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Drug-Target Interaction

Drug

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PubChem ID:69362
Structure:
Synonyms:
3-hydroxy-3-methylbutanoic acid
3-Hydroxy-3-methylbutyric acid
3-hydroxy-isovaleric acid
3-Hydroxyisovaleric acid
3-OH-isovaleric acid
55453_ALDRICH
55453_FLUKA
625-08-1
AC1L2BP5
AC1Q5VCY
beta-Hydroxy-beta-methylbutyrate
beta-hydroxy-beta-methylbutyric acid
beta-Hydroxy-methylbutyrate
beta-Hydroxyisovaleric acid
Butanoic acid, 3-hydroxy-3-methyl-
Butyric acid, 3-hydroxy-3-methyl-
CHEBI:37084
CID69362
H0701
Hmb-d6
LMFA01050396
SBB053604
TL8004167

Target

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Uniprot ID:CASP3_MOUSE
Synonyms:
Apopain
CASP-3
Caspase-3
CPP-32
Cysteine protease CPP32
LICE
SCA-1
SREBP cleavage activity 1
Yama protein
EC-Numbers:3.4.22.56
Organism:Mouse
Mus musculus
PDB IDs:-

Binding Affinities:

Ki: Kd:Ic 50:Ec50/Ic50:
----

References:

18840762
Mechanism of attenuation of muscle protein degradation induced by tumor necrosis factor-alpha and angiotensin II by beta-hydroxy-beta-methylbutyrate.. Helen L Eley; Steven T Russell; Michael J Tisdale (2008) American journal of physiology. Endocrinology and metabolism display abstract
Both tumor necrosis factor-alpha (TNF-alpha)/interferon-gamma (IFN-gamma) and angiotensin II (ANG II) induced an increase in total protein degradation in murine myotubes, which was completely attenuated by treatment with beta-hydroxy-beta-methylbutyrate (HMB; 50 microM). There was an increase in formation of reactive oxygen species (ROS) within 30 min, as well as an increase in the activity of both caspase-3 and -8, and both effects were attenuated by HMB. Moreover, inhibitors of caspase-3 and -8 completely attenuated both ROS formation and total protein degradation induced by TNF-alpha/IFN-gamma and ANG II. There was an increased autophosphorylation of double-stranded RNA-dependent protein kinase (PKR), which was attenuated by the specific caspase-3 and -8 inhibitors. Neither ROS formation or protein degradation occurred in myotubes expressing a catalytically inactive PKR variant, PKRDelta6, in response to TNF-alpha/IFN-gamma, compared with myotubes expressing wild-type PKR, although there was still activation of caspase-3 and -8. HMB also attenuated activation of PKR, suggesting that it was important in protein degradation. Formation of ROS was attenuated by rotenone, an inhibitor of the mitochondrial electron transport chain, nitro-l-arginine methyl ester, an inhibitor of nitric oxide synthase, and SB 203580, a specific inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), which also attenuated total protein degradation. Activation of p38 MAPK by PKR provides the link to ROS formation. These results suggest that TNF-alpha/IFN-gamma and ANG II induce muscle protein degradation by a common signaling pathway, which is attenuated by HMB, and that this involves the initial activation of caspase-3 and -8, followed by autophosphorylation and activation of PKR, which then leads to increased ROS formation via activation of p38 MAPK. Increased ROS formation is known to induce protein degradation through the ubiquitin-proteasome pathway.