Macronutrients
Chuong Pham-Huy, Bruno Pham Huy in Food and Lifestyle in Health and Disease, 2022
The name of an enzyme has two parts. The first part is the name of the substrate, and the second part is terminated with a suffix -ase (54). For example, protease is an enzyme of the substrate protein. For the international nomenclature, the name of an enzyme is preceded by the two letters EC (Enzyme Commission) followed by four numbers. For example, E.C.2.7.1.1. The first number denotes one of the six main classes: oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases. The second number denotes the subclass and the third number denotes the sub-subclass. The last number denotes the serial number of the enzyme in its sub-subclass (53–54). Enzymes are classified based on the reactions they catalyze into six classes cited above. Oxidoreductases such as glutathione reductase, lactate dehydrogenase, and glucose-6-phosphate dehydrogenase are the enzymes that catalyze oxidation-reduction reactions of their substrates. Transferases transfer a functional group between two substrates such as a methyl or phosphate group. Hydrolases catalyze the hydrolysis reactions of carbohydrates, proteins, and esters. Lyases cleave various chemical bonds by other means than hydrolysis and oxidation for the formation of double bonds. Isomerases are involved in isomerization of substrate where interconversion of cis-trans isomers is implicated. Ligases such as alanyl-t-RNA synthetase, glutamine synthetase, and DNA ligases join together two substrates with associated hydrolysis of a nucleoside triphosphate (53–54).
Role of Metabolism in Chemically Induced Nephrotoxicity
Robin S. Goldstein in Mechanisms of Injury in Renal Disease and Toxicity, 2020
Although the liver has generally been the focus of most drug metabolism studies and has been viewed as being quantitatively the most important site of metabolism in the body, numerous studies over the last 2 decades have shown that the kidneys are capable of carrying out extensive oxidative, reductive, hydrolytic, and conjugation processes (Anders, 1980; Jones et al., 1980). Enzyme systems similar to those responsible for these processes in extrarenal tissues are involved in renal drug metabolism. Examples include cytochrome P-450 with its associated NADPH-dependent reductase, the flavin-containing monooxygenase, alcohol and aldehyde dehydrogenases, epoxide hydrolase, esterases, acetylases, and the conjugation enzymes, including glucuronosyltransferases, sulfotransferases, and glutathione (GSH) S-transferases. Moreover, the kidneys are critical sites for biotransformation of many classes of xenobiotics, because certain metabolic pathways that are present at low activities in other tissues are present at high activities in specific regions of the nephron. One of the best examples of this type of drug metabolism pathway is the mercapturic acid pathway.
Hyperphenylalaninemia and defective metabolism of tetrahydrobiopterin
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
The classic presentation of abnormality in BH4 metabolism is of an infant who appears normal at birth, but is found on screening to have an elevated concentration of phenylalanine in blood. A tendency to low birth weight has been observed in patients with defective synthesis, especially with PTPS deficiency, and newborns frequently have low birth weights and clinical symptoms such as jitteriness but also hypoglycemia [23]. This is less common in reductase-deficient patients. Failure to thrive may be impressive. Development may be normal for two to three months; thereafter, a decrease in activity or a loss of head control may herald the onset of a progressive neurologic degenerative disease. Neurologic signs are progressive with truncal hypotonia, pinpoint pupils, and brisk tendon reflexes as well as movement disorders: hypokinesis, distal chorea, myoclonus, and oculogyric crises (see Figure 17.5). Hypotonia of the trunk and hypertonia of the limbs may develop (Figures 16.4–16.11) [6, 23, 24]. Onset may be with convulsions as early as three months of age [25].
