P peptide

Weidner, H., Engel, J., Fietzek, P, Peptides, Polypeptides and Proteins, Part V., John Wiley and Sons, New York 1974... 

Recently, a very interesting preparation of P-peptides has been carried out by Kanerva and coworkers through a two-step lipase-catalyzed reactions in which N-acetylated P-amino esters were first activated as 2,2,2-trifluoroethyl esters with CALB [55]. The activated esters were then used to react with a P-aminoester in the presence of CALA in dry diethylether or diisopropylether (Scheme 7.31). In this peptide synthesis, the aminoester was used in excess and the unreacted counterpart was easily separated and later recyded. 

BACE-1 (p-secretase) is one of the enzymes involved in breaking down APP to produce Ap (amyloid p-peptide, Ap40>42), the protein that eventually oligomerizes to form Ap plaques, the hallmark of Alzheimer s disease (AD). Thus an agent that... 

Mergler M, Tanner R, Gosteli J, Grogg P. Peptide synthesis by a combination of solid-phase and solution methods. I A new very acid-labile... 

The processes of both seed formation and fibril extension are dependent on temperature and on peptide concentration, with 37°C being required for establishing equilibrium within 24 h with 30 pM Pi 4o- A full description of the assay system may be found elsewhere [97,117], A 4 h reaction time is typically within the linear portion of the time course. This nucleus-dependent assay detects mainly inhibitors that are substoichiometric with the monomeric peptide, which is present at high concentration. It is relatively insensitive to inhibitors that target the monomeric peptide. Whether the inhibitors interact with the growing end of a seed or with a low abundance conformational form of the p peptide that is competent to add to the seed is difficult to determine at this time. Similar dose-response curves are obtained for Congo Red as an inhibitor with either thioflavin T (ThT) fluorescence or filtration of radioiodinated peptide readouts (Fig. 4) Caveats in the interpretation of both the ThT and radiometric filtration assays for the evaluation of putative inhibitors are discussed elsewhere [97]. 

NMR studies on polymers containing aspartic acid showed the presence of a relatively high proportion of P-peptide bonds (Andini et al 1975), i.e., the peptide bond involved the P-group of the acidic amino acid rather than the a-carboxyl group. 

The sustained attractiveness of photolabeling is apparent from its prominence in studies of y-secretase, an intramembrane protease that contributes to forming amyloid-p peptides and is a major target in Alzheimer s disease [60-62]. y-Secretase is a complex of at least four different polypeptides, and is difficult to engage with high-resolution structural methods. However, in a case of this kind that involves a known target, immunodetection of proteins can often specify the target of y-secretase inhibitor photoaffinity probes such as 19, and proteomic mass spectrometry is not needed. 

In common with the polylysine DNA-condensing peptide, the p peptide has also been shown to have nuclear localization properties. Confocal microscopy revealed that p peptide in a complex containing fluorescent lipid- and dye-labelled DNA associates with the nuclei and nucleoli of both dividing and nondividing cells within 15 minutes of exposure to the complex, thus suggesting an NLS function. However, this property was not detectable when the peptide became incorporated into a 3p-[N-(N, N -dimethylaminoethane)-carbamoyl]-cholesterol (DC-chol)/DOPE cationic liposome (149). It may be the case that the lipids may mask the critical residues. 

Fig. 10.6 Bigenic cluster (apolipoprotein E [APOE + preseirUin 1 [P iD-related serum levels of apolipoprotein E, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, amyloid-P peptide (1 2), and histamine in Alzheimer s disease. (Adapted from refs. 12 9, and 289.)...

Puglielli, L., Ellis, B.C., Saunders, A.J., Kovacs, D.M. (2003) Ceramide stabdizes P-site amyloid precursor protein-cleaving enzyme-1 and promotes amyloid P-peptide biogenesis. /. Biol. Chem., 278, 19777-19783. 

Cole, S.L., Grudzien, A., Manhart, I.O., Kelly, B.L., Oakley, H., Vassar, R. (2005) Statins cause intracellular accumulation of amyloid precursor protein, P-secretase-cleaved fragments, and amyloid P-peptide via an isoprenoid-dependent mechanism. J. Biol. Chem., 280, 18755-18770. 

Kim, W.S., Rahmant, A.S., Kamili, A., et al. (2006) Role of ABCGl and ABCAl in regulation of neuronal cholesterol efflux to apolipoprotein-E discs and suppression of amyloid-P peptide generation. J. Biol. Chem., 282, 2851-2861. 

---