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positive regulation of endopeptidase activity

Definition

Target type: biologicalprocess

Any process that increases the frequency, rate or extent of endopeptidase activity, the endohydrolysis of peptide bonds within proteins. [GOC:dph, GOC:tb]

Positive regulation of endopeptidase activity involves a complex interplay of cellular mechanisms that enhance the activity of endopeptidases, enzymes that break down peptide bonds within proteins. This process plays a crucial role in various biological functions, including protein degradation, signal transduction, and the regulation of cellular processes.

The regulation of endopeptidase activity can occur at multiple levels:

1. **Transcriptional Regulation:** The expression of endopeptidase genes can be modulated by transcription factors that bind to regulatory elements in the promoter regions of these genes. This can lead to increased or decreased synthesis of endopeptidases, ultimately affecting their overall activity.

2. **Post-translational Modifications:** After translation, endopeptidases can undergo various modifications, including phosphorylation, glycosylation, and ubiquitination. These modifications can alter the conformation, stability, or localization of the enzyme, thereby influencing its activity.

3. **Activation by Cofactors:** Some endopeptidases require cofactors, such as metal ions or small molecules, for their activity. The availability of these cofactors can influence the rate of endopeptidase activity.

4. **Regulation by Inhibitors:** Specific inhibitors can bind to and block the active site of endopeptidases, preventing them from interacting with their substrates. These inhibitors can be endogenous, such as proteins or peptides, or exogenous, such as drugs.

5. **Cellular Localization:** The compartmentalization of endopeptidases within cells can influence their activity. For instance, some endopeptidases are localized to specific organelles, such as lysosomes or the Golgi apparatus, where they can exert their specific functions.

6. **Interactions with Other Proteins:** Endopeptidases can interact with other proteins, forming complexes that regulate their activity. These interactions can involve scaffolding proteins that bring endopeptidases and their substrates together, or regulatory proteins that directly activate or inhibit the enzyme.

7. **Feedback Mechanisms:** The activity of endopeptidases can be regulated by feedback mechanisms. For example, the products of endopeptidase activity can act as inhibitors of the enzyme, preventing excessive degradation of substrates.

In summary, positive regulation of endopeptidase activity encompasses a multifaceted network of molecular events that ensure precise control of protein degradation and other essential biological processes. Understanding these regulatory mechanisms is critical for unraveling the intricate workings of cellular networks and for developing therapeutic strategies that target endopeptidase activity.'
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Proteins (4)

ProteinDefinitionTaxonomy
Gamma-secretase subunit PEN-2A gamma-secretase subunit PEN-2 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9NZ42]Homo sapiens (human)
Gamma-secretase subunit APH-1AA gamma-secretase subunit APH-1A that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q96BI3]Homo sapiens (human)
NicastrinA nicastrin that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q92542]Homo sapiens (human)
Gamma-secretase subunit APH-1BA gamma-secretase subunit APH-1B that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q8WW43]Homo sapiens (human)

Compounds (22)

CompoundDefinitionClassesRoles
7-amino-4-chloro-3-methoxy-2-benzopyran-1-oneisocoumarins
tarenflurbiltarenflurbil: R-enantiomer of flurbiprofen but not a COX inhibitor; modulates NF-kB, gamma-secretase, amyloid beta-protein;flurbiprofen
cholanic acid5beta-cholanic acids;
cholanic acid
t0901317T0901317: an LXRalpha and LXRbeta agonist
benzyloxycarbonylleucyl-leucyl-leucine aldehydebenzyloxycarbonylleucyl-leucyl-leucine aldehyde: proteasome inhibitor

N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal : A tripeptide that is L-leucyl-L-leucyl-L-leucine in which the C-terminal carboxy group has been reduced to the corresponding aldehyde and the N-terminal amino group is protected as its benzyloxycarbonyl derivative.
amino aldehyde;
carbamate ester;
tripeptide
proteasome inhibitor
n-(n-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl esterDAPT : A dipeptide consisting of alanylphenylglycine derivatised as a 3,5-difluorophenylacetamide at the amino terminal and a tert-butyl ester at the carboxy terminal. A gamma-secretase inhibitor.carboxylic ester;
difluorobenzene;
dipeptide;
tert-butyl ester
EC 3.4.23.46 (memapsin 2) inhibitor
sulindac sulfidesulindac sulfide : An aryl sulfide that is a metabolite of sulindac. A non-steroidal anti-inflammatory drug, which also has anticancer activity.

sulindac sulfide: sulfated analog of indomethacin & inhibitor of prostaglandin synthesis in vitro; RN given refers to cpd without isomeric designation; structure given in first source
aryl sulfide;
monocarboxylic acid;
organofluorine compound
antineoplastic agent;
apoptosis inducer;
non-steroidal anti-inflammatory drug
l 685458L 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
mk 0752
ly 450139peptide
chf 50741-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid: a beta-amyloid(1-42) lowering agent; structure in first source
ly 411575dibenzoazepine;
difluorobenzene;
lactam;
secondary alcohol
EC 3.4.23.46 (memapsin 2) inhibitor
4-(2-((1r)-1-(((4-chlorophenyl)sulfonyl)-2,5-difluoroanilino)ethyl)-5-fluorophenyl)butanoic acidsulfonamide
begacestat
e 2012
mrk 560MRK 560: a gamma-secretase inhibitor; MRK-560 is the (cis)-isomer; structure in first source
1, 3-di-(n-carboxybenzoyl-leucyl-leucyl)amino acetone1, 3-di-(N-carboxybenzoyl-leucyl-leucyl)amino acetone: structure in first source
pf 3084014nirogacestat : A member of the class of imidazoles that is 1H-imidazole substituted by a 1-[(2,2-dimethylpropyl)amino]-2-methylpropan-2-yl group at position 1 and a {N-[(2S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]-L-norvalyl}amino group at position 4. It is a gamma-secretase inhibitor whose hydrobromide salt is indicated for adult patients with progressing desmoid tumours who require systemic treatment.

nirogacestat: an antineoplastic agent
bms 708163BMS 708163: structure in first sourceoxadiazole;
ring assembly
ro 4929097dibenzoazepine;
dicarboxylic acid diamide;
lactam;
organofluorine compound
EC 3.4.23.46 (memapsin 2) inhibitor
jnj 40418677
(r)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1h-pyrazolo(4,3-c)quinoline(R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo(4,3-c)quinoline: gamma secretase inhibitor; structure in first source