アミロイド前駆体タンパク質βサイト切断酵素、βセクレターゼ

関: beta-secretase、beta-site APP cleaving enzyme

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2019/10/10 12:36:25」(JST)

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Beta-secretase 1 (BACE1), also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1, membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is encoded by the BACE1 gene.^[5]

BACE1 is an aspartic-acid protease important in the formation of myelin sheaths in peripheral nerve cells.^[6] The transmembrane protein contains two active site aspartate residues in its extracellular protein domain and may function as a dimer.

Role in Alzheimer's disease

Processing of the amyloid precursor protein

Generation of the 40 or 42 amino acid-long amyloid-β peptides that aggregate in the brain of Alzheimer's patients requires two sequential cleavages of the amyloid precursor protein (APP). Extracellular cleavage of APP by BACE1 creates a soluble extracellular fragment and a cell membrane-bound fragment referred to as C99. Cleavage of C99 within its transmembrane domain by γ-secretase releases the intracellular domain of APP and produces amyloid-β. Since gamma-secretase cleaves APP closer to the cell membrane than BACE1 does, it removes a fragment of the amyloid-β peptide. Initial cleavage of APP by α-secretase rather than BACE1 prevents eventual generation of amyloid-β.

Unlike APP and the presenilin proteins important in γ-secretase, no known mutations in the gene encoding BACE1 cause early-onset, familial Alzheimer's disease, which is a rare form of the disorder. However, levels of this enzyme have been shown to be elevated in the far more common late-onset sporadic Alzheimer's. The physiological purpose of BACE's cleavage of APP and other transmembrane proteins is unknown. BACE2 is a close homolog of BACE1 with no reported APP cleavage in vivo.

However a single residue mutation in APP reduces the ability of BACE1 to cleave it to produce amyloid-beta and reduces the risk of Alzheimer's disease and other cognitive declines.^[7]^[8]

BACE inhibitors

Drugs to block this enzyme (BACE inhibitors) in theory would prevent the buildup of beta-amyloid and (per the Amyloid hypothesis) may help slow or stop Alzheimer's disease.

For Alzheimer's disease

Several companies are in the early stages of development and testing of this potential class of treatment.^[9]^[10] In March 2008 phase I results were reported for CoMentis Inc's candidate CTS-21166.^[11]

In April 2012 Merck & Co., Inc reported phase I results for its candidate verubecestat (MK-8931).^[12] Merck began a Phase II/III trial of MK-8931 in December, 2012 estimated to be completed in July 2019.^[13] In February 2017, Merck halted its late-stage trial of verubecestat for mild to moderate Alzheimer's disease after it was reported as having "virtually no chance" of working according to an independent panel of experts. This came just three months after Eli Lilly & Co. announced its own setback with solanezumab. The results of Merck's trial of verubecestat on patients with early stage Alzheimer's are still expected in February 2019.

In September 2014 AstraZeneca and Eli Lilly and Company announced an agreement to codevelop lanabecestat (AZD3293).^[14] A pivotal Phase II/III clinical trial of lanabecestat started in late 2014,^[15] but was halted in 2018 before its planned conclusion due to poor results.^[16]

Another BACE1 inhibitor that has reached phase II trials is the Eli Lilly’s inhibitor LY2886721. The data on phase I trial were first presented at the Alzheimer’s Association International conference in 2012. Daily dosing during 2 weeks, reduced BACE1 activity by 50–75% and CSF Aβ42 by 72% (Willis et al., 2012; Bowman Rogers and Strobel, 2013). Recently, Lilly reported that the phase II trial of LY2886721 was terminated due to liver abnormalities that were found in 4 out of 45 patients (Rogers, 2013). This toxicity, however, does not have to be related to the working mechanism of the inhibitor, but can represent off-target effects as the livers of BACE1 knockout mice are normal.

