Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.2.1.1 (ACS)
 78,556 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Designed second mitochondrial activator of caspases (Smac) mimetics based on an accessible [7,5]-bicyclic scaffold bind to and antagonize protein interactions involving the inhibitor of apoptosis (IAP) proteins, X-chromosome-linked IAP (XIAP), melanoma IAP (ML-IAP), and c-IAPs 1 and 2 (cIAP1 and cIAP2). The design rationale is based on a combination of phage-panning data, peptide binding studies, and a survey of potential isosteres. The synthesis of two scaffolds is described. These compounds bind the XIAP-baculoviral IAP repeat 3 (BIR3), cIAP1-BIR3, cIAP2-BIR3, and ML-IAP-BIR domains with submicromolar affinities. The most potent Smac mimetic binds the cIAP1-BIR3 and ML-IAP-BIR domains with a K i of 50 nM. The X-ray crystal structure of this compound bound to an ML-IAP/XIAP chimeric BIR domain protein is compared with that of a complex with a phage-derived tetrapeptide, AVPW. The structures show that these compounds bind to the Smac-binding site on ML-IAP with identical hydrogen-bonding patterns and similar hydrophobic interactions. Consistent with the structural data, coimmunoprecipitation experiments demonstrate that the compounds can effectively block Smac interactions with ML-IAP. The compounds are further demonstrated to activate caspase-3 and -7, to reduce cell viability in assays using MDA-MB-231 breast cancer cells and A2058 melanoma cells, and to enhance doxorubicin-induced apoptosis in MDA-MB-231 cells.
ACS Chem Biol 2006 Sep 19
PMID:Design, synthesis, and biological activity of a potent Smac mimetic that sensitizes cancer cells to apoptosis by antagonizing IAPs. 1716 40

The S24F mutant of the chemokine RANTES was found to be partly acetylated when produced in recombinant Escherichia coli BL21(DE3)(pDIA17)(CCL5-S24F-pET-26b). Mass spectrometry and Edman sequencing of peptides generated by lys-C endopeptidase indicated that Lys-26, Lys-34, Lys-46, and Lys-57 were susceptible to acetylation. The extent of acetylation of the RANTES S24F polypeptide increased with temperature and with the time during which the culture was incubated after adding the inducer isopropyl-beta-D-thiogalactoside (IPTG). These findings suggest that induction at low temperature and for a short period of time should be preferred when spurious acetylation is a problem for the production of genuine recombinant polypeptides. Acetylation of the polypeptide was not affected by deleting acs, yfiQ, or speG, which encode acetyl-CoA synthetase, acetyl-CoA synthetase acetylase, and spermidine acetyl transferase, respectively, nor by the presence or absence of the pDIA17 plasmid, which harbours the cat gene encoding chloramphenicol acetyl transferase. By contrast, spontaneous acetylation of RANTES could be demonstrated by incubating either the purified polypeptide or inclusion bodies derived from an induced culture in the presence of acetyl-CoA.
Protein Expr Purif 2007 Sep
PMID:Time- and temperature-dependent acetylation of the chemokine RANTES produced in recombinant Escherichia coli. 1757 62

NFAT involvement in adipocyte physiological processes was examined by treatment with CsA and/or GSK3beta inhibitors (Li(+) or TZDZ-8), which prevent or increase NFAT nuclear translocation, respectively. CsA treatment reduced basal and TNFalpha-induced rates of lipolysis by 50%. Adipocytes preincubated with Li(+) or TZDZ-8 prior to CsA and/or TNFalpha, exhibited enhanced basal rates of lipolysis and complete inhibition of CsA-mediated decreased rates of lipolysis. CsA treatment dramatically reduced the mRNA levels of adipocyte-specific genes (aP2, HSL, PPARgamma, ACS and Adn), compared with control or TNFalpha-treatment, whereas Li(+) pretreatment blocked the inhibitory effects of CsA, and mRNA levels of aP2, HSL, PPARgamma, and ACS were found at or above control levels. NFAT nuclear localization, assessed by EMSA, confirmed that CsA or Li(+) treatments inhibited or increased NFAT nuclear translocation, respectively. These results show that NFAT proteins in mature adipocytes participate in the transcriptional control of genes involved in adipocyte metabolism and lipolysis.
Biochem Biophys Res Commun 2007 Sep 21
PMID:Nuclear factor of activated T cell (NFAT) transcription proteins regulate genes involved in adipocyte metabolism and lipolysis. 1765 92

