Disease relevance of AIDS-108089

• A beta-lactone related to lactacystin induces neurite outgrowth in a neuroblastoma cell line and inhibits cell cycle progression in an osteosarcoma cell line [1].
• Clasto-lactacystin beta-lactone is a time-dependent inhibitor of the Rhodococcus proteasome's ability to hydrolyze Suc-Leu-Leu-Val-Tyr-AMC, a substrate for this proteasome's single type of active site, and proceeds with a kinact/[I] of 1,700 M-1 s-1 [2].
• [reaction: see text] N-Benzyloxycarbonyl-L-serine beta-lactone (1) is shown to irreversibly inactivate the 3C cysteine proteinase of hepatitis A virus (HAV) with k(inact) = 0.70 min(-1), K(I) = 1.84 x 10(-4) M and k(inact)/K(I) = 3800 M(-1) min(-1) at an enzyme concentration of 0.1 microM [3].
• In addition, three closely related beta-lactone-containing molecules were isolated from strains representing three genera-Arthrobacter, Bacillus and Pseudomonas [4].
• The effect of the beta-lactone antibiotic diffusomycin (oxazolomycin) was investigated against vaccinia (Lister), herpes simplex type 1 (Kupka), influenza A (WSN; H1N1), and Coxsackie A9 viruses [5].

High impact information on AIDS-108089

• The proteasomal inhibitor clasto-lactacystin beta-lactone strongly inhibited endocytosis, but did not affect phagocytosis [6].
• When expressed in tobacco cells, the catalytic subunit of the dimeric ribosome inactivating protein, ricin, is first inserted into the endoplasmic reticulum (ER) and then degraded in a manner that can be partially inhibited by the proteasome inhibitor clasto-lactacystin beta-lactone [7].
• The observed structure-activity relationships suggest that lactacystin and its related beta-lactone may act via acylation of one or more relevant target molecule(s) in the cell [1].
• The p12(DOC-1)-mediated decrease of CDK2 was prevented if the p12(DOC-1) transfectants were grown in the presence of the proteosome inhibitor clasto-lactacystin beta-lactone, suggesting that p12(DOC-1) may target CDK2 for proteolysis [8].
• Both ISP-1 and clasto-lactacystin beta-lactone, an irreversible inhibitor of the proteasome, prevented BcR cross-linking-induced XIAP degradation [9].

Chemical compound and disease context of AIDS-108089

• Obafluorin, a novel beta-lactone produced by Pseudomonas fluorescens. Taxonomy, fermentation and biological properties [10].

Biological context of AIDS-108089

• Substrate hydrolysis by lysosomes or proteosomes was controlled for using NH(4)Cl and clasto-lactacystin beta-lactone, respectively [11].
• We have studied the kinetics of this reaction under appropriate in vitro conditions as well as the kinetics of lactathione accumulation and proteasome inhibition in cells treated with lactacystin or beta-lactone [12].
• The effects of different proteasome inhibitors to prevent Ikappa Balpha degradation and subsequent NF-kappaB translocation could also be discriminated; Leu-Leu-Leu aldehyde was only a partial inhibitor with an IC50 of 2 microM, while clastolactacystin beta-lactone was a complete inhibitor with an IC50 of 10 microM [13].
• Lactacystin and clasto-lactacystin beta-lactone modify multiple proteasome beta-subunits and inhibit intracellular protein degradation and major histocompatibility complex class I antigen presentation [14].
• Interestingly, both MG-132 and a second proteasome inhibitor beta-lactone significantly enhanced hormone response of transfected mouse glucocorticoid receptor toward transcriptional activation of glucocorticoid receptor-mediated reporter gene expression [15].

Anatomical context of AIDS-108089

• These studies, as well as the kinetic evidence presented, suggest that the beta-lactone inhibitors acylate HMG-CoA synthase in a reaction which appears to be irreversible in vitro, but is easily reversed in cultured cells and in animals [16].
• The TPPII inhibitor Ala-Ala-Phe-chloromethylketone (AAF-cmk) and clasto-lactacystin beta-lactone (lactacystin), an inhibitor of both TPPII and the proteasome, protected macrophages from Shigella-induced apoptosis [17].
• Surprisingly, the increased C/EBPbeta levels in beta-lactone-treated myotubes did not result in increased DNA-binding activity [18].
• Clasto-lactacystin beta-lactone also induced soluble TNFR1 (sTNFR1) release from the A549 pulmonary epithelial cell line, as well as from primary cultures of human small airway epithelial cells and human umbilical vein endothelial cells [19].
• Exposure of murine neocortical cultures to proteasome inhibitors (0.1-10 microm clasto-lactacystin beta-lactone or MG-132) for 48 h resulted in widespread neuronal death associated with a reduction in intracellular free calcium; higher inhibitor concentrations killed astrocytes [20].

Associations of AIDS-108089 with other chemical compounds

• In each of these cell lines degradation of alpha(1)-ATZ was inhibited by lactacystin, MG132, epoxomicin, and clasto-lactacystin beta-lactone [21].
• When protein synthesis was stopped in cells with brefeldin A-inhibited ER-to-Golgi transport, apoB degradation was visualized as a homogeneous decrease in fluorescence signal intensity throughout the ER that could be slowed with clasto-lactacystin beta-lactone, a proteasome inhibitor [22].
• Incorporation of [14C]acetate into cholesterol in mouse liver was inhibited in a reversible manner after oral administration of the beta-lactone inhibitor [16].
• Asynchronously growing Chinese hamster ovary (CHO) cells treated with the pro-drug, beta-lactone ring form of lovastatin were arrested in G(1)-phase [23].
• The results are consistent with beta-lactone ring opening by the active site Cys to form an enzyme bound thioester [24].

Gene context of AIDS-108089

• Here, we show that although stress caused by the proteasome inhibitors MG132 and clasto-lactacystine beta-lactone induces the expression of Hsp70, the formation of HSF1 granules is affected differently in comparison to heat shock [25].
• In this study, we investigated the effect of proteasomal inhibition on the induction of arylalkylamine-N-acetyltransferase (AA-NAT) enzyme in cultured rat pinealocytes, using two proteasome inhibitors, MG132 and clastolactacystin beta-lactone (c-lact) [26].
• Inhibition of proteasome activity by ALLN and beta-lactone resulted in significantly increased IL-8 secretion (5- to 22-fold) [27].
• In the present study, we show that proteasome inhibition with clasto-lactacystin beta-lactone (4 microM, 1 h) stabilizes the presence of a deglycosylated CFTR intermediate for up to 5 h without increasing the core glycosylated (band B) form of CFTR [28].
• We report here an improvement for the detection of ubiquitinated p21 using a proteasome inhibitor, clasto-lactacystin beta-lactone [29].

Analytical, diagnostic and therapeutic context of AIDS-108089

• However, crystallization of an enzyme-inhibitor adduct from the reaction mixture followed by X-ray structural analysis shows only covalent modification of the epsilon2-nitrogen of the surface His102 by the beta-lactone with no reaction at Cys172 [30].
• Treatment of cultured L6 myotubes, a rat skeletal muscle cell line, with the specific proteasome inhibitor beta-lactone resulted in increased nuclear levels of C/EBPbeta as determined by Western blotting and immunofluorescent detection [18].
• After three further steps, (2S,3S)-3a yielded the alpha, beta-substituted beta-lactone (3R,4R) 6 with a very high diastereoisomeric excess (> 95% by chiral gas chromatography) [31].

References