4- Hydroxyphenyl-pyruvic

Phenylalanine is hydroxylated to tyrosine and then sequentially to 4-hydroxyphenyl-pyruvate and by dioxygenation and rearrangement to 2,5-dihydroxyphenylpyruvate (Figure 3.16) (Arias-Barrau et al. 2004). Hydroxylation involves 6,7-dimethyltetrahydro-biopterin that is converted into the 4a-carbinolamine (Song et al. 1999). Copper is not a component of the active enzyme, although there is some disagreement on whether or not Fe is involved in the reaction for the hydroxylase from Chromobacterium violaceum (Chen and Frey 1998). 

Johnson-Winters K, VM Purpero, M Kavana, T Nelson, GR Moran (2003) (4-Hydroxyphenyl)pyruvate dioxygenase from Streptomyces avermitilis the basis for ordered substrate addition. Biochemistry 42 2072-2080. 

Hall MG Wilks ME, Provan WM, Eksborg S, Lumholtz B. (2001) Pharmaco-kinetics and pharmacodynamics of NTBC [2-(2-nitro-4-fluo-romethyl-benzoyl)-l,3-cyclohexanedione] and mesotrione, inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD) following a single dose to healthy male volunteers. Br J Clin Pharmacol 52 169-177. 

Kavana M, Moran GR. (2003) Interaction of (4-hydroxyphenyl)pyruvate dioxygenase with the specific inhibitor 2-[2-nitro-4-(trifluoromethyl) benzoyl]- ,3-cyclohexanedione. Biochemistry 42 10238-10245. 

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... 

Intramolecular nucleophilic substitution of electrogenerated phenoxonium ions has been investigated . In connection with naturally occurring bromo compounds, methyl 3,5-dibromo-4-hydroxyphenyl pyruvate oxime (98) was subjected to anodic oxidation (-1-1.3 V Vi. SCE 2.1 Fmol ) in MeOH to afford spiro-isoxazole 99 in almost quantitative yield . Methyl 3-bromo-4-hydroxyphenyl pyruvate oxime (100) was also electrolyzed under similar conditions to give three compounds 101, 102 and 103 in 34, 14 and 17% yields, respectively. The latter two products are formed by C—O and C—C radical couplings, respectively, as shown in Scheme 19 °. 

With carotenoid biosynthesis, plastoquinone is involved as an electron acceptor, which we encounter further in photosynthetic electron transport [2]. An important precursor in the synthesis of plastoquinone, which also serves as a cofactor for the PDS enzyme, is homogentisic acid, which is formed from 4-hydroxyphenyl-pyruvate by 4-hydroxyphenylpyruvate dioxygenase (HPPD)... 

Alkaloids possessing the 1-benzylisoquinoline skeleton are biosynthesized from two molecules of tyrosine, which are differentiated at the beginning of the biosynthetic pathway. Namely, the isoquinoline moiety, except for one carbon, originates from 3, 4 -dihydroxyphenylethylamine (dopamine), which is formed from tyramine following the decarboxylation of tyrosine. The other part of the alkaloid is derived from 4 -hydroxyphenylac-etaldehyde, which is formed from tyrosine via 4 -hydroxyphenyl pyruvic acid. These two compounds are coupled stereoselectively to give (S)-norcoclaurine. (S)-Norcoclaurine is transformed into (S)-coclaurine by 6-O-methylation, and further N-methylation, hydroxylation at the... 

C3a4b. Inhibition of 4-hydroxyphenyl-pyruvate-dioxygenase (F2) C3a4c. Inhibition of carotenoid biosynthesis (unknown target) (F3)... 

As a final alternative, the biosynthesis of fungal cyclopentenones may by-pass the terphenylquinone and pulvinic acid pathway altogether. Condensation of two 4-(hydroxyphenyl)pyruvate moieties, either directly or via the now familiar intermediate (9), could lead to the a-... 

Hydroxyphenyl-pyruvate dioxygenase (D 22) Hydroxylation, oxidative decarboxylation Fe +, ascorbic acid, requires a-ketoglutarate... 

Fig. 4.2. Increased tyrosine concentration is caused by inborn or acquired deficiency of the first two enzymes of the tyrosine degradation pathway (the increased tyrosine concentration of tyrosinemia type I is caused by secondary deficiency of 4-hydroxyphenyl-pyruvate dioxygenase). Hypertyrosinemia in the newborn is in most instances not due to inborn errors of tyrosine metabolism, but rather to liver immaturity or other unspecific liver affections. However, whenever hypertyrosinemia is found, the pathognomonic sign of tyrosinemia type I should be excluded by a sufficiently sensitive analysis of suc-cinylacetone and related metabolites. Decreased activity of porphobilinogen synthase activity in RBC is a sensitive and easily performed marker for increased concentrations of succinylacetone, which may be used as a first line diagnostic test before positive identification of succinylacetone and related metabolites by GC-MS can be achieved. It should also be noted that increased excretion of phenolic tyrosine metabolites is always found in hypertyrosinemia and is of no differential diagnostic value...

Neidig, M.L. et al. (2005). Spectroscopic and computational studies of NTBC bound to the non-heme iron enzyme (4-hydroxyphenyl) pyruvate dioxygenase active site contributions to drug inhibition. Biochem. Biophys. Res. Commun. 338, 206-214... 

Inhibition of pigment synthesis (bleaching) 4-Hydroxyphenyl-pyruvate-dioxy-genase (4-HPPD) ... 

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