Potential side effects

Tests in mice have indicated that BACE proteases, specifically BACE1, are necessary for the proper function of muscle spindles.^[17] These results raise the possibility that BACE inhibiting drugs currently being investigated for the treatment of Alzheimer's may have significant side effects related to impaired motor coordination,^[18] though BACE1 knockout mice are healthy.^[19]

Relationship to plasmepsin

BACE1 is distantly related to the pathogenic aspartic-acid protease plasmepsin, which is a potential target for future anti-malarial drugs.^[20]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000186318 - Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000032086 - Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ 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, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (Oct 1999). "Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE". Science. 286 (5440): 735–41. doi:10.1126/science.286.5440.735. PMID 10531052.
^ Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass C (Oct 2006). "Control of peripheral nerve myelination by the beta-secretase BACE1". Science. 314 (5799): 664–6. Bibcode:2006Sci...314..664W. doi:10.1126/science.1132341. PMID 16990514. Lay summary – The Scientist.
^ "Alzheimer's-fighting gene may inspire treatments". July 2012.
^ Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, Hoyte K, Gustafson A, Liu Y, Lu Y, Bhangale T, Graham RR, Huttenlocher J, Bjornsdottir G, Andreassen OA, Jönsson EG, Palotie A, Behrens TW, Magnusson OT, Kong A, Thorsteinsdottir U, Watts RJ, Stefansson K (Aug 2012). "A mutation in APP protects against Alzheimer's disease and age-related cognitive decline". Nature. 488 (7409): 96–9. Bibcode:2012Natur.488...96J. doi:10.1038/nature11283. PMID 22801501.
^ Walker LC, Rosen RF (Jul 2006). "Alzheimer therapeutics-what after the cholinesterase inhibitors?". Age and Ageing. 35 (4): 332–5. doi:10.1093/ageing/afl009. PMID 16644763.
^ Baxter EW, Conway KA, Kennis L, Bischoff F, Mercken MH, Winter HL, Reynolds CH, Tounge BA, Luo C, Scott MK, Huang Y, Braeken M, Pieters SM, Berthelot DJ, Masure S, Bruinzeel WD, Jordan AD, Parker MH, Boyd RE, Qu J, Alexander RS, Brenneman DE, Reitz AB (Sep 2007). "2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-site APP cleaving enzyme): Use of structure based design to convert a micromolar hit into a nanomolar lead". Journal of Medicinal Chemistry. 50 (18): 4261–4. doi:10.1021/jm0705408. PMID 17685503.
^ "CoMentis BACE Inhibitor Debuts". April 2008.
^ "Merck Presents Results of a Phase I Clinical Trial Evaluating Investigational BACE inhibitor MK-8931 at American Academy of Neurology". April 2012. Archived from the original on 2012-07-28.
^ "Merck Initiates Phase II/III Study of Investigational BACE Inhibitor, MK-8931, for Treatment of Alzheimer's Disease". December 2012.
^ "AstraZeneca and Lilly announce alliance to develop and commercialise BACE inhibitor AZD3293 for Alzheimer's disease". 16 Sep 2014. Retrieved 8 Oct 2014.
^ "AstraZeneca and Lilly move Alzheimer's drug into big trial". December 2014.
^ "Update on Phase III Clinical Trials of lanabecestat". 12 June 2018. Retrieved 20 June 2018.
^ Cheret, Cecil; Michael Willem; Florence R Fricker; Hagen Wende (June 2013). "Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles". EMBO Journal.
^ Pettersson, A.F.; Olsson, E.; Wahlund, L.-O. (2005). "Motor Function in Subjects with Mild Cognitive Impairment and Early Alzheimer's Disease". Dementia and Geriatric Cognitive Disorders. 19 (5–6): 299–304. doi:10.1159/000084555. ISSN 1420-8008. PMID 15785030.
^ Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, Freedman SB, Frigon NL, Games D, Hu K, Johnson-Wood K, Kappenman KE, Kawabe TT, Kola I, Kuehn R, Lee M, Liu W, Motter R, Nichols NF, Power M, Robertson DW, Schenk D, Schoor M, Shopp GM, Shuck ME, Sinha S, Svensson KA, Tatsuno G, Tintrup H, Wijsman J, Wright S, McConlogue L (Jun 2001). "BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics". Human Molecular Genetics. 10 (12): 1317–24. doi:10.1093/hmg/10.12.1317. PMID 11406613.
^ Russo I, Babbitt S, Muralidharan V, Butler T, Oksman A, Goldberg DE (Feb 2010). "Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte". Nature. 463 (7281): 632–6. Bibcode:2010Natur.463..632R. doi:10.1038/nature08726. PMC 2826791. PMID 20130644. Lay summary – sciencedaily.com.

