Aminotransferases Transaminases

Aminotransferase (transaminase) reactions form pymvate from alanine, oxaloacetate from aspartate, and a-ketoglutarate from glutamate. Because these reactions are reversible, the cycle also serves as a source of carbon skeletons for the synthesis of these amino acids. Other amino acids contribute to gluconeogenesis because their carbon skeletons give rise to citric acid cycle... 

EC2.6.1.1 L-aspartate aminotransferase (glutamate oxaloacetate transaminase) (aminotransferase (transaminase))... 

Pyridoxine (B ) Pyridoxal-P (PLP) Aminotransferases (transaminase) AST (GOT), ALT (GPT) 8-Aminolevulinate synthase Protein catabolism Heme synthesis MCC isoniazid therapy Sideroblastic anemia Cheilosis or stomatitis (cracking or scaling of lip borders and corners of the mouth) Convulsions... 

Aminotransferases (transaminases) catalyze the reversible interconversions of pairs of a-amino and a-keto acids or of terminal primary amines and the corresponding aldehydes by a shuttle mechanism in which the enzyme alternates between its PLP form and the corresponding PMP form. In the first half-reaction the PLP form of the enzyme binds the amino acid (or amine) and forms the coenzyme-substrate Schiff s base. Cleavage of the C-a—H bond is then followed by protonation at C-4. Hydrolysis of the resulting ketimine then gives a keto acid (or aldehyde), leaving the enzyme in the PMP form. The latter is recycled to the PLP form by condensation with an a-keto acid, deprotonation at C-4, protonation at C-a and transaldimina-tion to release the a-amino acid formed. 

D. Alanine aminotransferase (transaminase) requires pyridoxal phosphate. 

The vitamin Bg group comprises three natural forms pyridoxine (pyridoxol) (PA/), pyridoxamine (PM), and pyridoxal (PL), which are 4-substituted 2-methyl-3-hydroxyl-5-hydroxymethyl pyridines (Figure 30-13). During metabolic conversions, each vitamer becomes phosphorylated at the 5-hydroxymethyl substituent. Although both pyridox-amine-5 -phosphate (PMP) and pyridoxal-S -phosphate (PLP, P-5 -P) interconvert as coenzyme forms during aminotransferase (transaminase)-catalyzed reactions, PLP is the coenzyme form that participates in the large number of Bg-dependent enzyme reactions. 

DCA causes the liver to increase in volume as a result of a build-up of glycogen. Increases in aminotransferase (transaminase) levels have been observed during treatment with high doses of DCA, in both rodents and humans. DCA can cause focal, or even widespread, hepatocellular necrosis in mice, but no cases have been described in rats, dogs or humans, even when administered in high doses. Neurological toxicity in humans is limited to sedation and potential peripheral neuropathy that is reversible. 

Describe the reactions catalyzed by the aminotransferases (transaminases) and state the major function of these reactions. 

Deamination, Transamination. Two kiads of deamination that have been observed are hydrolytic, eg, the conversion of L-tyrosiae to 4-hydroxyphenyUactic acid ia 90% yield (86), and oxidative (12,87,88), eg, isoguanine to xanthine and formycia A to formycia B. Transaminases have been developed as biocatalysts for the synthetic production of chiral amines and the resolution of racemic amines (89). The reaction possibiUties are illustrated for the stereospecific synthesis of (T)-a-phenylethylamine [98-84-0] (ee of 99%) (40) from (41) by an (5)-aminotransferase or by the resolution of the racemic amine (42) by an (R)-aminotransferase. 

One class of enzymes that follow a ping-pong-type mechanism are aminotransferases (previously known as transaminases). These enzymes catalyze the transfer of an amino group from an amino acid to an a-keto acid. The products are a new amino acid and the keto acid corresponding to the carbon skeleton of the amino donor ... 

Pyridoxamine phosphate serves as a coenzyme of transaminases, e.g., lysyl oxidase (collagen biosynthesis), serine hydroxymethyl transferase (Cl-metabolism), S-aminolevulinate synthase (porphyrin biosynthesis), glycogen phosphoiylase (mobilization of glycogen), aspartate aminotransferase (transamination), alanine aminotransferase (transamination), kynureninase (biosynthesis of niacin), glutamate decarboxylase (biosynthesis of GABA), tyrosine decarboxylase (biosynthesis of tyramine), serine dehydratase ((3-elimination), cystathionine 3-synthase (metabolism of methionine), and cystathionine y-lyase (y-elimination). 

