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Cellular and Molecular Mechanisms of Ischemic Acute Renal Failure and Repair
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
Joseph V. Bonventre, Ralph Witzgall
Many cellular processes are critically dependent upon ATP hydrolysis. These processes cease or become markedly impaired when cellular ATP is markedly depleted. Ion gradients will dissipate without the ATP necessary for the ion transporter ATPases involved in maintenance of the ionic gradients. Sodium and calcium may accumulate in the cell. Deacylation, acylation cycling will be disrupted and fatty acids will accumulate due to the absence of energy required for the reacylation. Acidosis will develop as a consequence of increased glycolytic metabolism.
Internalization of Lipopolysaccharide by Phagocytes
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Richard L. Kitchens, Robert S. Munford
The actual biological role of LPS deacylation is uncertain. Deacylation of purified LPS occurs very slowly in both mononuclear phagocytes and neutrophils. Although very little is known about the ability of phagocytes to degrade the LPS that resides in native bacterial membranes, recent experiments found that rabbit peritoneal exudate macrophages deacylated the LPS in phagocytosed E. coli almost as rapidly as they cleaved the bacterial phospholipids, with removal of half of the nonhydroxylated (piggyback) fatty acids from the bacterial LPS within 4 hours. In contrast, the neutrophils in the exudate deacylated much less of the LPS in the E. coli they internalized (S. Katz, Y. Weinrauch, P. Elsbach, R. Munford, and J. Weiss, unpublished). These results point to a dominant role for macrophages in deacylating the LPS in bacterial membranes in vivo. Interestingly, even when macrophages were allowed to degrade phagocytosed bacteria for prolonged periods (20 hours), much of the LPS in the bacterial carcass remained at least partially acylated.
The Reaction Mechanism
Published in D. B. Keech, J. C. Wallace, Pyruvate Carboxylase, 2018
Another interesting facet of the interaction between pyruvate carboxylase and acetyl-CoA has been the observed sigmoidal velocity response to increasing concentrations of acetyl-CoA. This phenomenon was first reported by Barritt et al.77 using sheep kidney pyruvate carboxylase and later shown to be a property of other pyruvate carboxylases.203,761,771 With Hill coefficients (nH) approaching 3.0 for the chicken enzyme and 2.0 for the rat and sheep enzymes, it was concluded that acetyl-CoA bound to these enzymes in a highly cooperative manner.896 Despite a vast amount of research, this claim remained unsubstantiated and for a long time there were many more questions than answers. What was the mechanism of action of acetyl-CoA in stimulating the activity of pyruvate carboxylase? Was the "apparent" cooperativity a part of the mechanism? Why did the enzyme isolated from some sources require acetyl-CoA while others did not? What was the significance of the deacylation reaction?
Carbapenemase producing Klebsiella pneumoniae: implication on future therapeutic strategies
Published in Expert Review of Anti-infective Therapy, 2022
Ilias Karaiskos, Irene Galani, Vassiliki Papoutsaki, Lamprini Galani, Helen Giamarellou
Avibactam is the first BLBLI implemented within the clinical setting. Avibactam is a potent inhibitor of class A, C, and certain D β-lactamases, however, shows poor activity against organisms producing MBLs. Most interestingly, avibactam is a reversible covalent inhibitor and thus has a unique mechanism of inhibition among all β-lactamase inhibitors. Avibactam forms a noncovalent complex with the enzyme, then acylates the enzyme to give a covalent complex. Subsequent deacylation of the covalent complex proceeds through reversible cyclization and regeneration of the active inhibitor rather than undergoing hydrolysis [15,21]. Avibactam has been approved in combination with the third-generation cephalosporin ceftazidime with activity against P. aeruginosa [33]. Avibactam is currently in clinical trial in combination with aztreonam for the treatment of serious infections caused by MBL producing Gram-negative bacteria (Phase 3, Clinicaltrial.gov identifier: NCT03580044). Aztreonam has activity against MBL-producing pathogens, but it can be hydrolyzed by most Ambler class A, C, and D serine β-lactamases [34]. Avibactam, however, inhibits Ambler class A, C, and some D β-lactamases broadening the in vitro spectrum of aztreonam-avibactam combination. Avibactam with ceftaroline fosamil, which is a fifth-generation broad-spectrum parenteral cephalosporin with MRSA activity has completed a Phase 2 clinical trial (Clinicaltrial.gov identifier: NCT01281462).
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
The reaction of acetaldehyde oxidation by ALDH begins with the binding of NAD+ to the enzyme’s active site, which results in the conformational change of enzymatic protein and activation of Cys-302 thiol group. Nucleophilic attack of the –S– Cys-302 group on carbonyl carbon in the acetaldehyde leads to the formation of covalently bound tetrahedral thiohemiacetal oxyanion stabilised by two –NH groups in the protein chain. The transfer of hydrogen from the thiohemiacetal oxyanion to NAD+ results in the formation of a thio-ester intermediate compound. The nucleophilic attack of H2O molecule on the formed thioester results in its deacylation and a release of created acetate and NADH. The catalytic function in the last stage of the reaction (deacylation) is performed by Glu-268 (Marchitti et al., 2008).
Lipid–drug conjugates and associated carrier strategies for enhanced antiretroviral drug delivery
Published in Pharmaceutical Development and Technology, 2020
Funanani Takalani, Pradeep Kumar, Pierre P. D. Kondiah, Yahya E. Choonara, Viness Pillay
Triglycerides (TGs) are major constituents of dietary fat. In this conjugation, three fatty acids within the glycerol molecule are linked through an ester bond, resulting in TGs. Thus, drugs can bind to sn-1, sn-2, or sn-3 carbon atoms during conjugation (Markovic et al. 2019). However, one fatty acyl group amongst these located at position two is replaced by a drug conjugate to benefit from the unique metabolic pathway of TGs; process referred to as triglyceride deacylation–reacylation (Irby et al. 2017). This is a pathway whereby hydrolysis of TGs takes place in the gastrointestinal (GI) lumen, leading to the formation of 2-monoglyceride (2-MG) and free fatty acids. The monoglycerides are reacylated into enterocytes to yield triglycerides which are then integrated into lipoproteins to accumulate the lymphatic system (Han et al. 2014). The purpose of this conjugation is to target drugs in the lymphatic system while improving their absorption. As discussed under fatty acids, the chemistry of glyceride conjugation also involves activating agents that convert the hydroxyl group to a better leaving group such as chlorine (Zaro 2015).