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{{STRUCTURE_4ivs| right| PDB=4ivs | SCENE= |CAPTION= Crystal structure of BACE1 with its inhibitor, [[4ivs]] }} | {{STRUCTURE_4ivs| right| PDB=4ivs | SCENE= |CAPTION= Crystal structure of BACE1 with its inhibitor, [[4ivs]] }} | ||
__TOC__ | __TOC__ | ||
== Introduction == | == Introduction == | ||
BACE1, which stand for β-site of Amyloid precursor protein Cleaving Enzyme 1, is a β secretase also known as memapsin 2. It is an aspartyl protease that initiates the formation of β-amyloid which accumulation has a huge role in the Alzeimer disease. It had been brought to light that not only BACE1 levels rise in the brain of the patients suffering from this disease but that BACE1 knock out mices can’t produce β-amyloid, effectively preventing the formation of amyloid plaques and the development of the Alzheimer disease. This discovery makes the BACE1 a very interesting drug target for Alzheimer disease.The inhibition of this enzyme is a plausible course of action and several inhibitors like the ones that will be presented are considered. However, the total inhibition of BACE1 seems to leads to physiological and behavioural troubles. That would mean that BACE1 could also be involved in several other brain functions. So a regulation of BACE1 activity by partial inhibition seems to be a prefencial method. Anyway, a good understanding of the biological function, the structure and the mechanisms of inhibition of BACE1 is highly required. | |||
BACE1, which stand for β-site of Amyloid precursor protein Cleaving Enzyme 1, is a β secretase also known as memapsin 2. It is an aspartyl protease that initiates the formation of β-amyloid which accumulation has a huge role in the Alzeimer disease. It had been brought to light that not only BACE1 levels rise in the brain of the patients suffering from this disease but that BACE1 knock out mices can’t produce β-amyloid, effectively preventing the formation of amyloid plaques and the development of the Alzheimer disease. This discovery makes the BACE1 a very interesting drug target for Alzheimer disease.The inhibition of this enzyme is a plausible course of action and several inhibitors like the ones that will be presented are considered. However, the total inhibition of BACE1 seems to leads to physiological and behavioural troubles. That would mean that BACE1 could also be involved in several other brain functions. So a regulation of BACE1 activity by partial inhibition seems to be a prefencial method. Anyway, a good understanding of the biological function, the structure and the mechanisms of inhibition of BACE1 is highly required. | |||
== Localisation and Biological function == | == Localisation and Biological function == | ||
<Structure load='4ivs' size='300' frame='true' align='right' caption='Amino acid sequence of Beta secretase 1' scene='Insert optional scene name here' /> | |||
=== Localisation === | === Localisation === | ||
BACE1 is the result of the expression of the BACE1 gene (30 kb) on chromosome 11. It is composed of 9 exons that are linked together during the mRNA maturation. BACE1 is expressed in the majority of human tissues however, the highest levels of activity are found in the neuronal cell. This β secretase, which is a transmembrane protein mainly localised within cholesterol-rich lipid raft, is found in the acidic compartments of the secretory pathway (mostly endosomes and the Trans Golgi Network) with its catalytic site facing the lumen side. This enzyme is regulated both at the translation and transcription steps and its expression is correlated with cell stress signals. | BACE1 is the result of the expression of the BACE1 gene (30 kb) on chromosome 11. It is composed of 9 exons that are linked together during the mRNA maturation. BACE1 is expressed in the majority of human tissues however, the highest levels of activity are found in the neuronal cell. This β secretase, which is a transmembrane protein mainly localised within cholesterol-rich lipid raft, is found in the acidic compartments of the secretory pathway (mostly endosomes and the Trans Golgi Network) with its catalytic site facing the lumen side. This enzyme is regulated both at the translation and transcription steps and its expression is correlated with cell stress signals. | ||
=== Post translational modification === | === Post translational modification === | ||
BACE1 is synthetised in the endoplasmamic reticulum as a precursor, pro BACE1 and it is inactive. This precursor is then maturated in the Golgi apparatus. It undergoes glycosylation of 4 residus : <scene name='56/568015/Asn_153/1'> | BACE1 is synthetised in the endoplasmamic reticulum as a precursor, pro BACE1 and it is inactive. This precursor is then maturated in the Golgi apparatus. It undergoes glycosylation of 4 residus : <scene name='56/568015/Asn_153/1'>Asn(153)</scene>, <scene name='56/568015/Asn_172/1'>Asn(172)</scene>Asn(172), Asn(223), and Asn(354), it has a role in activity. 3 cysteine residues of the cytosolic tail are also palmitoylated , it is has a role in the localization of the mature enzyme. The propeptide domain is clived between Arg 45 and Glu 46 by a proprotein convertase (protease). This clivage is known to increase the activity of the enzyme. | ||
=== Biological functions === | === Biological functions === | ||
The main biological function of BACE1 is its role in the β amyloid formation by cleavage of the amyloid precursor protein (APP). Indeed the BACE1 cleaves the β secretase site Asp1 or Glu11 of the β amyloid sequence. That initiates the formation of β amyloid. This scission liberates two fragments: a secreted APP ectodomain called APPsβ and a membrane bound carboxy terminal fragment called C99. This C99 will then be cleaved by a ϒ-secretase. This second scission generates the C-terminus of the β amyloid. | |||
In Alzheimer disease, the β amyloid accumulates as fibrillar plaques in the brain of the patient. It triggers the local inflammation, the dysfunction and finally the death of the neurons. BACE1 is so a very important drug target for the inhibition of the β-amyloid production. | |||
It is interesting to note that APP can also be cleaved by α-secretase but, as it does not produce β-amyloid, it is said that it is a non-amyloidogenic pathway (contrary to the amyloidogenic pathway induced by BACE1). | |||
BACE1 may also be involved in other functions in the brain like the regulation of neuronal function, axonal growth, neuroprotection or synapse formation. It could ever have a role in the immunity system as several of its substrates are molecules of the immune system (like IL-1R2). These cross functions need to be investigated before any inhibitor is brought to the market. | |||