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Fumaryl acetoacetate

Leptospermone (34), a representative of an important new class of herbicides from the bottlebrush plant, Callistemon citrinus (Curtis) Skeels, has been found to have an inhibitory effect on the enzyme, -hydroxyphenylpyruvate dioxygenase (HPPD), involved in the synthesis of plastoquinone in plants. Nitisinone (35), a synthetic derivative of (34), has recently been introduced to the market for the treatment of hereditary tyrosinemia type 1 (HT-1), a severe genetic disease caused by a deficiency of fumaryl acetoacetate hydrolase (FAH). ... [Pg.26]

Nitisinone is a reversibile inhibitor of 4-hydroxy-phenylpyruvate oxidase, an enzyme that plays a crucial role in the tyrosine catabolic pathway. Nitisinone prevents the accumulation of the toxic metabolites fumaryl acetoacetate, succinyl acetoacetate and succinyl acetone. Nitisinone is used for the treatment of hereditary tyrosinemia type 1. After oral administration bioavailability is 90% and peak levels are reached at 2.5 hours after dosing. The drug is eliminated mainly in the urine but some CYP3A4-mediated metabolism seems to occur. The elimination half-life is 45 hours. Blood dyscrasias are frequently occurring side effects as are eye problems like conjunctivitis, corneal opacity and keratitis. Exfoliative dermatitis, erythematous rash and pruritus... [Pg.487]

Tyrosine is either used for the biosynthesis of proteins, thyroxine, epinephrine, or melanin, or catabo-lized to yield fumaryl acetoacetate. The biosynthesis of proteins and thyroxine is discussed elsewhere this discussion is restricted to epinephrine and melanin synthesis and tyrosine catabolism. Dopa 3,4-dihydroxy-phenylalanine is an intermediate common to epinephrine and melanin. To yield epinephrine, dopa is first decarboxylated by an enzyme called dopa decarboxylase. This enzyme is present in several mammalian tissues, including the adrenal medulla, where the reaction yields hydroxytryptamine chloride. From this... [Pg.174]

The cis and trans isomerization of maleyl- to fumaryl-acetoacetate is catalyzed by a liver enzyme which requires glutathione (GSH) as its coenzyme. This type of a reaction has not previously been shown to occur enzymically. There are indications that geometric isomerizations must also occur in the metabolism of vitamin A (1) and benzene (2). The nature of the reaction is also different from the one other enzyme reaction (glyoxa-lase) in which GSH plays a coenzyme role. [Pg.183]

The new intermediate could be distinguished from fumaryl-acetoacetate (4) by its ultraviolet absorption spectrum, particularly its lack of absorption in acid solution, and by its failure to be hydrolyzed by /3-diketonase. The two compounds were similar in most other respects, both giving the reactions of unsaturated /3,5-diketo-dicarboxylic acids. The new intermediate was converted to fumaryl-acetoacetate in 24 hr. at pH 1 and 4°, and more rapidly at higher temperatures, but not at all at alkaline pH. This acid isomerization has so far prevented isolation of the compound. The cts-configuration of maleyl-acetoacetate was established by alcoholic KOH hydrolysis followed by chromatographic identification of the maleic acid moiety, under conditions in which fumaric acid was obtained from fumaryl-acetoacetate. [Pg.184]

Due to the specificity of j3-diketonase, only the fumaryl-acetoacetate in a mixture of the two isomers can be hydrolyzed in the absence of glutathione. [Pg.184]

Fig. 1. The action of isomerase and -diketonase. Liver protein (0.3 mg.) containing both isomerase and -diketonase was added to a mixture of the substrates, in which the absorption at 330 m,u was due 30% to fumaryl-acetoaoetate and 70% to maleyl-acetoacetate, at pH 7.5. Lower curve 2.5 mM. GSH present initially produced complete hydrolysis. Upper curve Without GSH only fumaryl-acetoacetate was hydrolyzed, but after addition of GSH the maleyl-acetoacetate was also hydrolyzed. Fig. 1. The action of isomerase and -diketonase. Liver protein (0.3 mg.) containing both isomerase and -diketonase was added to a mixture of the substrates, in which the absorption at 330 m,u was due 30% to fumaryl-acetoaoetate and 70% to maleyl-acetoacetate, at pH 7.5. Lower curve 2.5 mM. GSH present initially produced complete hydrolysis. Upper curve Without GSH only fumaryl-acetoacetate was hydrolyzed, but after addition of GSH the maleyl-acetoacetate was also hydrolyzed.
On addition of glutathione to the mixed liver enzymes, the isomerase present converts maleyl- to fumaryl-acetoacetate and the latter can then be hydrolyzed. Both diketo-acids absorb at neutral pH in the near ultraviolet and their disappearance by these i-eactions was followed directly in the spectrophotometer (Fig. 1). When excess j3-diketonase was present, the second part of the reaction was a measure of the isomerase activity. [Pg.185]

Using the above assays both the isomerase and the 8-diketonase have been separated from each other by ethanol fractionation. Study of the purified enzymes showed that isomerization occurred only when both the isomerase and glutathione were present, and not at significant rates with either alone. The purified isomerase converted maleyl- to fumaryl-acetoacetate, which accumulated, but the reverse reaction did not occur. The purified /3-diketonase did not require glutathione and had no essential thiol groups. Its hydrolysis of maleyl-acetoacetate was immeasurably slow. [Pg.185]

The pathway from homogentisate (7) to acetoacetate (9) and fumarate (10) proceeds by oxidative fission of the aromatic ring of homogentisate to give maleyl acetoacetate (8), which is then iso-merised to fumaryl acetoacetate . Hydrolysis of this intermediate then yields fumarate and acetoacetate S Figure 4.1. [Pg.133]

This enzyme was discovered by Knox and Edwards 221). The cleavage of homogentisic acid yields maleylacetoacetate as would be logically expected. Because of the presence generally of the isomerase, fumaryl-acetoacetate was the product observed by Ravdin and Crandall 220)... [Pg.132]

Another coenzymic role of glutathione was described by Strittmatter and Ball in the DEN -linked fonnaldehyde dehydrogenase system of liver 128). The enzymic reduction of nitrate requires GSH 129) as a reducing agent. It has also been diown that GSH is the coenzyme of the enzymic isomerization of 4-maIeyl- to 4-fumaryl-acetoacetate 128a). [Pg.254]


See other pages where Fumaryl acetoacetate is mentioned: [Pg.59]    [Pg.115]    [Pg.64]    [Pg.183]    [Pg.348]    [Pg.59]    [Pg.115]    [Pg.64]    [Pg.183]    [Pg.348]    [Pg.654]   
See also in sourсe #XX -- [ Pg.133 ]




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