Z-Pro-Pro-aldehyde-dimethyl acetal

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Z-Pro-Pro-aldehyde-dimethyl acetal
* Please kindly note that our products are not to be used for therapeutic purposes and cannot be sold to patients.

Z-Pro-Pro-aldehyde-dimethyl acetal is a potent inhibitor of prolyl endopeptidase (PEP), a cytoplasmic serine endoprotease (IC50= 120 μM).

Category
Peptide Inhibitors
Catalog number
BAT-014996
CAS number
170116-63-9
Molecular Formula
C20H28N2O5
Molecular Weight
376.45
IUPAC Name
benzyl (2S)-2-[(2S)-2-(dimethoxymethyl)pyrrolidine-1-carbonyl]pyrrolidine-1-carboxylate
Synonyms
Z-PP-CHO
Appearance
White Powder
Purity
>98%
Density
1.2±0.1 g/cm3
Boiling Point
522.5±50.0 °C at 760 mmHg
InChI
InChI=1S/C20H28N2O5/c1-25-19(26-2)17-11-7-12-21(17)18(23)16-10-6-13-22(16)20(24)27-14-15-8-4-3-5-9-15/h3-5,8-9,16-17,19H,6-7,10-14H2,1-2H3/t16-,17-/m0/s1
InChI Key
FWRIGQASSHUNQU-IRXDYDNUSA-N
Canonical SMILES
COC(C1CCCN1C(=O)C2CCCN2C(=O)OCC3=CC=CC=C3)OC
1. Prolyl endopeptidase is revealed following SILAC analysis to be a novel mediator of human microglial and THP-1 cell neurotoxicity
Andis Klegeris, et al. Glia. 2008 Apr 15;56(6):675-85. doi: 10.1002/glia.20645.
Reactive microglial cells may exacerbate the pathology in some neurodegenerative disorders. Supernatants of stimulated human microglial cells, or their surrogate THP-1 cells, are lethal to cultured human neuroblastoma SH-SY5Y cells. To explore this neurotoxicity, we examined the spectrum of proteins generated by THP-1 cells using the technique of stable isotope labeling by amino acids in cell culture (SILAC). Unstimulated cells were grown in medium with light L-[(12)C(6)] arginine while cells stimulated by lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma) were grown in medium with heavy L-[(13)C(6)] arginine. Proteins isolated from the media were digested with trypsin, and relative concentrations of generated peptides determined by mass spectrometry. More than 1,500 proteins or putative proteins were identified. Of these, 174 were increased and 189 decreased by more than twofold in the stimulated cell supernatant. We selected one upregulated protein, prolyl endopeptidase (PEP), for further investigation of its potential contribution to neurotoxicity. We first confirmed its upregulation by comparing its enzymatic activity in stimulated and unstimulated cell supernatants. We then evaluated two specific PEP inhibitors, Boc-Asn-Phe-Pro-aldehyde and Z-Pro-Pro-aldehyde-dimethyl acetal, for their potential to reduce toxicity of stimulated THP-1 cell and human microglia supernatants towards SH-SY5Y cells. We found both to be partially protective in a concentration-dependent manner. Inhibition of PEP may be a therapeutic approach to neurodegenerative disorders including Alzheimer and Parkinson diseases.
2. Overexpression of prolylcarboxypeptidase enhances plasma prekallikrein activation on Chinese hamster ovary cells
Z Shariat-Madar, E Rahimy, F Mahdi, A H Schmaier Am J Physiol Heart Circ Physiol. 2005 Dec;289(6):H2697-703. doi: 10.1152/ajpheart.00715.2005. Epub 2005 Aug 19.
Plasma prekallikrein (PK) complexes with its receptor, high-molecular-weight kininogen (HK), on human umbilical vein endothelial cells (HUVEC). When assembled on endothelial cells, PK is activated to plasma kallikrein independent of factor XIIa by the serine protease prolylcarboxypeptidase (PRCP, Km= 9 nM). PRCP was shown to be a PK activator when isolated from HUVEC (J Biol Chem 277: 17962-17969, 2002) and produced as a recombinant protein (Blood 103: 4554-4561, 2004). To additionally confirm that human PRCP is a physiological PK activator, PRCP was overexpressed in Chinese hamster ovary (CHO) cells. CHO cells were transfected with full-length PRCP under the control of a cytomegalovirus promoter, and CHO recombinant PRCP was expressed as a fusion protein with COOH-terminal enhanced green fluorescence protein (EGFP). The presence of recombinant PRCP in transfected CHO cells was detected by real-time RT-PCR, immunoblot, and immunoprecipitation. PRCP mRNA and PK activation were two- to threefold higher in transfected than in control CHO cells. The increase in PRCP-induced PK activation in the transfected CHO cells paralleled the increase in PRCP antigen expression, as determined by anti-PRCP and anti-green fluorescence protein antibodies. PK activation of the transfected cells was blocked by small interfering RNA to PRCP. Anti-PRCP antibody and Z-Pro-Pro-aldehyde dimethyl acetate also blocked PK activation (IC50= 0.01 and 7.0 mM, respectively). Localization of PRCP in intact cells observed via confocal microscopy and flow cytometry also confirmed overexpression of PRCP on the external membrane. These investigations independently confirm that PRCP is expressed on cell membranes and that PRCP expression increases PK activation.
3. Identification and characterization of prolylcarboxypeptidase as an endothelial cell prekallikrein activator
Zia Shariat-Madar, Fakhri Mahdi, Alvin H Schmaier J Biol Chem. 2002 May 17;277(20):17962-9. doi: 10.1074/jbc.M106101200. Epub 2002 Feb 5.
Our recent investigations have postulated a human umbilical vein endothelial cell (HUVEC)-associated prekallikrein activator (PKA). When prekallikrein (PK) assembles on high molecular weight kininogen on HUVEC, PK is activated to kallikrein. PKA was found in the 15,800 x g pellet of HUVEC lysates using an assay that measures PK activation only when bound to high molecular weight kininogen linked to microtiter plates. Sequential DEAE, wheat germ lectin affinity, and hydroxyapatite chromatography resulted in four protein bands on SDS-PAGE. One protein in the 73-kDa band was identified by amino acid sequencing as prolylcarboxypeptidase (PRCP). On gel filtration, PKA activity was a single homogenous peak identical in migration to the 73-kDa immunoblot of PRCP. Anti-PRCP inhibits PKA activity and PK activation on HUVEC. Purified PKA was blocked by diisopropyl fluorophosphate (1 mm), phenylmethylsulfonyl fluoride (3 mm), leupeptin (100 microm), antipain (IC(50) = 2 microm), HgCl(2) (IC(50) = 500 microm), Z-Pro-Pro-aldehyde-dimethyl acetate (IC(50) = 1 microm), and corn trypsin inhibitor (IC(50) = 40 nm). PKA did not correct the coagulant defect in factor XII deficient plasma, was purified from HUVEC cultured in factor XII-deficient serum, was not detected by antibody to factor XII, did not activate FXI, and was not inhibited by a neutralizing antibody to FXII. Angiotensin II (IC(50) = 2 microm) or bradykinin (IC(50) = 100 microm), but not angiotensin II-(1-7) or bradykinin(1-5), and the prolyl oligopeptidase inhibitor Fmoc-Ala-Pyr-CN (IC(50) = 50 nm) also blocked purified PKA activation of PK. The K(m) of PK activation by PRCP is 6.7 nm. PRCP antigen is present on the membrane of fixed but not permeabilized HUVEC. PRCP appears to be a HUVEC-associated PK activator.

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