The dianionic NiN2S2 complex, Ni(ema)2-, ema=N,N'-ethylenebis-2-mercaptoacetamide, known as a reasonable model of the tripeptide complex Ni(CGC)2- (C=cysteine; G=glycine) with respect to the two carboxyamido nitrogens and cis-dithiolates in a (N2S2)4- ligand scaffold as found in acetyl CoA synthase, has been explored for S-based reactivity toward oxygenation and alkylation. The isolation and structural characterization of a sulfinato species, [Et4N]2[Ni(ema).O2], prepared through a unique direct reaction of molecular O2 with crystalline [Et4N]2[Ni(ema)] is described. Reaction of [Et4N]2[Ni(ema)] with Br(CH2)3Br yields a neutral N2S2 macrocyclic complex shown by DFT computations and electrostatic-potential mapping to be opposite in electron distribution from the neutral NiN2S2 complexes in which the anionic charge is localized on sulfur.
Inorg Chem 2007 Sep 03
PMID:An experimental and computational study of sulfur-modified nucleophilicity in a dianionic NiN2S2 complex. 1768 11

We investigated frequency/characteristics of acute coronary syndrome-like (ACS-like) electrocardiographic (ECG) profiles among patients with a final diagnosis of acute aortic syndrome (AAS), and explored pathophysiologic determinants and prognostic relevance within each Stanford subtype. We blindly reviewed presentation electrocardiograms of 233 consecutive patients with final diagnosis of AAS (164 Stanford type A) at a regional treatment center. Prevalence of ACS-like ECG findings was 27% (type A, 26%, type B, 29%); most were non-ST-elevation myocardial infarction-like. Patients with ACS-like ECG findings more often had coronary ostia involvement (p=0.002), pleural effusion (p=0.02), significant aortic regurgitation (p=0.01), and troponin positivity (p=0.001). ACS-like ECG profile in type A disease was independently associated with coronary ostia involvement (odds ratio [OR] 5.27, 95% confidence interval [CI] 1.75 to 15.88). ACS-like ECG profile predicted in-hospital mortality (OR 2.90, 95% CI 1.24 to 6.12), as did age (each incremental 10-year: OR 1.59, 95% CI 1.14 to 2.22), and syncope at presentation (OR 2.90, 95% CI 1.16 to 7.24). In conclusion, about 25% of our AAS patients (in either Stanford subtype) presented ACS-like ECG patterns-often with non-ST-elevation myocardial infarction characteristics-which could cause misdiagnosis. ACS-like ECG profile was associated with more complicated disease, and in type A disease was a strong independent predictor of in-hospital mortality.
Am J Cardiol 2007 Sep 15
PMID:Frequency, determinants, and clinical relevance of acute coronary syndrome-like electrocardiographic findings in patients with acute aortic syndrome. 1782 89


ACS Chem Biol 2007 Sep 21
PMID:Partly cloudy with a chance of showers. 1789 33


ACS Chem Biol 2007 Sep 21
PMID:Daniel E. Koshland, Jr. (1920-2007). 1789 36


ACS Chem Biol 2007 Sep 21
PMID:First International Meeting on Quadruplex DNA. 1789 37


ACS Chem Biol 2007 Sep 21
PMID:Chemistry as a vector for understanding biology. 1789 38

The membrane-bound bacterial D-alanyl- D-alanine peptidases or penicillin-binding proteins (PBPs) catalyze the final transpeptidation reaction of bacterial cell wall biosynthesis and are the targets of beta-lactam antibiotics. Rather surprisingly, the substrate specificity of these enzymes is not well understood. In this paper, we present measurements of the reactivity of typical examples of these enzymes with peptidoglycan-mimetic beta-lactams under in vivo conditions. The minimum inhibitory concentrations of beta-lactams with Escherichia coli-specific side chains were determined against E. coli cells. Analogous measurements were made with Streptococcus pneumoniae R6. The reactivity of the relevant beta-lactams with E. coli PBPs in membrane preparations was also determined. The results show that under none of the above protocols were beta-lactams with peptidoglycan-mimetic side chains more reactive than generic analogues. This suggests that in vivo, as in vitro, these enzymes do not specifically recognize elements of peptidoglycan structure local to the reaction center. Substrate recognition must thus involve extended structure.
ACS Chem Biol 2007 Sep 21
PMID:Reactions of peptidoglycan-mimetic beta-lactams with penicillin-binding proteins in vivo and in membranes. 1789 39


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>