Aspartate aminotransferase inhibition

Product inhibition is a cause of nonlinearity of reaction progress curves during fixed-time methods of enzyme assay. For example, oxaloacetate produced by the action of aspartate aminotransferase inhibits the enzyme, particularly the mitochondrial isoenzyme. The inhibitory product may be removed as it is formed by a coupled enzymatic reaction malate dehydrogenase converts the oxaloacetate to malate and at the same time oxidizes NADH to NADL... 

A cycloglutamate that inhibits An isomeric cycloglutamate tricholomic aspartate aminotransferase acid found in certain mushrooms... 

Soyasaponin I (1) inhibited the elevation of aspartate aminotransferase (AST) activity, which was comparable to that of glycyrrhizin (positive control). On the other hand, Kaikasaponin HI (21) was more effective than 1. Compound 21 showed antihepatotoxic activity at less than 100p.g/ml. Furthermore, the highest activity was observed even at lower doses (50, 100pg/ml). Therefore, sophoradiol OGs were concluded to be the anti-hepatotoxic principle in both crude drugs (Abri Heba and Puerariae Flos). 

Enzymes containing pyridoxal phosphate are prime targets for suicide inhibition because the chemistry is so naturally suitable. As discussed in Chapter 2, section C2, the pyridoxal ring acts as an electron sink that facilitates the formation of carbanions and also forms part of an extended system of conjugated double bonds. For example, vinyl glycine, CH2=CHCH(NH3+)C02, condenses with the pyridoxal phosphate of aspartate aminotransferase to form a Schiff base, as described in Chapter 2, equation 2.42.19 The a proton may be abstracted (as in equation 2.43) so that the isomerization shown in equation 9.13 readily occurs. 

The intermediate 9.14 is probably generated during the suicide inhibition of /3-aspartate decarboxylase,21 aspartate aminotransferase,22 and alanine racemase23,24 by /3-chloroalanine. These enzymes are inactivated by the intermediate, since they have not evolved to cope with it during the normal course of reaction. 

The hepatotoxicity produced by acute carbon tetrachloride-induced liver injury was found to be inhibited by essential oil from fennel, as evidenced by decreased levels of serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and bilirubin (Ozbek et al., 2003). 

Liver. In humans, chronic Cd exposure does not typically result in hepatotoxicity. In laboratory animals, the liver accumulates the largest concentrations of Cd after acute or chronic exposures. In chronically exposed rats, liver injury occurs prior to renal dysfunction. Chronic Cd effects in the liver include increased plasma activities of alanine and aspartate aminotransferases, structural irregularities in hepatocytes, and decreased microsomal mixed function oxidase and CYP450 activities. Acute exposures in rats result in hepatic necrosis, particularly in parenchymal cells. Additionally, rough endoplasmic reticulum deteriorates, while smooth endoplasmic reticulum proliferates. Mitochondria are also degraded. As is the case with chronic exposure, microsomal mixed function oxidases and CYP450s are inhibited. 

Aminolevulinate synthetase catalyzes the condensation of the Schiff s base of glycine with succinoyl-CoA. Recently, it has been found that 2-amino-4-methoxv-trans-3-butenolc acid, previously found to inhibit aspartate aminotransferase (13). also irreversibly Inactivates this enzyme (34). 

Inhibition of reverse transcriptase, alanine and aspartate aminotransferases 259,401 Inhibition of reverse transcriptase 401... 

Gostatin. Gostatin [43] Inhibits aspartate aminotransferase In wheat germ (1761. There Is a similarity In the mode of action of gostatin and gabacullne [41] (1771. 

The co-administration of M. oleifera seed powder with arsenic protects animals from arsenic induced oxidative stress and reduce body arsenic burden (49). Exposure of rats to arsenie (2.5 mg/kg, intraperitoneally for 6 weeks) increases the levels of tissue reaetive oxygen species (ROS), metallothionein (MT) and thiobarbitnrie aeid reaetive substance (TEARS) and is accompanied by a decrease in the aetivities in the antioxidant enzymes such as superoxide dismutase (SOD), eatalase and glutathione peroxidase (GPx). Also, Arsenic exposed mice exhibits hver injury as reflected by reduced acid phosphatase (AGP), alkaline phosphatase (ALP) and aspartate aminotransferase (AST) activities and altered heme synthesis pathway as shown by inhibited blood 8-aminolevulinic acid dehydratase (5-ALAD) activity. Co-administration of M. oleifera seed powder (250 and 500 mg/kg, orally) with arsenie significantly increases the activities of SOD, catalase, GPx with elevation in redueed GSH level in tissues (liver, kidney and brain). These ehanges are accompanied by approximately 57%, 64% and 17% decrease in blood ROS, liver metallothionein (MT) and lipid peroxidation respectively in animal eo-administered with M. oleifera and arsenic. There is a reduced uptake of arsenie in soft tissues (55% in blood, 65% in liver, 54% in kidneys and 34% in brain) following eo-administration of M. oleifera seed powder (particularly at the dose of 500 mg/kg). This points to the fact that administration of M. oleifera seed powder could be beneficial during chelation therapy with a thiol chelator (26). 

