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PubMed Journal Database | Biochemistry RSS

03:55 EDT 24th August 2019 | BioPortfolio

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For example view all recent relevant publications on Epigenetics and associated publications and clincial trials.

Showing PubMed Articles 1–25 of 990 from Biochemistry

Unusual Activity of a TET/JBP Family Enzyme.

The Structural Basis by Which the N-terminal Polypeptide Segment of Rhizopus chinensis Lipase Regulates Its Substrate Binding Affinity.

An important group of industrial enzymes, Rhizopus lipases exhibit valuable hydrolytic features that underlie their biological functions. Particularly important is their N-terminal polypeptide segment (NTPS), which is required for secretion and proper folding, but is removed in the process of enzyme maturation. A second common feature of this class of lipases is the α-helical "lid", which regulates accessibility of substrate to the enzyme active site. Some Rhizopus lipases also exhibit "interfacial activat...

Structure and Function of the Acetylpolyamine Amidohydrolase from the Deep Earth Halophile Marinobacter subterrani.

Polyamines are small organic cations essential for cellular function in all kingdoms of life. Polyamine metabolism is regulated by enzyme-catalyzed acetylation-deacetylation cycles in similar fashion to the epigenetic regulation of histone function in eukaryotes. Bacterial polyamine deacetylases are particularly intriguing, since these enzymes share the fold and function of eukaryotic histone deacetylases. Recently, acetylpolyamine amidohydrolase from the deep earth halophile Marinobacter subterrani (msAPAH...

Detection of Labile Conformations of Elastin's Prolines by Solid-State NMR and FTIR Techniques.

Samples of native elastin are prepared with high levels of enrichment at its prolines, which are believed to play a major role in the elasticity of elastin. Major and minor populations of trans and cis isomers at the XaaPro imide bonds are detected in two-dimensional (2D) 13C NMR experiments. One- and two-dimensional 13C NMR and isotope-edited FTIR experiments are also used to identify the prolines' folded and unfolded states, Type II β-turn and random coil, respectively, at physiological temperatures. Thi...

A Panel of Protein Kinase Chemosensors Distinguishes Different Types of Fatty Liver Disease.

The worldwide incidence of fatty liver disease continues to rise, which may account for concurrent increases in more aggressive liver ailments. Given the existence of histologically identical fatty liver disease subtypes, there is a critical need for the identification of methods that can classify disease and potentially predict progression. Herein, we show that a panel of protein kinase chemosensors can distinguish fatty liver disease subtypes. These direct activity measurements highlight distinct differen...

Off-target Editing by CRISPR-guided DNA base editors.

Base editing is a genome editing strategy that induces specific single nucleotide changes within genomic DNA. Two major DNA base editors, Cytosine base editors (CBEs) and Adenine base editors (ABEs), have been developed that consist of a Cas9 protein linked to a deaminase enzyme that catalyzes targeted base conversion directed by a sgRNA. This strategy has been used widely for precise genome editing because, unlike CRISPR-Cas nuclease-based genome editing systems, this strategy does not create double strand...

Structural and mutagenesis studies evince the role of the extended protuberant domain of ribosomal protein uL10 in protein translation.

The lateral stalk of ribosomes constituted the GTPase-associated centre and is responsible for recruiting translation factors to the ribosomes. Eukaryotic stalk contains a P-complex, in which one molecule of uL10 (formerly known as P0) protein binds two copies of P1/P2 heterodimers. Unlike bacterial uL10, eukaryotic uL10 has an extended protuberant (uL10ext) domain inserted in the N-terminal RNA-binding domain. Here, we determined the solution structure of the extended protuberant domain of Bombyx mori uL10...

Deuterium Kinetic Isotope Effects Resolve Low-Temperature Substrate Radical Reaction Pathways and Steps in B-Dependent Ethanolamine Ammonia-Lyase.

The first-order reaction kinetics of the cryotrapped 1,1,2,2-H-aminoethanol substrate radical intermediate state in the adenosylcobalamin (B)-dependent ethanolamine ammonia-lyase (EAL) from serovar Typhimurium are measured over the range of 203-225 K by using time-resolved, full-spectrum electron paramagnetic resonance spectroscopy. The studies target the fundamental understanding of the mechanism of EAL, the signature enzyme in ethanolamine utilization metabolism associated with microbiome homeostasis and...

Therapeutic Monosaccharides: Looking back, moving forward.

