Increase in the septal vasopressin content by prolyl endopeptidase inhibitors in rats

Miura, Naoyoshi; Shibata, Shigenobu; Watanabe, Soichi

doi:10.1016/0304-3940(95)11821-d

Cited by 39 publications

(26 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…23,[25][26][27] In general, peptide aldehyde analogs of the acyl portion of protease substrates are potent competitive inhibitors of serine and sulfhydryl proteases, because the aldehyde interacts with the active site serine to form a tetrahedral transition-state analog. Based on this, S. Wilk and M. Orlowski synthesized Z-prolyl-prolinal (K i 14 nM).…”

Section: Discussionmentioning

confidence: 99%

Prolyl Oligopeptidase Is Involved in Release of the Antifibrotic Peptide Ac-SDKP

et al. 2004

View full text Add to dashboard Cite

Abstract-N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a ubiquitous tetrapeptide hydrolyzed almost exclusively by angiotensin-converting enzyme (ACE). Chronic treatment with Ac-SDKP decreases cardiac and renal fibrosis and inflammatory cell infiltration in hypertensive rats. However, very little is known about endogenous synthesis of Ac-SDKP, except that thymosin-␤ 4 may be the most likely precursor. Two enzymes are potentially able to release Ac-SDKP from thymosin-␤ 4 : prolyl oligopeptidase (POP) and endoproteinase asp-N. POP is widely present and active in several tissues and biological fluids, whereas endoproteinase asp-N appears to be lacking in mammals. Therefore, we hypothesized that POP is the main enzyme involved in synthesizing the antifibrotic peptide Ac-SDKP. We investigated in vitro and in vivo production of Ac-SDKP. Using kidney cortex homogenates, we observed that Ac-SDKP was generated in a time-dependent manner in the presence of exogenous thymosin-␤ 4 , and this generation was significantly inhibited by several POP inhibitors (POPi), Z-prolyl-prolinal, Fmoc-prolyl-pyrrolidine-2-nitrile, and S17092. Long-term administration of S17092 in rats significantly decreased endogenous levels of Ac-SDKP in the plasma (from 1.76Ϯ0.2 to 1.01Ϯ0.1 nM), heart (from 2.31Ϯ0.21 to 0.83Ϯ0.09 pmol/mg protein), and kidneys (from 5.62Ϯ0.34 to 2.86Ϯ0.76 pmol/mg protein). As expected, ACE inhibitors significantly increased endogenous levels of Ac-SDKP in the plasma, heart, and kidney, whereas coadministration of POPi prevented this increase. We concluded that POP is the main enzyme responsible for synthesis of the antifibrotic peptide

show abstract

Section: Discussionmentioning

confidence: 99%

Prolyl Oligopeptidase Is Involved in Release of the Antifibrotic Peptide Ac-SDKP

et al. 2004

View full text Add to dashboard Cite

show abstract

“…Previous in vivo studies have shown that administration of selective PEP inhibitors provokes a significant increase in the cerebral concentration of SP (Toide et al, 1996;Bellemère et al, 2003), ␣-MSH (Bellemère et al, 2003), AVP (Miura et al, 1995;Toide et al, 1996), and TRH (Shinoda et al, 1995;Toide et al, 1996). To determine whether PEP may be actually involved in the metabolism of these neuropeptides, the localization of PEPexpressing cells has been compared with the distribution of the mRNAs encoding the SP receptors NK1 and NK3, the ␣-MSH receptors MC3 and MC4, the AVP receptors V1a and V1b, and the TRH receptors TRH-R1 and TRH-R2 (Table 1).…”

Section: Involvement Of Pep In Neuropeptide Catabolismmentioning

confidence: 99%

Localization of the mRNA encoding prolyl endopeptidase in the rat brain and pituitary

