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Organic & Biomolecular Chemistry May 2022Nitrogen heterocycles, especially polycyclic compounds, are significant skeletons in valuable molecules. Herein, we developed an efficient and practical...
Nitrogen heterocycles, especially polycyclic compounds, are significant skeletons in valuable molecules. Herein, we developed an efficient and practical visible-light-induced acylation/cyclization of active alkenes with acyl oxime derivatives for constructing acylated indolo/benzimidazo-[2,1,]isoquinolin-6(5) ones. This reaction was compatible with various functional groups and a series of fused indole/imidazole skeletons were prepared in up to 95% yield at room temperature.
Topics: Acylation; Alkenes; Cyclization; Light; Polycyclic Compounds
PubMed: 35438126
DOI: 10.1039/d2ob00528j -
Acylation of the Rat Brain Proteins is Affected by the Inhibition of Pyruvate Dehydrogenase in vivo.Biochemistry. Biokhimiia Jan 2023Organism adaptation to metabolic challenges requires coupling of metabolism to gene expression. In this regard, acylations of histones and metabolic proteins acquire...
Organism adaptation to metabolic challenges requires coupling of metabolism to gene expression. In this regard, acylations of histones and metabolic proteins acquire significant interest. We hypothesize that adaptive response to inhibition of a key metabolic process, catalyzed by the acetyl-CoA-generating pyruvate dehydrogenase (PDH) complex, is mediated by changes in the protein acylations. The hypothesis is tested by intranasal administration to animals of PDH-specific inhibitors acetyl(methyl)phosphinate (AcMeP) or acetylphosphonate methyl ester (AcPMe), followed by the assessment of physiological parameters, brain protein acylation, and expression/phosphorylation of PDHA subunit. At the same dose, AcMeP, but not AcPMe, decreases acetylation and increases succinylation of the brain proteins with apparent molecular masses of 15-20 kDa. Regarding the proteins of 30-50 kDa, a strong inhibitor AcMeP affects acetylation only, while a less efficient AcPMe mostly increases succinylation. The unchanged succinylation of the 30-50 kDa proteins after the administration of AcMeP coincides with the upregulation of desuccinylase SIRT5. No significant differences between the levels of brain PDHA expression, PDHA phosphorylation, parameters of behavior or ECG are observed in the studied animal groups. The data indicate that the short-term inhibition of brain PDH affects acetylation and/or succinylation of the brain proteins, that depends on the inhibitor potency, protein molecular mass, and acylation type. The homeostatic nature of these changes is implied by the stability of physiological parameters after the PDH inhibition.
Topics: Rats; Animals; Phosphorylation; Acylation; Pyruvate Dehydrogenase Complex; Oxidoreductases; Brain; Pyruvates
PubMed: 37068879
DOI: 10.1134/S0006297923010091 -
Scientific Reports Mar 2023Lysine Nɛ-acylations, such as acetylation or succinylation, are post-translational modifications that regulate protein function. In mitochondria, lysine acylation is...
Lysine Nɛ-acylations, such as acetylation or succinylation, are post-translational modifications that regulate protein function. In mitochondria, lysine acylation is predominantly non-enzymatic, and only a specific subset of the proteome is acylated. Coenzyme A (CoA) can act as an acyl group carrier via a thioester bond, but what controls the acylation of mitochondrial lysines remains poorly understood. Using published datasets, here we found that proteins with a CoA-binding site are more likely to be acetylated, succinylated, and glutarylated. Using computational modeling, we show that lysine residues near the CoA-binding pocket are highly acylated compared to those farther away. We hypothesized that acyl-CoA binding enhances acylation of nearby lysine residues. To test this hypothesis, we co-incubated enoyl-CoA hydratase short chain 1 (ECHS1), a CoA-binding mitochondrial protein, with succinyl-CoA and CoA. Using mass spectrometry, we found that succinyl-CoA induced widespread lysine succinylation and that CoA competitively inhibited ECHS1 succinylation. CoA-induced inhibition at a particular lysine site correlated inversely with the distance between that lysine and the CoA-binding pocket. Our study indicated that CoA acts as a competitive inhibitor of ECHS1 succinylation by binding to the CoA-binding pocket. Together, this suggests that proximal acylation at CoA-binding sites is a primary mechanism for lysine acylation in the mitochondria.
Topics: Lysine; Acylation; Acetylation; Acyl Coenzyme A; Protein Processing, Post-Translational; Binding Sites
PubMed: 36977698
DOI: 10.1038/s41598-023-31900-5 -
Angewandte Chemie (International Ed. in... Mar 2018We describe a selective and mild chemical approach for controlling RNA hybridization, folding, and enzyme interactions. Reaction of RNAs in aqueous buffer with an...
