Homogentisate dioxygenase

HOMOCYSTEINE S-METHYLTRANSEERASE HOMOGENEOUS CATALYSIS HOMOGENEOUS REACTION HOMOGENTISATE 1,2-DIOXYGENASE HOMOISOGITRATE DEHYDROGENASE Homoleptic,... 

Alkaptonuria <0.4 Tyrosine degradation Homogentisate 1,2-dioxygenase Dark pigment in urine late-developing arthritis... 

Hydroxyphenylpyravate dioxygenase (C 2.5) 2 homogentisate 1,2-dioxygenase 3 maleyl-acetoacetate isomerase, maleylacetoacetate lyase... 

The recently published structure of this dimeric enzyme that contains one type II Cu(II) catalytic center per monomer has revealed that it belongs to the cupin superfamily, that includes Fe-homogentisate 1,2-dioxygenase and Mn-oxalate oxidase, enzymes which are evolutionary related, in spite of their different metal preferences (4). The crystal structure shows that the Cu ion has two different coordinations. The first coordination environment, which represents approxi-... 

Examples include the liver enzymes, homogentisate dioxygenase (oxidase) and 3-hydroxyantliranilate dioxygenase (oxidase), that contain iron and L-trypto-phan dioxygenase (tryptophan pyrrolase) (Chapter 30), that utilizes heme. 

Another inheritable disease of phenylalanine catabolism is alkaptonuria, in which the defective enzyme is homogentisate dioxygenase (Fig. 18-23). Less serious than PKU, this condition produces few ill effects, although large amounts of homogentisate are excreted and its oxidation turns the urine black. Individuals with alkaptonuria are also prone to develop a form of arthri-... 

G. P. Titus, H.A. Mueller, J. Burgner, S. Rodriguez De Cordoba, M.A. Penalva, and D.E. Timm. 2000. Crystal structure of human homogentisate dioxygenase Mat. Struct. Biol. 7 542-546. (PubMed)... 

Another genetic disease that results from a deficiency of an enzyme in the pathway for phenylalanine degradation is al-captonuria, which is caused by lack of homogentisate dioxygenase. The only ill effect of this enzyme deficiency is black urine. The urine of those afflicted with alcaptonuria turns black because the homogentisate they excrete immediately oxidizes in the air. 

Homogentisate dioxygenase (E.C. 1.13.11.5- Homogentisate oxygen 1,2-oxidoreductase (decyclizing)... 

Alkaptonuria (homogentisate dioxygenase, HGD) Liver, kidney, intestine, prostate 3q21-q23 203500... 

Fig. 4.1. Tyrosine degradation pathway. Metabolic markers are framed. Possible metabolic disorders are marked with boxes, 4.1, fumarylacetoacetase 4.2, tyrosine aminotransferase 4.3, 4-hydroxyphenylpyruvate dioxygenase 4.5, homogentisate dioxygenase. Inhibition by succinylacetone and NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-l,3-cyclo-hexanedione) are indicated by crosses. 5-ALA, 5-aminolevulinate...

Denoya CD, DD Skinner, MR Morgenstern (1994) A Streptomyces avermitilis gene encoding a 4-hydroxy-phenylpyruvic acid dioxygenase-like protein that directs the production of homogentisic acid and an ochronotic pigment in Escherichia coli. J Bacterial 176 5312-5319. 

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. 

The enzyme p-hydroxyphenylpyruvate dioxygenase is involved in the conversion of p-hydroxyphenylpyruvate into homogentisate, a key step in plastoquinone biosynthesis. Inhibition of this enzyme has an indirect effect on carotenoid biosynthesis as plastoquinone is a co-factor of the enzyme phytoene desaturase. The new maize herbicide isoxaflutole and the triketone herbicides such as sulcotrione (Figure 2.7), inhibit p-hydroxyphenylpyruvate dioxygenase and this leads to the onset of bleaching in susceptible weeds and ultimately plant death.4... 

The 2-oxoacid p-hydroxyphenylpyruvate is decar-boxylated by the action of a dioxygenase (Eq. 18-49). The product homogentisate is acted on by a second dioxygenase, as indicated in Fig. 25-5, with eventual conversion to fumarate and acetoacetate. A rare metabolic defect in formation of homogentisate leads to tyrosinemia and excretion of hawkinsin97 a compound postulated to arise from an epoxide (arene oxide) intermediate (see Eq. 18-47) which is detoxified by a glutathione transferase (Box 11-B). 

Phenylalanine is first converted to tyrosine by the monooxygenase phenylalanine hydroxylase a reaction involving the coenzyme tetrahydrobiopterin. The tyrosine is then converted first by transamination and then by a dioxygenase reaction to homogentisate, which in turn is further metabolized to fumarate and acetoacetate. 

The metabolism of phenylalanine will now be considered in some detail, as two inborn errors of metabolism are known that affect this pathway. Phenylalanine is first hydroxylated by phenylalanine hydroxylase to form another aromatic amino acid tyrosine (Fig. 8). The coenzyme for this reaction is the reductant tetrahydrobiopterin which is oxidized to dihydrobiopterin. Phenylalanine hydroxylase is classified as a monooxygenase as one of the atoms of 02 appears in the product and the other in HzO. The tyrosine is then trans-aminated to p-hydroxyphenylpyruvate, which is in turn converted into homogentisate by p-hydroxyphenylpyruvate hydroxylase. This hydroxylase is an example of a dioxygenase, as both atoms of 02 become incorporated into the product (Fig. 8). The homogentisate is then cleaved by homogentisate oxidase, another dioxygenase, before fumarate and acetoacetate are produced... 

We end this section on enzyme inhibition with a case study about 4-hydroxyphenyl-pyruvate dioxygenase (HPPD) and disorders in tyrosine catabolism. After transamination of tyrosine, 4-hydroxyphenylpyruvate (148) is formed which is then decarboxylated, isomerized and oxygenated by HPPD to yield homogentisate (149) or by hydroxyman-delate synthase (HMS) to yield p-hydroxymandelate (150). 149 serves as the precursor for plastoquinones and tocopherols in plants . Thus, inhibitors of HPPD have been designed... 

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