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The Study of Drug Metabolism Using Radiotracers
Published in Graham Lappin, Simon Temple, Radiotracers in Drug Development, 2006
Conjugation with a number of amino acids may occur, but glycine and perhaps taurine are probably the most common. The mechanism for amino acid conjugation is quite complex (indeed more than one mechanism exists). One mechanism is via the acetyl-coenzyme A (CoA) activation of the xenobiotic. As an example, activation of benzoic acid to acetyl-CoA is catalyzed by acetyl-CoA synthetase, as shown in Figure 3.21. The formation of the glycine conjugate is catalyzed by acetyl-CoA amino acid N-acetyltransferase. Glycine conjugates are also known as hippuric acids.
Sirtuins as therapeutic targets for improving delayed wound healing in diabetes
Published in Journal of Drug Targeting, 2022
Fathima Beegum, Anuranjana P. V., Krupa Thankam George, Divya K. P., Farmiza Begum, Nandakumar Krishnadas, Rekha R. Shenoy
SIRT 3, 4 and 5 are found in the mitochondrial matrix and have mitochondrial targeting sequence in their N-terminal. SIRT 3 which is a mitochondrial sirtuin increases acetyl-CoA synthesis by moving along with ‘acetyl-CoA synthetase 2’and deacetylating lysine 642 in both in vitro and in vivo [66]. Role of SIRT 3 in fatty acid oxidisation is also observed during fasting studies which reported that the SIRT 3 knockout mice exhibited high levels of fatty acid oxidisation intermediates and reduced adenosine triphosphate levels [67]. During fasting, SIRT 3 removes the acetyl group in long-chain acyl-CoA dehydrogenase and upregulates its enzymatic activity. SIRT 4 has adenosine triphosphate ribosylation activity [68]. The insulin secretion in pancreatic β cells may be controlled by SIRT 4 by ADP-ribosylating glutamate dehydrogenase (GDH) [69]. The SIRT 5 has deacetylase activity which regulates the pancreatic beta cell proliferation and insulin secretion [70]. The mitochondrial sirtuins possess a vital role in calorie restriction and controlling metabolic adaptations to dietary conditions like fasting [71].
Gene expression profiling of rat livers after continuous whole-body exposure to low-dose rate of gamma rays
Published in International Journal of Radiation Biology, 2018
Acetyl-CoA is at the center of lipid metabolism. Cytosolic acetyl-CoA synthesis, which is essential for de novo lipogenesis, was reduced in response to the low-dose-rate radiation. The cytosolic pool of acetyl-CoA is mainly supplied by two different ATP-dependent reactions: cleavage of citrate, which is generated from TCA cycle, into oxaloacetate and acetyl-CoA by ATP citrate lyase (ACLY) or the ligation of acetate and CoA by acetyl-CoA synthetase (ACSS) (Schug et al. 2015). Both ACLY and ACSS2, the cytosolic ACSS, were transcriptionally down-regulated in this study. Another pathway in producing cytosolic acetyl-CoA was through converting acetoacetate to acetoacetyl-CoA by acetoacetyl-CoA synthetase (AACS) and subsequently to acetyl-CoA by acetyl-CoA acetyltransferase 2 (ACAT2). This acetyl-CoA synthesis was also decreased as both Aacs and Acat2 genes were down-regulated.
Molecular mechanisms of ethanol biotransformation: enzymes of oxidative and nonoxidative metabolic pathways in human
Published in Xenobiotica, 2020
Grażyna Kubiak-Tomaszewska, Piotr Tomaszewski, Jan Pachecka, Marta Struga, Wioletta Olejarz, Magdalena Mielczarek-Puta, Grażyna Nowicka
Acetic acid, which is a product of the reaction catalyzed by ALDH, is effectively released from liver cells to the peritoneal space, from where it enters the bloodstream. It is one of the factors determining the development of metabolic acidosis. This is despite the fact that in the cytosol of hepatocytes, acetyl-CoA synthetase (ACS, AceCS, AcCoAS, acetate:CoA ligase, EC 6.2.1.1) is present, which, interestingly, is one of the seven nickel metalloproteins identified in the body (Watt & Ludden, 1999). The cytoplasmic isoenzyme ACS1 (AceCS1) present in the liver is characterised by a high Km value in the reaction with acetate, which increases the importance of acetate activation to acetyl-CoA directly in the liver only at very high acetate concentrations (Fujino et al., 2001; Lumeng & Davis, 1973; Yamashita et al., 2001). At the same time, acetyl-CoA hydrolase (EC 3.1.2.1), present in cytosol, mitochondrial matrix and peroxisomes of hepatocytes, is activated by high concentrations of NADH + H+, which is a typical consequence of ethanol metabolism catalyzed by ADH and ALDH (ExPasy, 2020; Garras et al., 1995; Hovik et al., 1991; IUBMB, 2020; Yamashita et al., 2001). Thus, the likelihood of further use of metabolic acetate, formed as a result of ethanol biotransformation is close to zero in the liver itself. The situation is different in myocytes of the myocardium, where the mitochondrial isoenzyme of acetyl-CoA synthase (ACS2, AceCS2) shows a low Km value in comparison to the liver variant, with a low activity of acetyl-CoA hydrolase. Myocytes of skeletal muscles show a similar, but slightly less marked, enzymatic ability to use acetates. Thanks to the observed enzymatic differentiation, acetates released from the liver can become valuable energy and sometimes building substrates for heart muscle cells, skeletal muscle cells, and perhaps also for cells of other peripheral tissues. After activation to acetyl-CoA (Figure 10) they can be used as substrates in the Krebs cycle or, less commonly, in anabolic processes, e.g. synthesis of fatty acids (Fujino et al., 2001; Mittendorfer et al., 1998; Yamashita et al., 2001).