Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.2.1.1 (ACS)
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Amino acids enter rabbit jejunal brush border membrane vesicles via three major transport systems: (1) simple passive diffusion; (2) Na-independent carriers; and (3) Na-dependent carriers. The passive permeability sequence of amino acids is very similar to that observed in other studies involving natural and artificial membranes. Based on uptake kinetics and cross-inhibition profiles, at least two Na-independent and three Na-dependent carrier-mediated pathways exist. One Na-independent pathway, similar to the classical L system, favors neutral amino acids, while the other pathway favors dibasic amino acids such as lysine. One Na-dependent pathway primarily serves neutral L-amino acids including 2-amino-2-norbornanecarboxylic acid hemihydrate (BCH), but not beta-alanine or alpha-methylaminoisobutyric acid (MeAIB). Another Na-dependent route favors phenylalanine and methionine, while the third pathway is selective for imino acids and MeAIB. Li is unable to substitute for Na in these systems. Cross-inhibition profiles indicated that none of the Na-dependent systems conform to classical A or ACS paradigms. Other notable features of jejunal brush border vesicles include (1) no beta-alanine carrier, and (2) no major proline/glycine interactions.
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PMID:Multiple transport pathways for neutral amino acids in rabbit jejunal brush border vesicles. 680 39

The initiation codon dictates that the translation initiation event exclusively begins with methionine. We report here a new technology to reprogram the initiation event, where various amino acids and those bearing N (alpha)-acyl groups can be used as an initiator for peptide synthesis. The technology is built upon the concept of genetic code reprogramming, where methionine is depleted from the translation system and the initiation codon is reassigned to the desired amino acid. We have applied this technology to the synthesis of an antitumor cyclic peptide, G7-18NATE, closed by a physiologically stable bond, and it is also extended to the custom synthesis of its analogues with various ring sizes. Significantly, cyclization occurs spontaneously upon translation of the precursor linear peptides. To demonstrate the practicality of this methodology, we also prepared a small cyclic peptide library designated by 160 distinct mRNAs. Thus, this technology offers a new means to prepare a wide array of in vivo compatible cyclic peptide libraries for the discovery of peptidic drug candidates against various therapeutic targets.
ACS Chem Biol 2008 Feb 15
PMID:Reprogramming the translation initiation for the synthesis of physiologically stable cyclic peptides. 1827 47

Protein translation in nature always begins with an initiator transfer RNA (tRNA) carrying the amino acid methionine. This was circumvented in vitro with a reconstituted translation system utilizing initiator tRNA synthetically mischarged with the other natural amino acids. In addition, it was determined that this system could accommodate these non-methionine amino acids containing various N-alpha-acyl groups, many of which are useful for post-translational modification such as peptide cyclization.
ACS Chem Biol 2008 Feb 15
PMID:Unnatural translation initiation. 1821 17

Very little is known about the conformation of polypeptides emerging from the ribosome during protein biosynthesis. Here, we explore the dynamics of ribosome-bound nascent polypeptides and proteins in Escherichia coli by dynamic fluorescence depolarization and assess the population of cotranslationally active chaperones trigger factor (TF) and DnaK. E. coli cell-free technology and fluorophore-linked E. coli Met-tRNA f Met enable selective site-specific labeling of nascent proteins at the N-terminal methionine. For the first time, direct spectroscopic evidence captures the generation of independent nascent chain motions for a single-domain protein emerging from the ribosome (apparent rotational correlation time approximately 5 ns), during the intermediate and late stages of polypeptide elongation. Such motions are detected only for a sequence encoding a globular protein and not for a natively unfolded control, suggesting that the independent nascent chain dynamics may be a signature of folding-competent sequences. In summary, we observe multicomponent, severely rotationally restricted, and strongly chain length/sequence-dependent nascent chain dynamics.
ACS Chem Biol 2008 Sep 19
PMID:Chain dynamics of nascent polypeptides emerging from the ribosome. 1880 69