External links

The MEROPS online database for peptidases and their inhibitors: A01.004
beta-Secretase: Molecule of the Month, by David Goodsell, RCSB Protein Data Bank
Human BACE1 genome location and BACE1 gene details page in the UCSC Genome Browser.
PDBe-KB provides an overview of all the structure information available in the PDB for Human Beta-secretase 1

English Journal

Aging process alters hippocampal and cortical secretase activities of Wistar rats.

Bertoldi K1, Cechinel LR1, Schallenberger B2, Meireles L1, Basso C1, Lovatel GA3, Bernardi L4, Lamers ML4, Siqueira IR5.
Behavioural brain research.Behav Brain Res.2017 Jan 15;317:374-381. doi: 10.1016/j.bbr.2016.09.066. Epub 2016 Oct 1.
A growing body of evidence has demonstrated amyloid plaques in aged brain; however, little attention has been given to amyloid precursor protein (APP) processing machinery during the healthy aging process. The amyloidogenic and non-amyloidogenic pathways, represented respectively by β- and α-secre
PMID 27702637

Aβ42 oligomers modulate β-secretase through an XBP-1s-dependent pathway involving HRD1.

Gerakis Y1, Dunys J1, Bauer C1, Checler F1.
Scientific reports.Sci Rep.2016 Nov 17;6:37436. doi: 10.1038/srep37436.
The aspartyl protease β-site APP cleaving enzyme, BACE1, is the rate-limiting enzyme involved in the production of amyloid-β peptide, which accumulates in both sporadic and familial cases of Alzheimer's disease and is at the center of gravity of the amyloid cascade hypothesis. In this context, unr
PMID 27853315

Neurohormetic responses of quercetin and rutin in a cell line over-expressing the amyloid precursor protein (APPswe cells).

Martín-Aragón S1, Jiménez-Aliaga KL1, Benedí J1, Bermejo-Bescós P2.
Phytomedicine : international journal of phytotherapy and phytopharmacology.Phytomedicine.2016 Nov 15;23(12):1285-1294. doi: 10.1016/j.phymed.2016.07.007. Epub 2016 Jul 22.
BACKGROUND: Plant secondary metabolites may induce adaptive cellular stress-responses in a variety of cells including neurons at the sub-toxic doses ingested by humans. Such 'neurohormesis' phenomenon, activated by flavonoids such as quercetin or rutin, may involve cell responses driven by modulatio
PMID 27765347

Japanese Journal

Novel BACE1 inhibitors containing P_1-P_1' non-natural amino acid-guanidinyl analogues

SUZUKI Kenji,HAMADA Yoshio,OGATA Megumi,HAMADA Takashi,NOJIMA Satoshi,KINOMURA Naoya,MIMOTO Tsutomu,KISO Yoshiaki
Peptide science : proceedings of the ... Japanese Peptide Symposium 2010, 258, 2011-03-01
NAID 10028238097

Design of BACE1 Inhibitors Containing 5-Nitro-Isophthalamide

NAKANISHI Tomoya,HAMADA Yoshio,YAMAGUCHI Ryoji,YAMAGUCHI Makoto,HAMADA Takashi,HIDAKA Koushi,KIMURA Tooru,KISO Yoshiaki
Peptide science : proceedings of the ... Japanese Peptide Symposium 2010, 256, 2011-03-01
NAID 10028238088

Can the substrate of an enzyme turn into its inhibitor by vastly-reduced k_<cat> value?

HAMADA Yoshio,TAGAD Harichandra D.,HAMADA Takashi,KIMURA Tooru,KISO Yoshiaki
Peptide science : proceedings of the ... Japanese Peptide Symposium 2010, 255, 2011-03-01
NAID 10028238076

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★リンクテーブル★

リンク元	「βセクレターゼ」「beta-secretase」「beta-site APP cleaving enzyme」「アミロイド前駆体タンパク質βサイト切断酵素」
関連記事	「BA」「BAC」