When administering tacrine, the nurse must monitor the patient for liver damage. This is best accomplished by monitoring alanine aminotransferase (AIT) levels. ALT is an enzyme found predominately in the liver. Disease or injury to the liver causes a release of tiiis enzyme into the bloodstream, resulting in elevated ALT levels, hi patients taking tacrine, ALT levels should be obtained weekly from at least week 4 to week 16 after die initiation of tiierapy. After week 16, transaminase levels are monitored every 3 months. 

When administering the HMG-CoA reductase inhibitors and the fibric acid derivatives, the nurse monitors the patient s fiver function by obtaining serum transaminase levels before the drug regimen is started, at 6 and 12 weeks, then periodically thereafter because of the possibility of liver dysfunction with the drugs. If aspartate aminotransferase (AST) levels increase to three times normal, the primary care provider in notified immediately because the HMG-CoA reductase inhibitor therapy may be discontinued. 

Hepatocellular damage manifests as elevated serum aminotransferases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)]. The degree of transaminase elevation does not correlate with the remaining functional metabolic capacity of the liver. An AST level two-fold higher than ALT is indicative of alcoholic liver damage. 

Interferon beta 1a (Rebif) 44 meg SQ Three times per week Flu-like symptoms 28% Injection site reactions 66% Leukopenia 22% Increased aspartate aminotransferase/ alanine transaminase 1 7-27%... 

Interferon beta 1b (Betaseron) 0.25 mg SQ Every other day Flu-like symptoms 60-76% Injection site reactions 50-85% Asthenia 49% Menstrual disorder 1 7% Leukopenia 1 0-1 6% Increased aspartate aminotransferase/ alanine transaminase 4-1 9%... 

The aminotransferases, aspartate transaminase and alanine transaminase, are enzymes that have increased concentrations in plasma following hepatocellular injury. The highest concentrations are seen in acute viral infections, or ischemic or toxic liver injury. 

Glutamate oxalacetic transaminase (SGOT), now frequently referred to as aspartate aminotransferase (AST)... 

Figure 1.16 Enzyme aspartate transaminase (= aspartate aminotransferase)...

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 ... 

As examples, two enzymes that will be discussed again later in this chapter are alanine transaminase (alanine aminotransferase) and aspartate transaminase (aspartate aminotransferase). In both cases, the amino group is transferred to 2-oxoglutarate (also known as a-ketoglutarate), which is oxoacid, above, forming glutamate as amino acid2. For example, the alanine transaminase (ALT) reaction is ... 

Transaminase enzymes (also called aminotransferases) specifically use 2-oxoglutarate as the amino group acceptor to generate glutamate but some have a wide specificity with respect to the amino donor. For example, the three branched-chain amino acids leucine, isoleucine and valine, all serve as substrates for the same enzyme, branched-chain amino acid transaminase, BCAAT ... 

Catalytic domain 1 doubly wound parallel fi sheet Catalytic domain 2 classic doubly wound fi sheet (Fig. 76) Aspartate transaminase see Aspartate aminotransferase Aspartate transcarbamylase (Monaco et ah, 1978), see Aspartate carbamoyltransferase... 

The aminotransferases (ATs) (or transaminases) catalyze the exchange of an amino group between an amino acid and an oxoacid, so that the amino acid is converted into an oxoacid and vice versa (Equation (4)). 

ALT = alanine aminotransferase (newer name) GPT - glutamate-pyruvate transaminase (older name) AST = aspaitate aminotransferase (newer name) GOT = glutamate-oxaloacetate transaminase (older name)... 

The reactions are catalysed by enzymes known as aminotransferases (formerly known as transaminases). For the above reactions, they are (i) aspartate aminotransferase, (ii) alanine aminotransferase and (iii) leucine aminotransferase. Details of these reactions can be found in Appendix 8.4. 

Aminotransferases have received many names as fashions in nomenclature have changed. Two obsolete names are still used in chnical practice glutamate-oxaloacetate transaminase (abbreviated to GOT) is now aspartate aminotransferase, and glutamate-pyruvate transaminase (GPT) is now alanine aminotransferase. The new abbreviations are AST and ALT, respectively. 

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