Aminotransferases important

Enzymes catalyzing transfer of the a-amino group of an amino acid to the a-carbon of an a-keto acid (often a-ketoglutarate) are known as transaminases or aminotransferases. Important intermediates in such reactions are a series of Schiff bases that can be trapped by reduction with sodium borohydride (Fischer et al., 1958). These enzymes provide typical examples of double-displacement (ping-pong) mechanisms, whereby the pyridoxa-mine phosphate form is a discrete intermediate, and reaction with an a-keto acid is necessary to regenerate the pyridoxal form (Scheme 2). Although the... 

The drug of choice for chronic hepatitis B depends on the patient s past medical history, aminotransferase level, HBV DNA level, and most importantly, HBeAg status. 

Persons with confirmed chronic hepatitis B should be evaluated for treatment, which may include interferon, pegylated interferon, lamivudine, adefovir dipivoxil, or entecavir. The drug of choice for chronic hepatitis B depends on the patient s past medical history, aminotransferase level, HBV DNA level, and most importantly, HBeAg status. 

The malate-aspartate shuttle is the most important pathway for transferring reducing equivalents from the cytosol to the mitochondria in brain. This shuttle involves both the cytosolic and mitochondrial forms of aspartate aminotransferase and malate dehydrogenase, the mitochondrial aspartate-glutamate carrier and the dicarboxylic acid carrier in brain (Fig. 31-5) [69]. The electrogenic exchange of aspartate for glutamate and a... 

A group of enzymes which is particularly important in amino acid metabolism in the liver (and also in muscle) is the transaminases, (also called aminotransferases). These are vitamin B6 (pyridoxine) dependent enzymes which transfer an amino group from an amino acid to an oxo (keto) acid, thus ... 

Drug/Lab test interactions Asympiomai c reversible increases in AST and ALT aminotransferase levels have occurred in patients treated with LMWHs and heparin. Because aminotransferase determinations are important in the differential diagnosis of Ml, liver disease, and PE, interpret elevations that might be caused by LMWHs with caution. 

Serum chemistry markers play an important role in hepatotoxicity evaluation in human and animal safety studies. The classic markers of hepatotoxicity are alanine aminotransferase (ALT), aspartate aminotrasnferase (AST) and alkaline phosphatase (ALP) [124—127]. Drug-induced hepatotoxicity can be difficult to assess in some circumstances. Hepatotoxic responses can be intrinsic (predictable, dose-related) or idiosyncratic (unpredictable, non-dose-related). ALT, AST and ALP are generally not useful for predicting idiosyncratic responses. The administration of some drugs, such as isoniazid, can lead to a high incidence of ALT elevation, but are tolerated by most patients without severe hepatotoxicity. Adverse drug reactions can be masked... 

The reactions catalyzed by two of the most important of these enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are shown below. 

Among the numerous enzymes that utilize pyridoxal phosphate (PLP) as cofactor, the amino acid racemases, amino acid decarboxylases (e.g., aromatic amino acids, ornithine, glutamic acid), aminotransferases (y-aminobutyrate transaminase), and a-oxamine synthases, have been the main targets in the search for fluorinated mechanism-based inhibitors. Pharmaceutical companies have played a very active role in this promising research (control of the metabolism of amino acids and neuroamines is very important at the physiological level). 

The most common adverse effects of indinavir are indirect hyperbilirubinemia and nephrolithiasis due to crystallization of the drug. Nephrolithiasis can occur within days after initiating therapy, with an estimated incidence of approximately 10%. Consumption of at least 48 ounces of water daily is important to maintain adequate hydration. Thrombocytopenia, elevations of serum aminotransferase levels, nausea, diarrhea, insomnia, dry throat, dry skin, and indirect hyperbilirubinemia have also been reported. Insulin resistance may be more common with indinavir than with the other Pis, occurring in 3-5% of patients. There have also been rare cases of acute hemolytic anemia. 

The SGOT and SGPT tests are also important in occupational medicine, to determine whether people exposed to carbon tetrachloride, chloroform, or other industrial solvents have suffered liver damage. Liver degeneration caused by these solvents is accompanied by leakage of various enzymes from injured hepato-cytes into the blood. Aminotransferases are most useful in the monitoring of people exposed to these chemicals, because these enzyme activities are high in liver and can be detected in very small amounts. 

GABA analogs are used in the treatment of epilepsy and hypertension. Levels of GABA can also be increased by administering inhibitors of the GABA-degrading enzyme GABA aminotransferase. Another important neuro-transmitter, serotonin, is derived from tryptophan in a two-step pathway. 

Substrate specificity of aminotransferases Each amnolrans ferase is specific for one or, at most, a few amino group donors. Aminotransferases are named after the specific amino gap donor, because the acceptor of the amino group is almost always a-ketoglutarate. The two most important aminotrans ferase reactions are catalyzed by alanine aminotransferase ati aspartate aminotransferase (Figure 19.8). 

Amino groups are tunneled to glutamate from all amino acids except lysine and threonine. The enzymes are aminotransferases, and they are reversible. The two most important of these enzymes are alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Aminotransferases require pyridoxal phosphate as a coenzyme. The presence of elevated levels of aminotransferases in the plasma can be used to diagnose liver disease. 

Many enzymes exist within a cell as two or more isoenzymes, enzymes that catalyze the same chemical reaction and have similar substrate specificities. They are not isomers but are distinctly different proteins which are usually encoded by different genes.22 23 An example is provided by aspartate aminotransferase (Fig. 2-6) which occurs in eukaryotes as a pair of cytosolic and mitochondrial isoenzymes with different amino acid sequences and different isoelectric points. Although these isoenzymes share less than 50% sequence identity, their internal structures are nearly identical.24-27 The two isoenzymes, which also share structural homology with that of E. coli,28 may have evolved separately in the cytosol and mitochondria, respectively, from an ancient common precursor. Tire differences between them are concentrated on the external surface and may be important to as yet unknown interactions with other protein molecules. 

This transamination reaction is a widespread process of importance in many aspects of the nitrogen metabolism of organisms. A large series of transaminases (aminotransferases), for which glutamate is most often one of the reactants, have been shown to catalyze the reactions of other oxoacids and amino acids.141-143... 

Racemization. A proton can be added back to the original alpha position but without stereospecificity. A racemase which does this is important to bacteria. They must synthesize D-alanine and D-glu-tamic acid from the corresponding L-isomers for use in formation of their peptidoglycan envelopes.153-1543 The combined actions of alanine racemase plus D-alanine aminotransferase, which produces D-glutamate as a product, provide bacteria with both d amino acids. 

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