negative regulation of amyloid precursor protein biosynthetic process
Definition
Target type: biologicalprocess
Any process that stops, prevents, or reduces the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of amyloid precursor protein (APP), the precursor of amyloid-beta. [GOC:go_curators]
Negative regulation of amyloid precursor protein (APP) biosynthetic process is a complex biological pathway that aims to reduce the production of amyloid-beta (Aβ) peptides, which are the primary constituents of amyloid plaques found in the brains of individuals with Alzheimer's disease. This process involves multiple cellular mechanisms, including transcriptional regulation, post-translational modifications, and proteolytic processing of APP.
Transcriptional regulation involves the control of APP gene expression. Specific transcription factors can bind to the APP gene promoter, either activating or repressing its transcription. Factors that decrease APP transcription, such as the transcription factor REST, contribute to negative regulation.
Post-translational modifications, such as phosphorylation and glycosylation, can also influence APP processing. Specific enzymes can modify APP, affecting its stability, trafficking, and interactions with other proteins, ultimately impacting Aβ production.
Proteolytic processing of APP is the central step in Aβ production. APP undergoes cleavage by two main proteases: β-secretase and γ-secretase. β-secretase initiates the cleavage, generating a soluble fragment and a C-terminal fragment. γ-secretase then cleaves the C-terminal fragment, resulting in Aβ peptides. Negative regulation of this process can involve inhibiting the activity of β-secretase or γ-secretase, reducing the overall production of Aβ peptides.
Several key proteins are involved in the negative regulation of APP biosynthetic process. These include:
- **α-secretase (ADAM10):** This enzyme cleaves APP within the Aβ sequence, generating a soluble fragment and preventing Aβ production.
- **γ-secretase inhibitors:** These compounds target γ-secretase activity, blocking the generation of Aβ peptides.
- **APP-binding proteins:** Some proteins bind to APP, preventing its interaction with β-secretase or influencing its trafficking and degradation.
- **Microtubule-associated proteins:** These proteins can regulate the trafficking and processing of APP within neurons.
By targeting these various mechanisms, interventions aimed at negatively regulating APP biosynthetic process can potentially reduce Aβ production, offering a therapeutic approach to Alzheimer's disease.'
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Proteins (2)
| Protein | Definition | Taxonomy |
|---|---|---|
| Beta-secretase 2 | A beta-secretase 2 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9Y5Z0] | Homo sapiens (human) |
| Protein argonaute-2 | A protein argonaute-2 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9UKV8] | Homo sapiens (human) |
Compounds (11)
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| sulfaguanidine | sulfaguanidine : A sulfonamide incorporating a guanidine moiety used to block the synthesis of folic acid; mostly used in veterinary medicine Sulfaguanidine: A sulfanilamide antimicrobial agent that is used to treat enteric infections. | sulfonamide antibiotic | antiinfective agent |
| sulfanilamide | substituted aniline; sulfonamide; sulfonamide antibiotic | antibacterial agent; drug allergen; EC 4.2.1.1 (carbonic anhydrase) inhibitor | |
| sulfisomidine | sulfisomidine : A sulfonamide consisting of pyrimidine having methyl substituents at the 2- and 6-positions and a 4-aminobenzenesulfonamido group at the 4-position. Sulfisomidine: A sulfanilamide antibacterial agent. | pyrimidines; sulfonamide; sulfonamide antibiotic | antiinfective agent |
| uridine monophosphate | uridine 5'-monophosphate : A pyrimidine ribonucleoside 5'-monophosphate having uracil as the nucleobase. Uridine Monophosphate: 5'-Uridylic acid. A uracil nucleotide containing one phosphate group esterified to the sugar moiety in the 2', 3' or 5' position. | pyrimidine ribonucleoside 5'-monophosphate; uridine 5'-phosphate | Escherichia coli metabolite; human metabolite; mouse metabolite |
| om99-2 | OM99-2: eight-residue memapsin 2 inhibitor; structure in first source | ||
| om00-3 | OM00-3: second-generation 8-residue memapsin 2 inhibitor; structure in first source | ||
| l 685458 | L 685458: a gamma-secretase inhibitor; structure in first source L-685,458 : A peptide and carboxamide that is L-leucyl-L-phenylalaninamide, L-Leu-L-Phe-NH2, which has been acylated on the N-terminus by a Phe-Phe hydroxyethylene dipeptide isotere, 2R-benzyl-5S-tert-butoxycarbonylamino-4R-hydroxy-6-phenylhexanoic acid. Compounds based on the structure of L-685,458 are potent inhibitors of gamma-secretase, which mediates the final catalytic step that generates the amyloid beta-peptide (Abeta), which assembles into the neurotoxic aggregates in the brains of sufferers of Alzheimer's disease. | carbamate ester; monocarboxylic acid amide; peptide; secondary alcohol | EC 3.4.23.46 (memapsin 2) inhibitor; peptidomimetic |
| gsk188909 | GSK188909: a potent and selective non-peptidic BACE-1 inhibitor; structure in first source | ||
| ly2811376 | |||
| azd3839 | AZD3839: a BACE1 inhibitor; structure in first source | ||
| ly2886721 |