused by P32/98. We also found that the effects of genistein and P32/98 on NHE3 activity were not additive. In contrast, forskolin/ IBMX and P32/98 had additive inhibitory effects on NHE3 activity. These findings suggested that the effect of DPPIV inhibitors to reduce NHE3 activity results from inhibition of a tyrosine kinase signaling pathway rather than by activation of PKA. We conclude that DPPIV plays an unexpected role in modulating Na ϩ /H ϩ exchange mediated by NHE3 in proximal tubule cells. sodium/hydrogen exchange; diprotin A; P32/98; tyrosine kinase NA ϩ

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“…Steady State Kinetic Analyses-For continuous assay of LeAPP2 activity, H-Lys(Abz)-Pro-Pro-pNA (Bachem; Bubendorf, Switzerland) was used as an internally quenched fluorogenic substrate (31). Unless stated otherwise, the assays contained 125 ng of the GST⅐APP2 fusion protein and 50 M of the substrate in a total volume of 500 l of 0.1 M Tris-HCl pH 7.5, 4 mM MnCl 2 , and the fluorescence was recorded in a Kontron SFM 25 fluorimeter ( ex : 320 nm, em : 411 nm).…”

Section: Methodsmentioning

confidence: 99%

Cloning, Expression, and Characterization of Tomato (Lycopersicon esculentum) Aminopeptidase P

Hauser

Strassner

Schaller

2001

Journal of Biological Chemistry

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A cDNA (LeAPP2) was cloned from tomato coding for a 654 amino acid protein of 72.7 kDa. The deduced amino acid sequence was >40% identical with that of mammalian aminopeptidase P, a metalloexopeptidase. All amino acids reported to be important for binding of the active site metals and catalytic activity, respectively, were conserved between LeAPP2 and its mammalian homologues. LeAPP2 was expressed in Escherichia coli in N-terminal fusion with glutathione S-transferase and was purified from bacterial extracts. LeAPP2 was verified as an aminopeptidase P, hydrolyzing the amino-terminal Xaa-Pro bonds of bradykinin and substance P. LeAPP2 also exhibited endoproteolytic activity cleaving, albeit at a reduced rate, the internal -Phe-Gly bond of substance P. Proline is unique among the proteinogenic amino acids in that its side chain is bonded to both the ␣-carbon and the amino group. The resulting cyclic structure imposes conformational restraints on proline-containing peptides relevant for structure and function of many physiologically important biomolecules. A key role for proline residues is the protection against nonspecific proteolytic degradation. Hence proline is frequently found and conserved in peptide hormones, neuropeptides, and growth factors (1-3). Many bioactive polypeptides share a Xaa-Pro motif at their N termini shielding them against nonspecific N-terminal degradation. The degradation of these peptides requires proteases with specificity for the Xaa-Pro motif including proline-selective dipeptidases (dipeptidyl peptidases II and IV, cleaving the post-Pro bond) and aminopeptidase P (Xaa-Pro aminopeptidase, cleaving the pre-Pro bond). Cleavage of the Xaa-Pro motif by either one of these peptidases may initiate the proteolytic degradation/inactivation of the peptide or may result in an altered bioactivity (2-4).Aminopeptidase P (APP, 1 EC 3.4.11.9) was first isolated from Escherichia coli (5) and has subsequently been characterized from many microbial and mammalian sources (reviewed in Ref. 4). Mammalian APPs are now known to comprise at least two distinct forms, a cytosolic form and a membrane-bound form attached to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor (6 -14). APPs hydrolyze the peptide bond between any amino acid and a penultimate proline residue at the N termini of oligopeptide and protein substrates. A free amino group is required at the N terminus and the scissile bond must be in the trans configuration (15). The hydrolysis of dipeptides is very slow compared with the hydrolysis of longer chains, indicating the existence of a third subsite for substrate binding, which was confirmed for E. coli and mammalian APPs (10, 15). Likely physiological substrates of APP include bradykinin, substance P, and peptide-YY (15-18), and APP has been implicated in the regulation of cardiovascular and pulmonary functions in vivo (19 -21).In higher plants, only very few peptides with hormone-like functions are presently known (22, 23), but a more general role for peptides as signal molecu...

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Thioxo amino acid pyrrolidides and thiazolidides: new inhibitors of proline specific peptidases

Cited by 41 publications

References 50 publications

The purification and characterisation of novel dipeptidyl peptidase IV-like activity from bovine serum

The purification and characterisation of novel dipeptidyl peptidase IV-like activity from bovine serum

Role of dipeptidyl peptidase IV in regulating activity of Na⁺/H⁺exchanger isoform NHE3 in proximal tubule cells

Cloning, Expression, and Characterization of Tomato (Lycopersicon esculentum) Aminopeptidase P

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Thioxo amino acid pyrrolidides and thiazolidides: new inhibitors of proline specific peptidases

Cited by 41 publications

References 50 publications

The purification and characterisation of novel dipeptidyl peptidase IV-like activity from bovine serum

The purification and characterisation of novel dipeptidyl peptidase IV-like activity from bovine serum

Role of dipeptidyl peptidase IV in regulating activity of Na+/H+exchanger isoform NHE3 in proximal tubule cells

Cloning, Expression, and Characterization of Tomato (Lycopersicon esculentum) Aminopeptidase P

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Role of dipeptidyl peptidase IV in regulating activity of Na⁺/H⁺exchanger isoform NHE3 in proximal tubule cells