Ethylene biosynthesis is directed by a family of 1-aminocyclopropane-1-carboxylic acid (ACC) synthases (ACS) that convert S-adenosyl-l-methionine to the immediate precursor ACC. Members of the type-2 ACS subfamily are strongly regulated by proteolysis with various signals stabilizing the proteins to increase ethylene production. In Arabidopsis, this turnover is mediated by the ubiquitin/26 S proteasome system, using a broad complex/tramtrack/bric-a-brac (BTB) E3 assembled with the ETHYLENE OVERPRODUCER 1 (ETO1) BTB protein for target recognition. Here, we show that two Arabidopsis BTB proteins closely related to ETO1, designated ETO1-like (EOL1) and EOL2, also negatively regulate ethylene synthesis via their ability to target ACSs for breakdown. Like ETO1, EOL1 interacts with type-2 ACSs (ACS4, ACS5 and ACS9), but not with type-1 or type-3 ACSs, or with type-2 ACS mutants that stabilize the corresponding proteins in planta. Whereas single and double mutants affecting EOL1 and EOL2 do not show an ethylene-related phenotype, they exaggerate the effects caused by inactivation of ETO1, and further increase ethylene production and the accumulation of ACS5 in eto1 plants. The triple eto1 eol1 eol2 mutant phenotype can be effectively rescued by the ACS inhibitor aminoethoxyvinylglycine, and by silver, which antagonizes ethylene perception. Together with hypocotyl growth assays showing that the sensitivity and response kinetics to ethylene are normal, it appears that ethylene synthesis, but not signaling, is compromised in the triple mutant. Collectively, the data indicate that the Arabidopsis BTB E3s assembled with ETO1, EOL1 and EOL2 work together to negatively regulate ethylene synthesis by directing the degradation of type-2 ACS proteins.
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PMID:The BTB ubiquitin ligases ETO1, EOL1 and EOL2 act collectively to regulate ethylene biosynthesis in Arabidopsis by controlling type-2 ACC synthase levels. 1880 54

We present a combined study of the adsorption and ordering of the l-tyrosine amino acid on the close-packed Ag(111) noble-metal surface in ultrahigh vacuum by means of low-temperature scanning tunneling microscopy (STM), X-ray photoelectron spectroscopy (XPS) and near-edge X-ray absorption fine structure (NEXAFS) spectroscopy. On this substrate the biomolecules self-assemble at temperatures exceeding 320 K into linear structures primarily following specific crystallographic directions and evolve with larger molecular coverage into two-dimensional nanoribbons which are commensurate with the underlying atomic lattice. Our high resolution topographical STM data reveal noncovalent molecular dimerization within the highly ordered one-dimensional nanostructures, which recalls the geometrical pattern already seen in the l-methionine/Ag(111) system and supports a universal bonding scheme for amino acids on smooth and unreactive metal surfaces. The molecules desorb for temperatures above 350 K, indicating a relatively weak interaction between the molecules and the substrate. XPS measurements reveal a zwitterionic adsorption, whereas NEXAFS experiments show a tilted adsorption configuration of the phenol moiety. This enables the interdigitation between aromatic side chains of adjacent molecules via parallel-displaced pi-pi interactions which, together with the hydrogen-bonding capability of the hydroxyl functionality, presumably mediates the emergence of the self-assembled supramolecular nanoribbons.
ACS Nano 2010 Feb 23
PMID:L-tyrosine on Ag(111): universality of the amino acid 2D zwitterionic bonding scheme? 2009 57