We describe a selective and mild chemical approach for controlling RNA hybridization, folding, and enzyme interactions. Reaction of RNAs in aqueous buffer with an azide-substituted acylating agent (100-200 mm) yields several 2'-OH acylations per RNA strand in as little as 10 min. This poly-acylated ("cloaked") RNA is strongly blocked from hybridization with complementary nucleic acids, from cleavage by RNA-processing enzymes, and from folding into active aptamer structures. Importantly, treatment with a water-soluble phosphine triggers a Staudinger reduction of the azide groups, resulting in spontaneous loss of acyl groups ("uncloaking"). This fully restores RNA folding and biochemical activity.
Topics: Acylation; Azides; Molecular Structure; Phosphines; RNA; RNA Folding
PubMed: 29370460
DOI: 10.1002/anie.201708696 -
The Journal of Biological Chemistry Sep 2023S-acylation is a reversible posttranslational protein modification consisting of attachment of a fatty acid to a cysteine via a thioester bond. Research over the last...
S-acylation is a reversible posttranslational protein modification consisting of attachment of a fatty acid to a cysteine via a thioester bond. Research over the last few years has shown that a variety of different fatty acids, such as palmitic acid (C16:0), stearate (C18:0), or oleate (C18:1), are used in cells to S-acylate proteins. We recently showed that GNAI proteins can be acylated on a single residue, Cys3, with either C16:0 or C18:1, and that the relative proportion of acylation with these fatty acids depends on the level of the respective fatty acid in the cell's environment. This has functional consequences for GNAI proteins, with the identity of the acylating fatty acid affecting the subcellular localization of GNAIs. Unclear is whether this competitive acylation is specific to GNAI proteins or a more general phenomenon in the proteome. We perform here a proteome screen to identify proteins acylated with different fatty acids. We identify 218 proteins acylated with C16:0 and 308 proteins acylated with C18-lipids, thereby uncovering novel targets of acylation. We find that most proteins that can be acylated by C16:0 can also be acylated with C18-fatty acids. For proteins with more than one acylation site, we find that this competitive acylation occurs on each individual cysteine residue. This raises the possibility that the function of many different proteins can be regulated by the lipid environment via differential S-acylation.
Topics: Acylation; Cysteine; Palmitic Acid; Proteome; HEK293 Cells; HeLa Cells; Humans; Stearic Acids
PubMed: 37495107
DOI: 10.1016/j.jbc.2023.105088 -
ELife Feb 2021Protein acylation is critical for many cellular functions across all domains of life. In bacteria, lipoproteins have important roles in virulence and are targets for the...
Protein acylation is critical for many cellular functions across all domains of life. In bacteria, lipoproteins have important roles in virulence and are targets for the development of antimicrobials and vaccines. Bacterial lipoproteins are secreted from the cytosol via the Sec pathway and acylated on an N-terminal cysteine residue through the action of three enzymes. In Gram-negative bacteria, the Lol pathway transports lipoproteins to the outer membrane. Here, we demonstrate that the Aat secretion system is a composite system sharing similarity with elements of a type I secretion systems and the Lol pathway. During secretion, the AatD subunit acylates the substrate CexE on a highly conserved N-terminal glycine residue. Mutations disrupting glycine acylation interfere with membrane incorporation and trafficking. Our data reveal CexE as the first member of a new class of glycine-acylated lipoprotein, while Aat represents a new secretion system that displays the substrate lipoprotein on the cell surface.
Topics: Acylation; Escherichia coli; Glycine; Lipoproteins; Protein Transport
PubMed: 33625358
DOI: 10.7554/eLife.63762 -
European Journal of Pharmaceutical... Jun 2019Polymer degradation within the controlled-release depots comprising of lactide and glycolide (PLGA) forms an acidic microenvironment, in which severe acylation of the...
Polymer degradation within the controlled-release depots comprising of lactide and glycolide (PLGA) forms an acidic microenvironment, in which severe acylation of the peptide by the polymer degradation products takes place. The aim of this study was to make out the role of the inner μpH on peptide acylation within the microspheres and how could it influence the reaction. The effects of pH on the acylation reaction within microspheres were composed of two aspects. Firstly, the inherent effect of pH on the acylation reaction itself was figured out: with the pH environment going up from acid to neutral, a model peptide (octreotide acetate) acylation became more and more serious. Then, the multivariate effect of pH on the dynamic microsphere delivery system especially the state of the acylation substrates (drug and oligomer) was investigated. When the inner pH was neutralized by Ca(OH) to varying degrees, polymer degradation rate, drug release rate, polymer degradation mechanism and oligomer accumulation state within the microspheres all changed. These changes highly affected the mass transfer of the acylation substrates to the external release medium. Neutralization of the μpH prolonged the retention time of drug and oligomer within the microspheres. Water absorption and single microsphere swelling experiments all showed a higher retention amount of acylation substrates during the critical period for peptide acylation. Generally, when the inner μpH was neutralized, except that the neutral environment itself promoted acylation reaction, the effects of pH on the dynamic system were also highly responsible for the serious acylation within the microspheres.