「βセクレターゼ」

BACE1
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1FKN, 1M4H, 1PY1, 1SGZ, 1TQF, 1UJJ, 1UJK, 1W50, 1W51, 1XN2, 1XN3, 1XS7, 1YM2, 1YM4, 2B8L, 2B8V, 2F3E, 2F3F, 2FDP, 2G94, 2HIZ, 2HM1, 2IQG, 2IRZ, 2IS0, 2NTR, 2OAH, 2OF0, 2OHK, 2OHL, 2OHM, 2OHN, 2OHP, 2OHQ, 2OHR, 2OHS, 2OHT, 2OHU, 2P4J, 2P83, 2P8H, 2PH6, 2PH8, 2Q11, 2Q15, 2QK5, 2QMD, 2QMF, 2QMG, 2QP8, 2QU2, 2QU3, 2QZK, 2QZL, 2VA5, 2VA6, 2VA7, 2VIE, 2VIJ, 2VIY, 2VIZ, 2VJ6, 2VJ7, 2VJ9, 2VKM, 2VNM, 2VNN, 2WEZ, 2WF0, 2WF1, 2WF2, 2WF3, 2WF4, 2WJO, 2XFI, 2XFJ, 2XFK, 2ZDZ, 2ZE1, 2ZHR, 2ZHS, 2ZHT, 2ZHU, 2ZHV, 2ZJH, 2ZJI, 2ZJJ, 2ZJK, 2ZJL, 2ZJM, 2ZJN, 3BRA, 3BUF, 3BUG, 3BUH, 3CIB, 3CIC, 3CID, 3CKP, 3CKR, 3DM6, 3DUY, 3DV1, 3DV5, 3EXO, 3FKT, 3H0B, 3HVG, 3HW1, 3I25, 3IGB, 3IN3, 3IN4, 3IND, 3INE, 3INF, 3INH, 3IVH, 3IVI, 3IXJ, 3IXK, 3KYR, 3L38, 3L3A, 3LHG, 3LNK, 3MSJ, 3MSK, 3MSL, 3N4L, 3NSH, 3OOZ, 3QI1, 3R1G, 3RSV, 3RTM, 3RVI, 3S2O, 3S7L, 3S7M, 3TPJ, 3TPL, 3TPP, 3TPR, 3UDH, 3UDJ, 3UDK, 3UDM, 3UDN, 3UDP, 3UDQ, 3UDR, 3UDY, 3UFL, 3UQP, 3UQR, 3UQU, 3UQW, 3UQX, 3VEU, 3VF3, 3VG1, 3VV6, 3VV7, 3ZMG, 3ZOV, 4ACU, 4ACX, 4AZY, 4B00, 4B05, 4B0Q, 4B1C, 4B1D, 4B1E, 4B70, 4B72, 4B77, 4B78, 4BEK, 4BFD, 4D83, 4D85, 4D88, 4D89, 4D8C, 4DH6, 4DI2, 4DJU, 4DJV, 4DJW, 4DJX, 4DJY, 4DPF, 4DPI, 4DUS, 4DV9, 4DVF, 4EWO, 4EXG, 4FCO, 4FGX, 4FM7, 4FM8, 4FRI, 4FRJ, 4FRK, 4FRS, 4FS4, 4FSE, 4FSL, 4GMI, 4H1E, 4H3F, 4H3G, 4H3I, 4H3J, 4HA5, 4HZT, 4I0E, 4I0F, 4I0G, 4I0H, 4I0J, 4I0Z, 4I10, 4I11, 4I12, 4I1C, 4J0T, 4J0V, 4J0Y, 4J0Z, 4J17, 4J1C, 4J1E, 4J1F, 4J1H, 4J1I, 4J1K, 4JOO, 4JP9, 4JPC, 4JPE, 4K8S, 4K9H, 4KE0, 4KE1, 3K5C, 3K5D, 3K5F, 3K5G, 3KMX, 3KMY, 3KN0, 3L58, 3L59, 3L5B, 3L5C, 3L5D, 3L5E, 3L5F, 3LPI, 3LPJ, 3LPK, 3OHF, 3OHH, 3PI5, 3QBH, 3R2F, 3RSX, 3RTH, 3RTN, 3RU1, 3SKF, 3SKG, 3U6A, 4GID, 4LXA, 4LXK, 4LXM, 3WB4, 3WB5, 4I0D, 4I0I, 4IVS, 4IVT, 4J0P, 4L7G, 4L7H, 4L7J, 4LC7, 4N00, 4PZW, 4PZX, 4R5N, 4R8Y, 4R91, 4R92, 4R93, 4R95, 4RCD, 4RCE, 4RCF, 4RRN, 4RRO, 4RRS, 4WY1, 4WY6, 4X2L, 4X7I, 4XKX, 4XXS, 4YBI, 4TRW, 4TRZ, 4ZSM, 4ZSP, 4ZSQ, 4ZSR, 4TRY, 4ZPF, 4ZPG, 5CLM, 5F01, 5EZZ, 5DQC, 5F00, 5EZX, 5HE7, 5HD0, 5HDX, 5HDV, 5HE5, 5HE4, 5HDU, 5HDZ, 5I3X, 5I3W, 5I3V, 5IE1, 5I3Y, 5ENK
Identifiers
Aliases	BACE1, ASP2, BACE, HSPC104, beta-secretase 1
External IDs	OMIM: 604252 MGI: 1346542 HomoloGene: 8014 GeneCards: BACE1
Gene location (Human)
Chr.	Chromosome 11 (human)
End	117,316,259 bp
Gene location (Mouse)
Chr.	Chromosome 9 (mouse)
End	45,864,399 bp
RNA expression pattern
	More reference expression data
Gene ontology
Molecular function	• endopeptidase activity; • amyloid-beta binding; • beta-aspartyl-peptidase activity; • protein binding; • enzyme binding; • hydrolase activity; • peptidase activity; • aspartic-type endopeptidase activity;
Cellular component	• multivesicular body; • late endosome; • endoplasmic reticulum lumen; • membrane; • plasma membrane; • cell surface; • axon; • endoplasmic reticulum; • Golgi-associated vesicle lumen; • endosome membrane; • cytoplasmic vesicle membrane; • cytoplasmic vesicle; • integral component of plasma membrane; • membrane raft; • Golgi apparatus; • integral component of membrane; • endosome; • trans-Golgi network; • lysosome; • early endosome; • synaptic vesicle; • dendrite; • neuronal cell body; • recycling endosome; • hippocampal mossy fiber to CA3 synapse; • presynapse;
Biological process	• cellular protein metabolic process; • protein catabolic process; • proteolysis; • amyloid-beta metabolic process; • membrane protein ectodomain proteolysis; • modulation of chemical synaptic transmission; • response to radiation; • response to lead ion; • positive regulation of neuron apoptotic process; • detection of mechanical stimulus involved in sensory perception of pain; • prepulse inhibition; • cellular response to copper ion; • cellular response to manganese ion; • cellular response to amyloid-beta; • regulation of synaptic vesicle exocytosis;
	Sources:Amigo / QuickGO
Orthologs
	23621
	23821
	ENSG00000186318
	ENSMUSG00000032086
	P56817
	P56818
NM_138973; NM_001207048; NM_001207049; NM_012104; NM_138971;
	NM_138972
	NM_001145947; NM_011792
NP_001193977; NP_001193978; NP_036236; NP_620427; NP_620428;
	NP_620429; NP_036236.1
	NP_001139419; NP_035922
	Wikidata
View/Edit Human	View/Edit Mouse