Bellemère

Vaudry

Mounien

et al. 2004

J of Comparative Neurology

View full text Add to dashboard Cite

Prolyl endopeptidase (EC 3.4.21.26, PEP), a serine protease that hydrolyzes peptides at the carboxyl side of proline residues, is involved in the breakdown of several proline-containing neuropeptides and, thus, may contribute to the regulation of behavioral activities. In this study, the distribution of PEP mRNA was investigated in the central nervous system and pituitary of rat by means of quantitative reverse transcriptase-polymerase chain reaction analysis and in situ hybridization histochemistry. High densities of PEP transcripts were found in cerebellar Purkinje and granule cells, within most hypothalamic nuclei, in pyramidal neurons of the Ammon's horn, in granule cells of the dentate gyrus, and within the basolateral complex of the amygdala. Moderate levels of PEP mRNA were observed in layers 3-5 of the cerebral cortex, the anterior thalamic group, the septal region, the substantia nigra, the magnocellular neurons of the red nucleus, and the motor nuclei of the cranial nerves. Low concentrations of PEP mRNA were detected in the deep mesencephalic nuclei, the reticular formation, the pretectum, and the tectum. A high density of PEP mRNA was found in the intermediate and the anterior lobes of the pituitary, while the neural lobe was devoid of labeling. In several brain regions, the distribution pattern of PEP mRNA overlapped that of various neuropeptide receptors, suggesting that PEP is actually involved in the inactivation of regulatory neuropeptides.

show abstract

“…Prolyl oligopeptidase (EC 3.4.21.26) is implicated in the metabolism of peptide hormones and neuropeptides (18 -20). Because specific inhibitors relieve scopolamine-induced amnesia (21)(22)(23)(24), the enzyme is of pharmaceutical interest. The activity of prolyl oligopeptidase has also been associated with depression (25,26) and blood pressure regulation (27 The three-dimensional structure determination of prolyl oligopeptidase has revealed that the carboxyl-terminal peptidase domain of the enzyme displays an ␣/␤ hydrolase fold and that its catalytic triad (Ser 554 , His 680 , Asp 641 ) is covered by the central tunnel of an unusual ␤-propeller (28).…”

mentioning

confidence: 99%

Substrate-dependent Competency of the Catalytic Triad of Prolyl Oligopeptidase

Szeltner¹,

Rea²,

Juhász³

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Prolyl oligopeptidase, a serine peptidase unrelated to trypsin and subtilisin, is implicated in memory disorders and is an important target of drug design. The catalytic competence of the Asp 641 residue of the catalytic triad (Ser 554 , Asp 641 , His 680 ) was studied using the D641N and D641A variants of the enzyme. Both variants displayed 3 orders of magnitude reduction in k cat /K m for benzyloxycarbonyl-Gly-Pro-2-naphthylamide. Using an octapeptide substrate, the decrease was 6 orders of magnitude, whereas with Z-Gly-Pro-4-nitrophenyl ester there was virtually no change in k cat /K m . This indicates that the contribution of Asp 641 is very much dependent on the substrate-leaving group, which was not the case for the classic serine peptidase, trypsin. The rate constant for benzyloxycarbonyl-Gly-Pro-thiobenzylester conformed to this series as demonstrated by a method designed for monitoring the hydrolysis of thiolesters in the presence of thiol groups. Alkylation of His 680 with Z-Gly-Pro-CH 2 Cl was concluded with similar rate constants for wild-type and D641A variant. However, kinetic measurements with Z-Gly-Pro-OH, a product-like inhibitor, indicated that the His 680 is not accessible in the enzyme variants. Crystal structure determination of these mutants revealed subtle perturbations related to the catalytic activity. Many of these observations show differences in the catalysis between trypsin and prolyl oligopeptidase.

show abstract

Increase in the septal vasopressin content by prolyl endopeptidase inhibitors in rats

Cited by 39 publications

References 25 publications

Prolyl Oligopeptidase Is Involved in Release of the Antifibrotic Peptide Ac-SDKP

Prolyl Oligopeptidase Is Involved in Release of the Antifibrotic Peptide Ac-SDKP

Localization of the mRNA encoding prolyl endopeptidase in the rat brain and pituitary

Substrate-dependent Competency of the Catalytic Triad of Prolyl Oligopeptidase

Contact Info

Product

Resources

About