Rational design of biodegradable sulphonamide candidates treating septicaemia by synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Nada H. El-Dershaby, Soad A. El-Hawash, Shaymaa E. Kassab, Hoda G. Dabees, Ahmed E. Abdel Moneim, Ibrahim A. Abdel Wahab, Mohammad M. Abd-Alhaseeb, Mostafa M. M. El-Miligy
All the newly synthesised compounds were evaluated for their in vitro antibacterial activities against the human pathogens: Staphylococcus aureus (RCMB 0100183), Staphylococcus epidermidis (RCMB 0100183), Streptococcus mutans (RCMB 0100172), and Bacillus subtilis (RCMB 0100162) as examples of Gram-positive bacteria and Pseudomonas aeruginosa (RCMB 0100243), Escherichia coli (RCMB 010052), Salmonella typhi (RCMB 0100104), Shigella dysenteriae (RCMB 0100542) and Proteus vulgaris (RCMB 010085) as examples of Gram-negative bacteria using Ampicillin and levofloxacin as standard Gram-positive and Gram-negative antibacterial agents respectively[6] (Table 5, page S5 supplementary file) see experimental section. The results showed that, most of the tested compounds did not exhibit significant in vitro antibacterial activity, whereas compounds (5 b, 5i, 5j, 5k, 5 m, 5n, and 5o) displayed weak in vitro antibacterial activity this could be assigned to the fact that the investigated compounds were azo co-drugs. Hence, metabolic biotransformation by azo-reductase enzyme into their active metabolites is a requirement for expressing their activities.
Evaluation of the drug–drug interaction potential for trazpiroben (TAK-906), a D2/D3 receptor antagonist for gastroparesis, towards cytochrome P450s and transporters
Published in Xenobiotica, 2021
Mitsuhiro Nishihara, Diane Ramsden, Suresh K. Balani
The reductase involved in [14C]trazpiroben metabolism was estimated based on the effect of reductase inhibitors using HLC. Typical reductase inhibitors were selected according to information in the literature (Rosemond et al.2004, Ramsden et al.2018). Phenobarbital, flufenamic acid, zopolrestat, chenodeoxycholic acid, and dexamethasone were used as aldo-keto reductase (AKR), 4-methylpyrazole was as an alcohol dehydrogenase inhibitor, disulphiram was as an aldehyde dehydrogenase inhibitor, quercetin and menadione were as short-chain dehydrogenase/reductase (SDR) and carbonyl reductase (CR) inhibitors, and dicumarol was as a quinone reductase inhibitor, respectively. The remaining activity was calculated as the percentage to the total radioactivity of the M23 peak in the sample with each inhibitor when the corresponding percentage in each control sample was regarded as 100%. The inhibition was calculated using the following equation: samp is the percentage to the total radioactivity of the M23 peak in the sample with each inhibitor (%) and PRcont is the percentage to the total radioactivity of the M23 peak in each control sample (%).
Lasmiditan: an additional therapeutic option for the acute treatment of migraine
Published in Expert Review of Neurotherapeutics, 2021
Daniele Martinelli, Vito Bitetto, Cristina Tassorelli
Lasmiditan is rapidly absorbed after oral administration [38,39] (average Tmax = 1.8 hours) also during the migraine attacks. Even though high-fat meals can modify some parameters (increase in Cmax and AUC by 22% and 19%, respectively), RCTs showed that the efficacy of the drug is not affected by food intake. At therapeutic concentrations, the drug is quite strongly bound by plasma proteins (55–60%) and is then eliminated with a geometric mean t½ value of approximately 5.7 hours; no accumulation was observed with daily dosing [39,40]. The primary elimination is through metabolism, mainly with ketone reduction, while renal excretion is a minor route of clearance. Lasmiditan undergoes hepatic and extrahepatic metabolism primarily by non-CYP enzymes. Significantly, many important enzymes are not involved in its metabolism: MAO-A, MAO-B, flavin monooxygenase 3, CYP450 reductase, xanthine oxidase, alcohol dehydrogenase, aldehyde dehydrogenase, aldo-keto reductases. On the other hand, lasmiditan inhibits P-glycoprotein (P-gp) and BCRP in vitro, therefore the concomitant use of lasmiditan and drugs that are substrates of P-gp or breast cancer resistance protein (BCRP) should be avoided.
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