Transaminases properties

Fenvalerate inhibits intercellular communication between fibroblast cells and enhances the development of hepatocyte foci in rat liver at nonhepatotoxic dose levels. Chemicals that possess these properties are likely to be tumor promoters (Flodstrom et al. 1988). Fenvalerate alone induced no hepatotoxic effects in rat liver, as judged by transaminase activities and histology. However, some rats that were partially hepatectomized and insulted with nitrosodiethylamine — a carcinogen and tumor initiator — had significantly elevated numbers of liver foci after administrations of fenvalerate. This response suggests that fenvalerate is a potential tumor promoter (Flodstrom et al. 1988). 

The association between vitamin B6 deficiency and transamination emerged from 1945 when Schlenk and Fisher noted that pyridoxine-deficient rats had a diminished capacity for transamination. In the same year Gunsalus and his colleagues found transamination in Streptococcus faecalis depended on pydridoxal phosphate. The properties of the heat-stable component in purified glutamic-oxaloacetate transaminase were similar to those of pydridoxal phosphate. Later pyri-doxal phosphate was established as an essential coenzyme in many amino acid transformations. 

Turning to l-AAO, Pantaleone s industrial research group have reported" on the properties and use of an l-AAO from Proteus myxofaciens, overexpressed in Escherichia coli This l-AAO, unusually, appears not to produce H2O2 in the catalytic reaction, thus making the addition of catalase unnecessary. The enzyme has a broad specificity, with a preference for nonpolar amino acids. This l-AAO was used in conjunction with a D-amino acid transaminase (d-AAT) and an alanine racemase (AR) to allow an efficient conversion of L-amino acid in to D-amino acid (Scheme 4). 

The liver is also the principal metabolic center for hydrophobic amino acids, and hence changes in plasma concentrations or metabolism of these molecules is a good measure of the functional capacity of the liver. Two of the commonly used aromatic amino acids are phenylalanine and tyrosine, which are primarily metabolized by cytosolic enzymes in the liver [1,114-117]. Hydroxylation of phenylalanine to tyrosine by phenylalanine hydroxylase is very efficient by the liver first pass effect. In normal functioning liver, conversion of tyrosine to 4-hy-droxyphenylpyruvate by tyrosine transaminase and subsequent biotransformation to homogentisic acidby 4-hydroxyphenylpyruvic acid dioxygenase liberates CO2 from the C-1 position of the parent amino acid (Fig. 5) [1,118]. Thus, the C-1 position of phenylalanine or tyrosine is typically labeled with and the expired C02 is proportional to the metabolic activity of liver cytosolic enzymes, which corresponds to functional hepatic reserve. Oral or intravenous administration of the amino acids is possible [115]. This method is amenable to the continuous hepatic function measurement approach by monitoring changes in the spectral properties of tyrosine pre- and post-administration of the marker. 

Danazol is a weak androgen and also has a series of other hormonal and anti-hormonal properties. It inhibits pituitary gonadotropin and has been used in the treatment of endometriosis, fibrocystic disease of the breast, idiopathic thrombocytopenic purpura, and hereditary angioedema. Its hepatotoxic effects include reversible rises in serum transaminases and cholestatic hepatitis a few cases of hepatocellular tumors have been reported. 

Owen, T.G. and Hochachka, P.W. (1974). Purification and properties of dolphin muscle aspartate and alanine transaminases and their possible roles in the energy metabolism of diving mammals. Biochemical Journal 143,541-553. 

GABA is converted to succinic semialdehyde [via GABA transaminase (GABAT) + pyri-doxal phosphate] which is thence oxidized to succinic acid which is further oxidized via the TCA cycle. 4-Hydroxybenzaldehyde from Gastrodia elata (Orchidaceae), a plant with antiepileptic properties, is an inhibitor of GABAT, as is the synthetic antiepileptic valproic acid (2-propenylpropanoic acid) (Table 6.6). 

A small historical study evaluated the effect of DMPA on six patients with either chronic active viral hepatitis or primary biliary cirrhosis. The study showed that DMPA actually improved transaminase levels and the metabolic ability of the liver. The investigators suggested that the immune-modifying properties of medroxyprogesterone may make the hormone a therapeutic alternative [2]. There were limitations in that this was a very small, non-randomised study, and therefore it is difficult to make specific recommendations based on the outcome. Another study of the metabolic effects of DMPA in women who had used the method for five years or more suggested that there was a significant rise in plasma insulin, alkaline phosphatase and morning cortisol levels in the DMPA users [31]. 

N4. Nisselbaum, J. S., and Bodansky, O., Immunochemical and kinetic properties of anionic and cationic glutamic-oxaloacetic transaminases separated from human heart and human liver. J. Biol. Chem. 239, 4232-4236 (1964). 

IFN-P shares 29% amino acid homology with IFN-a and has been used in the treatment of multiple sclerosis. Type 1 interferons (a and P) differ from Type II interferons (y) in biochemical properties, biological function, and receptor specificity. Side effects common to both classes of interferons include chills, fever, rigors, headache, myalgia s, hypotension, nausea, vomiting, anorexia, constipation, fatigue, neutropenia, and elevated transaminases. This constellation of symptoms frequently results in mild to moderate hypotension and volume depletion and could potentially contribute to prerenal azotemia or acute tubular necrosis. 

FIGURE 104 Vigabatrin inhibits GABA transaminases and has anticonvulsant properties. 

There are several examples of d to l inversion of amino acids in the literature. D-Phenylalanine may have therapeutic properties in endogenous depression and is converted to L-phenylalanine in humans [145]. o-Leucine is inverted to the L-enantiomer in rats. When o-enantiomer is administered, about 30% of the enantiomer is converted to the L-enantiomer with a measurable inversion from l to o-enantiomer. As indicated in Fig. 13, D-leucine is inverted to the L-enantiomer by two steps. It is first oxidized to a-ketoisocarproate (KIC) by o-amino acid oxidase. This a-keto acid is then asymmetrically reaminated by transaminase to form L-leucine. In addition, KIC may be decarboxylated by branched-chain a-keto acid dehydrogenase, resulting in an irreversible loss of leucine (Fig. 13) [146]. D-Valine undergoes a similar two-step inversion process, and this can be antagonized by other amino acids such as o-leucine. The primary factor appears to be interference with the deamination process [147]. 

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