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Diagnosis and Pathobiology
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
The epigenetic machinery can be separated into a number of interconnected components such as histone PTMs, DNA methylation (the most well-studied epigenetic alteration), noncoding RNAs (ncRNAs), and undercharacterized modifications (not discussed here) such as chromatin modifications, chromatin accessibility, histone (H) variants (e.g., H3.3, H2A.X, H2A.Z), and RNA modifications (e.g., N6-methyladenosine (m6A)) [296, 364, 367, 391, 393, 399, 402]. Many epigenetic modifications involve covalent bond modifications; however, the main noncovalent epigenetic mechanisms include incorporation of histone variants, nucleosome remodeling, and noncoding RNAs [369]. Chromatin structure and gene expression are regulated by specific amino acids of histone protein tails (consisting of 15–38 amino acids) that undergo various PTMs [366]. Due to the complex diversity among PTMs, the following are considered types of acylation: acetylation, propionylation, butyrylation, crotonylation, 2-hydroxy isobutyrylation, malonylation, succinylation, and glutarylation [403]. Ubiquitylation, sumoylation of lysine residues, and phosphorylation of serine (S) and threonine (T) residues, as well as formylation, O-GlcNAcylation, propionylation, adenosine diphosphate (ADP)-ribosylation, deamination, proline/aspartic acid isomerization, citrullination/eamination, biotinylation, and crotonylation, are reported histone modifications (>200 known modifications) that occur at more than 60 amino acid residues [296, 364, 386, 387, 394, 395].
The Chemical Synthesis of Lipid A
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Shoichi Kusumoto, Koichi Fukase, Masato Oikawa
In the scheme in Figures 4 and 5, knowledge accumulated up to now concerning the chemical synthesis of lipid A is concentrated to represent a simplified route to this complex bacterial glycoconjugate and its analogs. The total yield of 4 (Fig. 4), for example, amounted to 6.9% in 13 steps starting from N-Trocglucosamine. Further effort is still being made in the authors’ laboratory to elaborate a more divergent route through which the two hydroxy and two amino groups can be differentiated for acylation. Such a route will be soon available to construct a completely divergent family of acyl analogs on the common hydrophilic backbone of lipid A.
Structural Aspects of Luteinizing Hormone Actions
Published in Mario Ascoli, Luteinizing Hormone Action and Receptors, 2019
Wayne L. Gordon, Darrell N. Ward
For the β-subunit little published evidence is available concerning the amino terminal group sensitivity. In our laboratory we have recently shown that over 98% of the amino terminus of rabbit lutropin is blocked by a pyroglutamyl residue.47a Moreover, B. Shome and A. F. Parlow have confirmed that their rabbit lutropin preparations also have a blocked N-terminus on the β-subunit.47b Thus, the proposition that acylation of the amino terminus may not be a particularly sensitive reactive site seems reasonably safe. Therefore, interpretation in terms of effects on the remaining ε-amino groups on lysine residues is not unwarranted.
Determination of carnitine ester profile in the children with type 1 diabetes: a valuable step towards a better management
Published in Archives of Physiology and Biochemistry, 2022
Parisa Rahmani, Ruhollah Abolhasani, Ghobad Heidari, Ali Mohebbi, Fatemeh Sayarifard, Ali Rabbani, Nahid Vafaei, Jabar Lotfi
A significant decrease in plasma free carnitine and an increase in plasma and urine acylcarnitine level have been found in diabetic ketosis (Genuth and Hoppel 1979). The study also found that the acylation rate is dependent on tissue carnitine availability (Genuth and Hoppel 1979). In line with our findings, increased levels of free carnitine, short-chain (C2, C3, C4, C5), medium-chain (C6, C8, C10, C10:1) and long-chain (C14:1, C16, C18, C18:1) ACs have been reported in type 2 diabetic patients (Möder et al.2003, Adams et al.2009, Mihalik et al.2010, Reuter and Evans 2012, Mai et al.2013). Elevated medium-chain (C6, C8, C10) and long-chain (C14, C18:1) ACs of plasma has been reported in African-American women with type 2 diabetes (Adams et al.2009), On the other hand; another study found an increase in short-chain (C3, C4, C5), medium-chain (C6, C8, C10:1) and long-chain (C14:1, C16, C18, C18:1) ACs in type 2 diabetes patients (Mihalik et al.2010). Similar increase was found in our type I diabetes patients.
Poly(lactic-co-glycolic acid) microsphere production based on quality by design: a review
Published in Drug Delivery, 2021
Yabing Hua, Yuhuai Su, Hui Zhang, Nan Liu, Zengming Wang, Xiang Gao, Jing Gao, Aiping Zheng
Currently, most of the sustained-release PLGA microspheres approved by FDA are loaded with peptide drugs. However, the chemical interactions between PLGA and peptides pose a significant obstacle for the successful development of these formulations. The nucleophilic primary amine groups (such as N-terminal and lysine side chains), and the carboxylic acid end groups of PLGA or PLGA degradation products can interact to form acylated adducts, which may have harmful effects, including loss of activity, immunogenicity, and toxicity (Houchin et al., 2007; Houchin & Topp, 2008). Generally, the electrostatically driven sorption of the peptide to PLGA is a common precursor to its acylation and is followed by the release of the acylated peptide. Many studies have focused on inhibiting the acylation of polypeptide drugs in PLGA. For instance, Zhang & Schwendeman (2012) found that peptide acylation is strongly inhibited in formulations containing divalent cations and/or carboxymethyl cassava starch as excipients. Moreover, Jiwei et al. (2019) neutralized the inner pH of microspheres, to varying degree, using Ca(OH)2; the polymer degradation rate, drug release rate, polymer degradation mechanism, and oligomer accumulation state within the microsphere are all affected. Houchin & Topp (2008) further summarized the chemical degradation reactions of peptide/protein in PLGA microspheres and their mechanisms, while discussing certain methods for stabilizing these drugs in PLGA systems.
Toward the identification of ZDHHC enzymes required for palmitoylation of viral protein as potential drug targets
Published in Expert Opinion on Drug Discovery, 2020
Mohamed Rasheed Gadalla, Michael Veit
Instrumental for high throughput screening is a fluorescent assay which was developed for autoacylation of purified Erf2 [186] and self-palmitoylation of Bet3 [131]. The palmitoylation reaction (protein + Pal‐CoA → protein‐Pal + CoA) produces free CoA, which is coupled to the following enzymatic reaction: CoA + α‐ketoglutarate + NAD + KDH → succinyl‐CoA + NADH + KDH. The second reporter reaction is catalyzed by α-ketoglutarate dehydrogenase (KDH), which uses NAD as a cofactor that is reduced to NADH for the formation of succinyl-CoA. The production of NADH is detected by its fluorescence emission peak at 465 nm. This assay allows determining the kinetics and stoichiometry of the acylation reaction and its fatty acid specificity. Using the Erf2 assay a group of inhibitors based on a bis-cyclic-piperazine backbone were identified from a scaffold ranking library. It is currently unknown whether these compounds are specific for Erf2 or are general palmitoylation inhibitors [187].