　　[★]

英: beta-secretase、beta-site APP cleaving enzyme、BACE
関: セクレターゼ、アミロイド前駆体タンパク質βサイト切断酵素、γセクレターゼ、アミロイド前駆タンパク質分泌酵素、β-セクレターゼ、αセクレターゼ

「beta-secretase」

　　[★]

βセクレターゼ

関: alpha-secretase、amyloid precursor protein secretase、BACE、beta-site APP cleaving enzyme、gamma-secretase、secretase

「beta-site APP cleaving enzyme」

　　[★]

アミロイド前駆体タンパク質βサイト切断酵素、βセクレターゼ

関: BACE、beta-secretase

「アミロイド前駆体タンパク質βサイト切断酵素」

　　[★]

英: beta-site APP cleaving enzyme、BACE
関: βセクレターゼ

「BA」

　　[★]

「BAC」

　　[★]

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000186318 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000032086 - Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid10531052-5] 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, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (Oct 1999). "Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE". Science. 286 (5440): 735–41. doi:10.1126/science.286.5440.735. PMID 10531052.

[pmid16990514-6] Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass C (Oct 2006). "Control of peripheral nerve myelination by the beta-secretase BACE1". Science. 314 (5799): 664–6. Bibcode:2006Sci...314..664W. doi:10.1126/science.1132341. PMID 16990514. Lay summary – The Scientist.