Skin rashes occur in approximately 10% of patients treated with clindamycin, and may be more common in patients with HIV infection. Other reactions, which are uncommon, include exudative erythema multiforme (Stevens-Johnson syndrome), reversible elevation of aspartate aminotransferase and alanine aminotransferase, granulocytopenia, thrombocytopenia, and anaphylactic reactions. Local thrombophlebitis may follow intravenous administration of the drug. Clindamycin can inhibit neuromuscular transmission and may potentiate the effect of a neuromuscular blocking agent administered concurrently. 

Fig. 25.7. The development of alcohol-induced hepatitis. (1) Acetaldehyde adduct formation decreases protein synthesis and impairs protein secretion. (2) Free radical injury results partly from acetaldehyde adduct formation with glutathione. (3) Induction of MEOS increases formation of free radicals, which leads to Upid peroxidation and cell damage. (4) Mitochondrial damage inhibits the electron transport chain, which decreases acetaldehyde oxidation. (5) Microtubule damage increases VLDL and protein accumulation. (6) CeU damage leads to release of the hepatic enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

Aspartate Aminotransferase Urea Nitrogen (BUN) Dibucaine (% Inhibition)... 

Two observations indicate that aspartate is formed primarily by a transamination reaction, probably from glutamate, rather than by a direct amination with NH4 in A. cylindrica. First, N-label in aspartate was reduced more than 90% by the presence of aminooxy acetate, while labeling of glutamate and glutamine was not reduced (IS). Second, [ N]aspartate was not detected when glutamate formation was inhibited either directly, by azaserine, or indirectly, when glutamine s)mthesis was inhibited by methionine sulfoximine (13). Moreover, activity of a glutamate-aspartate aminotransferase reaction has been detected in vitro in two strains of A. cylindrica (1,26). 

In rats provided with drinking water containing 1% valerian tincture (estimated dose 200-250 mg/kg daily) for 12 weeks with intramuscular injection of haloperidol (equivalent to 1 mg/kg daily), an increase in lipid peroxidation levels and dichlorofluorescein-reactive species production was observed in the hepatic tissue. In the liver and kidneys, 8-aminolevulinate dehydratase activity was inhibited. Serum alanine aminotransferase (ALT) was elevated, as compared to controls, while aspartate aminotransferase (AST) levels were unchanged (Dalla Corte et al. 2008). 

A number of studies have shown that natural metabolites can inhibit transamination. With a partially purified mung bean preparation which could use lysine, methionine, or aromatic amino acids as amino donors, it was found that the aliphatic substrates (e.g., lysine and methionine) inhibited the transamination of phenylalanine. The extent of this inhibition was related to their effectiveness as substrates, suggesting that they competed with phenylalanine (Gamborg, 1965). Using the highly purified but multispecific aromatic amino acid (and aspartate) aminotransferase from bush bean. Forest and Wightman (1973) demonstrated that 40 mM aspartate inhibited transamination of L-phenylalanine (40 mM) by 85%. Further experiments showed that elevated concentrations of phenylalanine reduced the inhibition by aspartate double-reciprocal plots indicated competitive inhibition. These... 

The enzyme inhibition by each oral administration of hypatin 125mg and 250mg/kg of body weight could reduce significantly 25.44% and 17.61% for alanine aminotransferase (ALT. GPT), 23.90% and 26.63% for aspartate aminotransferase (AST. GOT), and 1.96% and 10.41%, respectively for bilirubin content on their extents of increase in three enzyme activities when compared to that (the enzyme inhibition) in untreated mice induced by carbon tetrachloride (CCI4). 

Inhibitors of this type have been used in the irreversible inhibition of pyridoxal-linked aspartate aminotransferase, y-cystathionase, and tryptophan synthetase. These inhibitors are y-unsaturated amino acids. Aspartate aminotransferase is inhibited by molecules 1 and 2,... 

Chloroalanine has been found to be an irreversible inhibitor of the pyridoxal phosphate-linked yS-aspartate decarboxylase/ aspartate aminotransferase/ and alanine racemase. The mechanism of inhibition is shown above by Eq. (7) (the sulfate reacts in the same manner) amino-ethane sulfonate irreversibly inhibits pyridoxal phosphate-linked GABA transaminase and L-serine-O-sulfate irreversibly inhibits aspartate aminotransferase. ... 

Propargylglycine is an irreversible inhibitor of both pyridoxal-linked y-cystathionase and aspartate aminotransferase. The mechanism of inhibition of y-cystathionase involves the following sequence of steps. 

---