In this review we focus on the metabolism of mammalian glycan-associated monosaccharides, where the vast majority of our current knowledge comes from research done during the 1960's and 1970's. Most monosaccharides enter the cell using distinct, often tissue specific transporters from the SLC2A family. If not catabolized, these monosaccharides can be activated to donor nucleotide sugars and used for glycan synthesis. Apart from exogenous and dietary sources, all monosaccharides and their associated nucleoti...

Structural and kinetic insight into the biosynthesis of H2S and L-lanthionine from L-cysteine by a PLP-dependent enzyme from Fusobacterium nucleatum.

Fusobacterium nucleatum is a common oral bacterium and a major producer of H2S, a toxic gas linked to the pathogenesis of periodontal disease. The bacterium encodes a fold type II pyridoxal-L-phosphate (PLP)-dependent enzyme, Fn1220 or lanthionine synthase (LS) that generates H2S and L-lanthionine (a component of the peptidoglycan layer) through β-replacement of L-cysteine by a second molecule of L-cysteine. Herein, we show through detailed kinetic analysis that LS elicits catalytic promiscuity as demonstr...

Sugar Vinyl Sulfoxide Glycoconjugation of Peptides and Lysozyme: Abrogation of Proteolysis at the Lysine Sites.

We describe a glycoconjugation strategy, wherein a sugar vinyl sulfoxide, acting as Michael donor, reacts with amine nucleophiles arising from lysine side chain in peptides and proteins, at physiological pH and temperature efficiently. The method permits glycoconjugation of the lysine residues present in lysozyme with the sugar vinyl sulfoxide. The glycoconjugation of the protein abrogates the trypsin-mediated proteolysis at the lysine sites. The modified protein catalyzes digestion of Gram-negative E. coli...

Unveiling the biochemistry of the epigenetic regulator SMYD3.

SET and MYND domain-containing protein 3 (SMYD3) is a lysine methyltransferase that plays a central role in a variety of cancer diseases, exerting its pro-oncogenic activity by methylation of key proteins, both of nuclear and cytoplasmic nature. However, the role of SMYD3 in the initiation and progression of cancer is not yet fully understood and further biochemical characterization is required to support the discovery of therapeutics targeting SMYD3. We have therefore developed robust protocols for the pro...

Insights into the autoproteolytic processing and catalytic mechanism of the virulence-associated protease CPAF.

CPAF (chlamydial protease-like activity factor) is a protease that is translocated into the host cytosol during infection. CPAF activity results in dampened host inflammation signaling, cytoskeletal remodeling, and suppressed neutrophil activation. Although CPAF is an emerging antivirulence target, its catalytic mechanism has been unexplored to date. Steady state kinetic parameters were obtained for recombinant CPAF with vimentin-derived peptide substrates using an HPLC-based discontinuous assay ( = 45 ± ...

Molecular determinants of epistasis in HIV-1 protease: Elucidating the interdependence of L89V and L90M mutations in resistance.

Protease inhibitors have the highest potency among antiviral therapies against HIV-1 infections, yet the virus can evolve resistance. Darunavir (DRV), currently the most potent FDA approved protease inhibitor, retains potency against single site mutations. However, complex combinations of mutations can confer resistance to DRV. While the interdependence between mutations within HIV-1 protease is key for inhibitor potency, the molecular mechanisms that underlie this control remain largely unknown. In this st...

Mechanistic and Structural Insights into Cysteine-Mediated Inhibition of Pyruvate Kinase Muscle Isoform 2.

Cancer cells regulate key enzymes in the glycolytic pathway to control the glycolytic flux, which is necessary for their growth and proliferation. One of the enzymes is pyruvate kinase muscle isoform 2 (PKM2), which is allosterically regulated by various small molecules. Using detailed biochemical and kinetic studies, we demonstrate that cysteine inhibits wild-type (wt) PKM2 by shifting from an active tetramer to a mixture of tetramer and less active dimer/monomer equilibrium and that the inhibition is depe...

NMR solution structure and functional behavior of the human proton channel.

The human voltage gated proton channel (Hv11 or VSDO2) plays an important role in the human innate immune system. Its structure differs considerably from other cation channels. It is build solely of a voltage-sensing domain and thus lacks the central pore domain, which is essential for other cation channels. Here, we determined the solution structure of a N- and C-terminal truncated human Hv1 (Δ-Hv1) in the resting state by nuclear magnetic resonance (NMR) spectroscopy. Δ-Hv1 comprises the typical voltage...

A Bounty of New Challenging Targets in Oncology for Chemical Discovery.

Nucleation of an Activating Conformational Change by a Cation-π Interaction.