Topics: Acylation; Aminoacylation; Drug Delivery Systems; Drug Development; Drug Liberation; Hydrogen-Ion Concentration; Kinetics; Microspheres; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers
PubMed: 31002985
DOI: 10.1016/j.ejps.2019.04.017 -
Chembiochem : a European Journal of... Feb 2022Lysine acetylation is one of the most basic molecular mechanisms to mediate protein functions in living organisms, and its abnormal regulation has been linked to many...
Lysine acetylation is one of the most basic molecular mechanisms to mediate protein functions in living organisms, and its abnormal regulation has been linked to many diseases. The drug development associated to this process is of great significance but severely hindered by the complex interplay of lysine acetylation and deacetylation in thousands of proteins, and we reasoned that targeting a specific protein acetylation or deacetylation event instead of the related enzymes should be a feasible solution to this issue. Toward this goal, we devised an orthogonal lysine acylation and deacylation (OKAD) system, which potentially could precisely dissect the biological consequence of an individual acetylation or deacetylation event in living cells. The system includes a genetically encoded acylated lysine (PhOAcK) that is not a substrate of endogenous deacetylases, and an evolved sirtuin (CobB2/CobB3) that displays PhOAcK deacylase activities as well as reduced deacetylase activities. We believe the strategy introduced here holds potential for future in-depth biological applications.
Topics: Acylation; Histone Deacetylases; Lysine; Molecular Structure
PubMed: 34904351
DOI: 10.1002/cbic.202100551 -
Food Chemistry Sep 2022This study investigated correlations between gut microbiota and type 2 diabetic (T2D) indexes using either native resistant starch (RS, from high amylose maize starch,...
This study investigated correlations between gut microbiota and type 2 diabetic (T2D) indexes using either native resistant starch (RS, from high amylose maize starch, HAMS) or acylated starch via short-chain fatty acids (SCFAs) acylation. Compared to HAMS, consumption of acylated starch achieved a greater impact on the improvement of T2D indexes in term of body weight loss, fasting blood glucose, serum insulin level and amino acid metabolism. Intervention with acylated starches alleviated metabolism disorders and modified the gut microbiota. This study found all the acylated starch significantly enhanced the growth of SCFAs-producing bacteria compared to its native HAMS, and this change was highly consistent with their corresponding SCFAs concentration both in serum and fecal samples. This is the first reported to reveal that propionylated HAMS promoted the abundance of Bifidobacterium, while acetylated and butylated HAMS benefited the enrichment of Coprococcus, Butyricimonas and Blautia, which may indicate their different intervention pathway.
Topics: Acylation; Diabetes Mellitus, Type 2; Fatty Acids, Volatile; Feces; Gastrointestinal Microbiome; Humans; Starch
PubMed: 35490527
DOI: 10.1016/j.foodchem.2022.133089 -
Carbohydrate Polymers Dec 2017Chitosan nanofibers (CSNFs) have potential applications in biomaterials, oil recovery and food packaging, but their instability in moist environment has limited their...
Chitosan nanofibers (CSNFs) have potential applications in biomaterials, oil recovery and food packaging, but their instability in moist environment has limited their full utilization. Here we report that CSNFs can be O-acylated in a post-electrospinning treatment by using pyridine as catalyst and short-chain (C2, C3, C4, C5 and C6) and long-chain (C8 and C12) fatty acid anhydrates as acylation agents. The effects of O-acylation to CSNFs were analyzed in detail. FT-IR, H NMR and elemental analysis indicated that the hydroxyl groups of chitosan in CSNFs were acylated in 2h. XRD spectra indicated that the O-acylation modification altered the crystal structure of the native fibers and the acyl substituents packed in a laterally aligned and layered structure. SEM examinations showed that the acylation modification could effectively control the fibrous structure of CSNFs and improve their stability in moist environment. The O-acylated CSNFs generally have an average diameter about 100nm except for laurelated CSNFs (∼200nm). Water contact angle measurement indicated that the wetting properties of O-acylated CSNFs were affected by the length of acyl side chains. This fiber acylation strategy can tune the material properties of CSNFs and expand their potential applications.
Topics: Acylation; Chitosan; Fatty Acids; Nanofibers; Spectroscopy, Fourier Transform Infrared
PubMed: 28962759
DOI: 10.1016/j.carbpol.2017.08.132