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

Carbon monoxide dehydrogenase/acetyl-CoA synthase (CODH/ACS) utilizes a unique Ni-M bimetallic site in the biosynthesis of acetyl-CoA, where a square-planar Ni ion is coordinated to two thiolates and two deprotonated amides in a Cys-Gly-Cys motif. The identity of M is currently a matter of debate, although both Cu and Ni have been proposed. In an effort to model ACS's unusual active site and to provide insight into the mechanism of acetyl-CoA formation and the role of each of the metals ions, we have prepared and structurally characterized a number of Ni(II)-peptide mimic complexes. The mononuclear complexes Ni(II) N, N'-bis(2-mercaptoethyl)oxamide (1), Ni(II) N, N'-ethylenebis(2-mercaptoacetamide) (2), and Ni(II) N, N'-ethylenebis(2-mercaptopropionamide) (3) model the Ni(Cys-Gly-Cys) site and can be used as synthons for additional multinuclear complexes. Reaction of 2 with MeI resulted in the alkylation of the sulfur atoms and the formation of Ni(II) N, N'-ethylenebis(2-methylmercaptoacetamide) (4), demonstrating the nucleophilicity of the terminal alkyl thiolates. Addition of Ni(OAc)(2).4H(2)O to3 resulted in the formation of a trinuclear species (5), while 2 crystallizes as an unusual paddlewheel complex (6) in the presence of nickel acetate. The difference in reactivity between the similar complexes 2 and 3 highlights the importance of ligand design when synthesizing models of ACS. Significantly,5 maintains the key features observed in the active site of ACS, namely a square-planar Ni coordinated to two deprotonated amides and two thiolates, where the thiolates bridge to a second metal, suggesting that 5 is a reasonable structural model for this unique enzyme.
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PMID:Modeling carbon monoxide dehydrogenase/acetyl-CoA synthase (CODH/ACS): a trinuclear nickel complex employing deprotonated amides and bridging thiolates. 1473 32

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.
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PMID:An experimental and computational study of sulfur-modified nucleophilicity in a dianionic NiN2S2 complex. 1768 11

The increasing emergence of antibiotic resistance necessitates the development of anti-infectives with novel modes of action. Targeting bacterial virulence is considered a promising approach to develop novel antibiotics with reduced selection pressure. The extracellular collagenase elastase (LasB) plays a pivotal role in the infection process of Pseudomonas aeruginosa and therefore represents an attractive antivirulence target. Mercaptoacetamide-based thiols have been reported to inhibit LasB as well as collagenases from clostridia and bacillus species. The present work provides an insight into the structure-activity relationship (SAR) of these fragment-like LasB inhibitors, demonstrating an inverse activity profile compared to similar inhibitors of clostridial collagenase H (ColH). An X-ray cocrystal structure is presented, revealing distinct binding of two compounds to the active site of LasB, which unexpectedly maintains an open conformation. We further demonstrate in vivo efficacy in a Galleria mellonella infection model and high selectivity of the LasB inhibitors toward human matrix metalloproteinases (MMPs).
ACS Infect Dis 2018 06 08
PMID:Binding Mode Characterization and Early in Vivo Evaluation of Fragment-Like Thiols as Inhibitors of the Virulence Factor LasB from Pseudomonas aeruginosa. 2948 68

Mercaptoacetamide histone deacetylase inhibitors are neuroprotective agents that do not exhibit the genotoxicity associated with more commonly used hydroxamate inhibitors. Here, we present the crystal structure of a selective mercaptoacetamide complexed with the C-terminal catalytic domain of HDAC6. When compared with the structure of a mercaptoacetamide bound to the class I isozyme HDAC8, different interactions are observed with the conserved tandem histidine pair in the active site. These differences likely contribute to the selectivity for inhibition of HDAC6, an important target for cancer chemotherapy and the treatment of neurodegenerative disease.
ACS Med Chem Lett 2018 Dec 13
PMID:Molecular Basis for the Selective Inhibition of Histone Deacetylase 6 by a Mercaptoacetamide Inhibitor. 3061 44