[APP2012-7] "Alzheimer's-fighting gene may inspire treatments". July 2012.

[Jonsson2012-8] Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, Hoyte K, Gustafson A, Liu Y, Lu Y, Bhangale T, Graham RR, Huttenlocher J, Bjornsdottir G, Andreassen OA, Jönsson EG, Palotie A, Behrens TW, Magnusson OT, Kong A, Thorsteinsdottir U, Watts RJ, Stefansson K (Aug 2012). "A mutation in APP protects against Alzheimer's disease and age-related cognitive decline". Nature. 488 (7409): 96–9. Bibcode:2012Natur.488...96J. doi:10.1038/nature11283. PMID 22801501.

[pmid16644763-9] Walker LC, Rosen RF (Jul 2006). "Alzheimer therapeutics-what after the cholinesterase inhibitors?". Age and Ageing. 35 (4): 332–5. doi:10.1093/ageing/afl009. PMID 16644763.

[pmid17685503-10] Baxter EW, Conway KA, Kennis L, Bischoff F, Mercken MH, Winter HL, Reynolds CH, Tounge BA, Luo C, Scott MK, Huang Y, Braeken M, Pieters SM, Berthelot DJ, Masure S, Bruinzeel WD, Jordan AD, Parker MH, Boyd RE, Qu J, Alexander RS, Brenneman DE, Reitz AB (Sep 2007). "2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-site APP cleaving enzyme): Use of structure based design to convert a micromolar hit into a nanomolar lead". Journal of Medicinal Chemistry. 50 (18): 4261–4. doi:10.1021/jm0705408. PMID 17685503.

[11] "CoMentis BACE Inhibitor Debuts". April 2008.

[12] "Merck Presents Results of a Phase I Clinical Trial Evaluating Investigational BACE inhibitor MK-8931 at American Academy of Neurology". April 2012. Archived from the original on 2012-07-28.

[13] "Merck Initiates Phase II/III Study of Investigational BACE Inhibitor, MK-8931, for Treatment of Alzheimer's Disease". December 2012.

[14] "AstraZeneca and Lilly announce alliance to develop and commercialise BACE inhibitor AZD3293 for Alzheimer's disease". 16 Sep 2014. Retrieved 8 Oct 2014.

[15] "AstraZeneca and Lilly move Alzheimer's drug into big trial". December 2014.

[16] "Update on Phase III Clinical Trials of lanabecestat". 12 June 2018. Retrieved 20 June 2018.

[17] Cheret, Cecil; Michael Willem; Florence R Fricker; Hagen Wende (June 2013). "Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles". EMBO Journal.

[18] Pettersson, A.F.; Olsson, E.; Wahlund, L.-O. (2005). "Motor Function in Subjects with Mild Cognitive Impairment and Early Alzheimer's Disease". Dementia and Geriatric Cognitive Disorders. 19 (5–6): 299–304. doi:10.1159/000084555. ISSN 1420-8008. PMID 15785030.

[19] Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, Freedman SB, Frigon NL, Games D, Hu K, Johnson-Wood K, Kappenman KE, Kawabe TT, Kola I, Kuehn R, Lee M, Liu W, Motter R, Nichols NF, Power M, Robertson DW, Schenk D, Schoor M, Shopp GM, Shuck ME, Sinha S, Svensson KA, Tatsuno G, Tintrup H, Wijsman J, Wright S, McConlogue L (Jun 2001). "BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics". Human Molecular Genetics. 10 (12): 1317–24. doi:10.1093/hmg/10.12.1317. PMID 11406613.

[pmid20130644-20] Russo I, Babbitt S, Muralidharan V, Butler T, Oksman A, Goldberg DE (Feb 2010). "Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte". Nature. 463 (7281): 632–6. Bibcode:2010Natur.463..632R. doi:10.1038/nature08726. PMC 2826791. PMID 20130644. Lay summary – sciencedaily.com.

v t e Proteases: aspartate proteases (EC 3.4.23)
Vertebrate	Pepsin Chymosin Renin Signal peptide peptidase Beta secretase 1 2
Pathogenic	Plasmepsin HIV-1 protease
Plant	Nepenthesin
Cathepsin	D E

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

匿名

検索

案内

案内

BACE