Aspartic proteases 3-secretase

Vassar, R., Bennett, B. D., Babu-Khan, S. et al. P-secretase cleavage of Alzheimer s amyloid precusor protein by the transmembrane aspartic protease BACE. Science 286 735-741, 1999. 

Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., Luo, Y., Fisher, S., et al. (1999). Beta-secretase cleavage of Alzheimer s amyloid precursor protein by the transmembrane aspartic protease BAGE. Science 286, 735—741. 

Weihofen, A., Lemberg, M.K., Friedmann, E., et al. (2003) Targeting presenilin-type aspartic protease signal peptide peptidase with y-secretase inhibitors. J. Biol. Chem., 278, 16528-16533. 

Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, File J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G Citron M. (1999) Beta-secretase cleavage of Alzheimer s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286 735-741. 

Lin, X., Koelsch, G, Wu, S., Downs, D., Dashti, A., Tang, J. Human aspartic protease memapsin 2 cleaves the (3-secretase site of (3-amyloid precursor protein. Proc. Natl. Acad. Sci. USA 2000, 97, 1456-1460. 

The pharmacological evidence compiled for y-secretase is indicative of the activity of an aspartic protease requiring at least one additional cofactor. The location of the active site within the membrane makes y-secretase quite unique. Currently, there is only one precedent for a similar, tricky enzyme, signal peptidase, which shares several features and most of the problems associated with inner-membrane location [25]. It will not, unfortunately, be easy to isolate and purify the membrane-stabilized protease while retaining its activity. It has, therefore, so far escaped crystallization and X-ray structure determination. Mutation analysis of the two conserved aspartic acids of all presenilins supports their key role in y-secretase... 

More recently, the principles for designing inhibitors of aspartic proteases have been applied to the design of inhibitors of j8-secretase (BACEor Memapsin-2)as potential agents for treating or preventing Alzheimer s disease (95, 96). Both statine-derived inhibitors (43) and hydro3 ethylene-derived BACE inhibitors have been reported (Fig. 15.21)07,98). A crystal structure of (44) bound to j3-secretase has been reported (99). As expected, the hy-... 

More recently, the substrate specificity of /9-secretase has been explored and compared with that of other aspartic proteases using a range of dodecameric substrates based mainly on the j3 -cleavage site of APP (67). The substrate recognition site of /3-secretase extended over several amino acids, and /9-secretase accepted a wide range of peptidic substrates. In common with other aspartic proteases, /9-secretase prefers a leucine residue at position PI. However, unlike these enzymes, /3-sccrctasc accepts polar or even acidic residues at positions PI and P2. and prefers bulky hydrophobic residues, preferably valine, at position P3. 

Hussain I, Powell DJ, Howlett DR, Tew DG, Meek TD, et al. 1999. Identification of a novel aspartic protease (Asp2) as beta-secretase. Mol. Cell. Neurosci. 14 419-27... 

Gruninger-Leitch F, Schlatter D, Kung E, Nelbock P, Dobeli H. 2002. Substrate and inhibitor profile of BACE (beta-secretase) and comparison with other mammalian aspartic proteases. J. Biol. Chem. 277 4687-93... 

Alzheimer s disease is characterized by plaques in the brain consisting primarily of the 40-42 amino acid amyloid / -peptide (A/ ) [258]. AfS derives from proteolysis of the amyloid precursor protein (APP) by the fS and y sec-retases to create the N and C-termini of the peptide respectively [259]. The / -secretase has recently been identified as a 501 amino-acid transmembrane protein by several research groups [260-263], The enzyme, variously named BACE, memapsin2, and Asp2, is an aspartic protease related to pepsin, cathepsin D, and renin, with all the properties expected of the /i-sccrctasc. 

M. A. Jarosinski, A. L. Biere, E. Curran, T. Burgess, J. C. Louis, F. Collins, J. Treanor, G. Rogers, M. Citron, beta-Secretase Cleavage of Alzheimer s Amyloid Precursor Protein by the Transmembrane Aspartic Protease BACE. Science. 1999, 286, 735-741. 

Hussain I, Powell D, Hewlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, Smith TS, Simmons DL, Walsh FS, Dingwall C, Christie G (1999) Identification of a novel aspartic protease (Asp2) as P-secretase. Mol Cell Neurosci 14 419-427 Ikemoto A, Nitta A, Furukawa S, Ohishi M, Nakamura A, Fuji Y, Okuytuna H (2000) Dietary n-3 fatty acid deficiency decreases nerve growth factor content in rat hippocampus. Neurosci Lett 285 99-102... 

Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N Jr, Frautschy SA, Cole GM (2005) A diet enriched with the omega-3 fatty add docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J Neurosd 25 3032-3040 Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J (2000) Human aspartic protease memapsin 2 cleaves the )-secretase site of P-amyloid precursor protein. Proc Natl Acad Sci USA 97 1456-1460... 

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