As a key molecule in biology, adenosine tri-phosphate (ATP) has numerous crucial functions in, for instance, energetics, post-translational modifications, nucleotide biosynthesis, and co-factor metabolism. Here, we have discovered an intricate interplay between the enzyme adenylate kinase and its substrate ATP. The side-chain of an arginine residue was found to be an efficient sensor of the aromatic moiety of ATP through the formation of a strong cation-π interaction. In addition to recognition, the intera...

The Electronic Structure of the Metal Active Site Determines the Geometric Structure and Function of the Metalloregulator NikR.

NikR is a nickel-responsive metalloregulator protein that controls the level of Ni2+ ions in living cells. Previous studies have shown that NikR can bind a series of first row transition metal ions, but only binds to DNA with high affinity as a Ni2+ complex. To understand this metal selectivity, S K-edge XAS of NikR bound to different metal ions was used to evaluate the different electronic structures. The experimental results are coupled with DFT calculations on relevant models. This study shows that both ...

Structure and Chemical Reaction Mechanism of LigU, an Enzyme that Catalyzes an Allylic Isomerization in the Bacterial Degradation of Lignin.

LigU from Novosphingobium sp. strain KA1 catalyzes the isomerization of (4E)-oxalomesaconate (OMA) to (3Z)-2-keto-4-carboxy-3-hexenedioate (KCH) as part of the protocatechuate (PCA) 4,5-cleavage pathway during the degradation of lignin. The three-dimensional structure of the apo-form of the wild-type enzyme was determined by X-ray crystallography and the structure of the K66M mutant enzyme was determined in the presence of the substrate OMA. LigU is a homodimer requiring no cofactors or metal ions with a di...

Gα and the Phospholipase Cβ3 X-Y Linker Regulate Adsorption and Activity on Compressed Lipid Monolayers.

Phospholipase Cβ (PLCβ) enzymes are peripheral membrane proteins required for normal cardiovascular function. PLCβ hydrolyzes phosphatidylinositiol-4,5-bisphosphate (PIP), producing second messengers that increase intracellular Ca and activate protein kinase C (PKC). Under basal conditions, PLCβ is autoinhibited by its C-terminal domains and by the X-Y linker, which contains a stretch of conserved acidic residues required for interfacial activation. Following stimulation of G protein coupled receptors, ...

Structural and Functional Characterization of YdjI, an Aldolase of Unknown Specificity in Escherichia coli K12.

The ydj gene cluster is found in 80% of sequenced Escherichia coli genomes and other closely related species found in the human microbiome. Based on the annotations of the enzymes located in this cluster, it is expected that together they catalyze the catabolism of an unknown carbohydrate. The focus of this investigation is on YdjI, which is found in the ydj gene cluster of E. coli K-12. It is predicted to be a class II aldolase of unknown function. Here we describe a structural and functional characterizat...

Incorporating 2-thiouracil into short dsRNA-binding PNAs for enhanced recognition of A-U pairs and for targeting a microRNA hairpin precursor.

Chemically-modified short Peptide Nucleic Acids (PNAs) recognize RNA duplexes at near physiological conditions by major-groove PNA·RNA-RNA triplex formation and show a great promise in developing RNA-targeting probes and therapeutics. Thymine (T) and uracil (U) are often incorporated into PNAs to recognize A-U pairs through major-groove T·A-U and U·A-U triple formation. Incorporation of a modified nucleobase, 2-thiouracil (s2U), into triplex-forming oligonucleotides (TFOs) stabilizes both DNA and RNA tri...

Mechanism of single-stranded DNA activation of recombinase intein splicing.

Inteins, or intervening proteins, are mobile genetic elements translated within host polypeptides and removed through protein splicing. This auto-catalytic process breaks two peptide bonds and rejoins the flanking sequences, called N- and C-exteins, with the intein scarlessly escaping the host protein. Traditionally viewed as purely selfish genetic elements, recent work has demonstrated that the conditional protein splicing (CPS) of several naturally occurring inteins can be regulated by a variety of enviro...

Tumor suppressor p53-mediated structural reorganization of the transcriptional coactivator p300.

Transcriptional coactivator p300, a critical player in eukaryotic gene regulation, primarily functions as a histone acetyltransferase (HAT). It is also an important player in acetylation of a number of non-histone proteins, p53 being the most prominent one. Recruitment of p300 to p53 is pivotal in the regulation of p53-dependent genes. Emerging evidence suggest that p300 adopts an active conformation upon binding to the tetrameric p53, resulting in its enhanced acetylation activity. As a modular protein, p3...


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