Because of their complex geometric and electronic structures, the active sites and cofactors of bioorganometallic enzymes, which are characterized by their metal-carbon bonds, pose a major challenge for computational chemists. However, recent progress in computer technology and theoretical chemistry, along with insights gained from mechanistic, spectroscopic, and X-ray crystallographic studies, have established an excellent foundation for the successful completion of computational studies aimed at elucidating the electronic structures and catalytic cycles of these species. This chapter briefly reviews the most popular computational approaches employed in theoretical studies of bioorganometallic species and summarizes important information obtained from computational studies of (i) the enzymatic formation and cleavage of the Co-C bond of coenzyme B(12); (ii) the catalytic cycle of methyl-coenzyme M reductase and its nickel-containing cofactor F(430); (iii) the polynuclear active-site clusters of the bifunctional enzyme carbon monoxide dehydrogenase/acetyl-coenzyme A synthase; and (iv) the magnetic properties of the active-site cluster of Fe-only hydrogenases.
Met Ions Life Sci 2009
PMID:Computational studies of bioorganometallic enzymes and cofactors. 2087 2

Protein lysine methyltransferases (PKMTs) play crucial roles in normal physiology and disease processes. Profiling PKMT targets is an important but challenging task. With cancer-relevant G9a as a target, we have demonstrated success in developing S-adenosyl-L-methionine (SAM) analogues, particularly (E)-hex-2-en-5-ynyl SAM (Hey-SAM), as cofactors for engineered G9a. Hey-SAM analogue in combination with G9a Y1154A mutant modifies the same set of substrates as their native counterparts with remarkable efficiency. (E)-Hex-2-en-5-ynylated substrates undergo smooth click reaction with an azide-based probe. This approach is thus suitable for substrate characterization of G9a and expected to further serve as a starting point to evolve other PKMTs to utilize a similar set of cofactors.
ACS Chem Biol 2011 Jul 15
PMID:Expanding cofactor repertoire of protein lysine methyltransferase for substrate labeling. 2149 74

Identification of pathways of drug metabolism provides critical information regarding efficacy and safety of these compounds. Particularly challenging cases involve stereospecific processes. We found that broad classes of compounds containing methylsulfinyl groups are reduced to methylsulfides specifically by methionine sulfoxide reductase A, which acts on the S-stereomers of methionine sulfoxides, whereas the R-stereomers of these compounds could not be efficiently reduced by any methionine sulfoxide reductase in mammals. The findings of efficient reduction of S-methylsulfinyls and deficiency in the reduction of R-methylsulfinyls by methionine sulfoxide reductases suggest strategies for improved efficacy and decreased toxicity of drugs and natural compounds containing methylsulfinyls through targeted use of their enantiomers.
ACS Chem Biol 2011 Oct 21
PMID:Selective reduction of methylsulfinyl-containing compounds by mammalian MsrA suggests a strategy for improved drug efficacy. 2182 15

Assimilatory sulfate reduction supplies prototrophic organisms with reduced sulfur that is required for the biosynthesis of all sulfur-containing metabolites, including cysteine and methionine. The reduction of sulfate requires its activation via an ATP-dependent activation to form adenosine-5'-phosphosulfate (APS). Depending on the species, APS can be reduced directly to sulfite by APS reductase (APR) or undergo a second phosphorylation to yield 3'-phosphoadenosine-5'-phosphosulfate (PAPS), the substrate for PAPS reductase (PAPR). These essential enzymes have no human homologue, rendering them attractive targets for the development of novel antibacterial drugs. APR and PAPR share sequence and structure homology as well as a common catalytic mechanism, but the enzymes are distinguished by two features, namely, the amino acid sequence of the phosphate-binding loop (P-loop) and an iron-sulfur cofactor in APRs. On the basis of the crystal structures of APR and PAPR, two P-loop residues are proposed to determine substrate specificity; however, this hypothesis has not been tested. In contrast to this prevailing view, we report here that the P-loop motif has a modest effect on substrate discrimination. Instead, by means of metalloprotein engineering, spectroscopic, and kinetic analyses, we demonstrate that the iron-sulfur cluster cofactor enhances APS reduction by nearly 1000-fold, thereby playing a pivotal role in substrate specificity and catalysis. These findings offer new insights into the evolution of this enzyme family and extend the known functions of protein-bound iron-sulfur clusters.
ACS Chem Biol 2012 Feb 17
PMID:Iron-sulfur cluster engineering provides insight into the evolution of substrate specificity among sulfonucleotide reductases. 2202 93


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