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Chemistry of Essential Oils
Published in K. Hüsnü Can Başer, Gerhard Buchbauer, Handbook of Essential Oils, 2020
Many enzymes need cofactors as reagents or energy providers. Coenzyme-A has already been mentioned earlier. It is a thiol and is used to form thioesters with carboxylic acids. This has two effects on the acid in question. First, the thiolate anion is a better leaving group than alkoxide and so the carbonyl carbon of the thioester is reactive toward nucleophiles. Second, the thioester group increases the acidity of the protons adjacent to the carbonyl group and therefore promotes the formation of the corresponding carbanions. In biosynthesis, a key role of adenosine triphosphate (ATP) is to make phosphate esters of alcohols (phosphorylation). One of the phosphate groups of ATP is added to the alcohol to give the corresponding phosphate ester and adenosine diphosphate. Another group of cofactors of importance to biosynthesis includes pairs such as NADP/NADPH, TPN/TPNH, and DPN/DPNH. These cofactors contain an N-alkylated pyridine ring. In each pair, one form comprises an N-alkylated pyridinium salt and the other the corresponding N-alkyl-1,4-dihydropyridine. The two forms in each pair are interconverted by gain or loss of a hydride anion and therefore constitute redox reagents. In all of the cofactors mentioned here, the reactive part of the molecule is only a small part of the whole. However, the bulk of the molecule has an important role in molecular recognition. The cofactor docks into the active site of the enzyme through recognition, and this holds the cofactor in the optimum spatial configuration relative to the substrate.
Multiple acyl CoA dehydrogenase deficiency/glutaric aciduria type II ethylmalonic-adipic aciduria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The mitochondrial oxidations of glutaryl-CoA and other intermediates in branched-chain amino acid metabolism, and the β-oxidation of fatty acids (see Figure 45.1) are catalyzed by mitochondrial flavinadenine dinucleotide (FAD)-dependent enzymes [8–11]. Each of the dehydrogenase enzymes of fatty acid oxidation, and the amino acid catabolic enzymes catalyze the dehydrogenation of saturated acylCoA compounds to form the 2,3-unsaturated or enoylCoA thioesters (Figure 45.2). Both sarcosine and dimethylglycine are catabolized by specific N-methyldehydrogenases containing covalently bound FAD and dissociable folic acid cofactors [12–14], and thus these two compounds may also accumulate in this disease. Each dehydrogenase enzyme contains a molecule of FAD.
Radiolabeled Enzyme Inhibitors
Published in William C. Eckelman, Lelio G. Colombetti, Receptor-Binding Radiotracers, 2019
Suicide inhibitors possess latent reactive groups that are selectively activated by the target enzyme. Once generated, the reactive group covalently binds to the enzyme leading to its irreversible inhibition. The first and best studied example of this approach was Bloch and co-workers’ use of β,γ-acetylenic thioesters to inactivate β-hydroxy decanoyl thioester dehydrase in E. coli.40 As shown in Figure 9, the dehydrase catalyzes the formation of the highly reactive conjugated allenic thioester from the acetylenic precursor. The aliène group then alkylates a histidine residue at the active site. The thioester of 3-decynoic acid, both in vitro and in vivo, completely inactivates the dehydrase at a concentration of 10−5M.
Bempedoic acid, an inhibitor of ATP citrate lyase for the treatment of hypercholesterolemia: early indications and potential
Published in Expert Opinion on Investigational Drugs, 2020
Bempedoic acid is a prodrug, able to cross cell membranes, that is activated intracellularly by conversion to bempedoic acid-Coenzyme A (CoA) through very long-chain acyl-CoA synthetase-1 (ACSVL1), predominantly expressed in hepatocytes and smaller amounts in renal cells, but not in muscle cells [21,22] (Figure 1). The active form, bempedoic acid-CoA thioester, inhibits fatty acid and sterol synthesis by modulation of two key enzymes: adenosine triphosphate-citrate lyase (ACL) and adenosine monophosphate-activated protein kinase (AMPK) [22]. ACL is a cytosolic enzyme upstream of HMG-CoA reductase, the target enzyme of statins. ACL converts citrate and CoA to oxaloacetate and acetyl-CoA, which is the substrate for fatty acid and cholesterol synthesis. Hence, inhibition of ACL by bempedoic acid decreases the cytosolic cholesterol concentration, which activates the sterol recognition element binding protein (SREBP) pathway leading to increased expression of LDL-receptors [23]. The higher number of LDL-receptors on the hepatocyte surface then enhances the removal of circulating LDL-particles from the bloodstream.
Structure-activity relationship of atorvastatin derivatives for metabolic activation by hydrolases
Published in Xenobiotica, 2020
Kenta Mizoi, Masato Takahashi, Sachiko Sakai, Takuo Ogihara, Masami Haba, Masakiyo Hosokawa
Thioester prodrugs are specifically metabolically activated by HLM because of the high HLM/HIM ratio (Table 2). However, in the comparison of thioesters with the corresponding esters, the hydrolytic activity by hCESs was complicated (Figure 2). The rate at which thioesters are hydrolyzed by HLM and HIM is considered to be higher than the corresponding esters because thiolate anion is more stable than alkoxide ion. However, it is thought that the hydrolysis rate of hCESs became complicated when considering the sulfur atom has lower electronegativity and a larger atomic radius than an oxygen atom, or the steric structure of the substituent. Therefore, these results suggested that the hydrolytic activity of hCESs may be regulated by the balance between steric hindrance and the electron density in a thioester.
Nanoparticle-based drug delivery in the inner ear: current challenges, limitations and opportunities
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Rahul Mittal, Stefanie A. Pena, Angela Zhu, Nicolas Eshraghi, Arian Fesharaki, Elijah J. Horesh, Jeenu Mittal, Adrien A. Eshraghi
The surface of NPs can be modified to target specific structures by conjugating ligands to the surface using bio-conjugation techniques. Some newer methods include expressed protein ligation (EPL) and click chemistry [36,37]. In EPL, a site-specific chemical ligation is made between a recombinant protein with a C-terminal thioester and a peptide or protein with an N-terminal cysteine. A C-terminal thioester can then be added onto a targeting ligand through the use of inteins (autoprocessing proteins) which are then placed between the ligand and an affinity tag. After bacterial expression and affinity purification steps, the ligand is released from the affinity tag to create a reactive thioester at the C-terminus. The thioester can then react with any peptide containing an N-terminal cysteine [17]. On the other hand, click chemistry adds ligands to NPs through a Cu I- catalyzed terminal alkyne-azide cycloaddition [17]. A drawback of click chemistry is the reaction process, which may degrade or modify the target of interest. Recently, EPL and click chemistry techniques have been combined to allow for the conjugation of targeting ligands to NPs that are site specific. The combined method allows for a stereospecific ligand attachment onto the NP surface. This method has been used to conjugate full antibodies, peptides and drugs onto the NP surface [38].