Significant phenylalanine hydroxylation in vivo in patients with classical phenylketonuria.

Thompson, Greg; Halliday, D.

doi:10.1172/jci114701

Cited by 30 publications

(24 citation statements)

References 34 publications

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“…This startlingly highphenylalanine-hydroxylating activity was attributed to tyrosine hydroxylase (45). As discussed already, the results summarized in Fig.…”

Section: ϫDphe͞dt ϭ ϫVsupporting

confidence: 68%

“…The present model of phenylalanine metabolism is relevant to the conclusion reached by Thompson and his colleagues (45,46), on the basis of results obtained by infusion of subjects with deuterium-labeled phenylalanine and tyrosine, that classical PKU patients have ''substantial'' PAH activity that is equal to (1999)about 76% that of control subjects. This startlingly highphenylalanine-hydroxylating activity was attributed to tyrosine hydroxylase (45).…”

Section: ϫDphe͞dt ϭ ϫVmentioning

confidence: 89%

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A model of human phenylalanine metabolism in normal subjects and in phenylketonuric patients

Kaufman

1999

Proc. Natl. Acad. Sci. U.S.A.

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The derivation of a quantitative model of phenylalanine metabolism in humans is described. The model is based on the kinetic properties of pure recombinant human phenylalanine hydroxylase and on estimates of the in vivo rates of phenylalanine transamination and protein degradation. Calculated values for the steady-state concentration of blood phenylalanine, rate of clearance of phenylalanine from the blood after an oral load of the amino acid, and dietary tolerance of phenylalanine all agree well with data from normal as well as from phenylketonuric patients and obligate heterozygotes. These calculated values may help in the decision about the degree of restriction of phenylalanine intake that is necessary to achieve a satisfactory clinical outcome in classical patients and in those with milder forms of the disease.The initial and rate-limiting step in the complete catabolism of phenylalanine to CO 2 and water is its hydroxylation to tyrosine, a reaction catalyzed by the phenylalanine hydroxylating system. The system is complex, consisting of phenylalanine hydroxylase (PAH), the pterin coenzyme tetrahydrobiopterin (BH 4 ), and several enzymes that serve to regenerate BH 4 , i.e., dihydropteridine reductase and pterin 4␣-carbinolamine dehydratase (1, 2).Although the benzene ring of phenylalanine cannot be ruptured without first being hydroxylated in the para position, the alanine side-chain of the amino acid can be metabolized even in the absence of the ring-hydroxylation step. This alternate pathway is initiated by transamination of phenylalanine to phenylpyruvate followed by conversion of the latter compound to metabolites such as phenyllactate, phenylacetate, and o-hydroxyphenylacetate.

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“…This startlingly highphenylalanine-hydroxylating activity was attributed to tyrosine hydroxylase (45). As discussed already, the results summarized in Fig.…”

Section: ϫDphe͞dt ϭ ϫVsupporting

confidence: 68%

Section: ϫDphe͞dt ϭ ϫVmentioning

confidence: 89%

A model of human phenylalanine metabolism in normal subjects and in phenylketonuric patients

Kaufman

1999

Proc. Natl. Acad. Sci. U.S.A.

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“…The basic model used for this study of phenylalanine disposal is the two-pool model based on the assumptions that the free phenylalanine and tyrosine pools are homogeneous and in rapid equilibrium, that phenytalanine only enters the pool when fasted from protein degradation, and that the only exit pathway is via protein synthesis and hydroxylation to tyrosine (Thompson and Halliday 1990). This model does not take into account loss of phenylalanine transamination metabolites.…”

Section: Discussionmentioning

confidence: 99%

“…We used a stableisotope infusion of [2Hs]phenylalanine to measure protein turnover, phenylalanine hydroxylation and excretion of phenylalanine transamination metabolites according to an established model (Thompson et al 1989;Thompson and Halliday 1990).…”

mentioning

confidence: 99%

In vivo disposal of phenylalanine in phenylketonuria: A study of two siblings

Treacy

Pitt

Seller

et al. 1995

J of Inher Metab Disea

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Mutation at the phenylalanine hydroxylase (PAH) locus is a cause of hyperphenylalaninaemia. Genotype-phenotype correlation relative to the predicted PAH activity may differ at the metabolite level and at the IQ level in untreated phenylketonuria. Discordant metabolic phenotypes have been noted in siblings; influences on transport and metabolism of phenylalanine determining homeostasis may account for differing metabolic phenotypes. We report two siblings of different sex and identical genotype at the PAH locus who demonstrate a difference in phenylalanine disposal. A stable isotope infusion of [2H5]phenylalanine was used to measure protein turnover, phenylalanine hydroxylation and excretion of phenylalanine transamination metabolites. The siblings were observed to have identical hydroxylation rates under the experimental conditions of the study while manifesting differences in renal excretion rates of phenylalanine transamination metabolites and protein accretion.

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“…Ten subjects with classical PKU (eight male, two female; mean age 19.3 y, range [14][15][16][17][18][19][20][21][22][23][24], two with hyperphenylalaninemia (one male, one female; ages 22 and 45 y) and six age-matched normal controls (all male, mean age 20.8 y, range 19-23) were studied. Some of these subjects have been studied previously using [2H5]phenylalanine techniques to measure phenylalanine hydroxylase activity in vivo (2 1,22).…”

Section: Subjectsmentioning

confidence: 99%

Protein Metabolism in Phenylketonuria and Lesch-Nyhan Syndrome

Thompson¹,

Pacy²,

Watts

et al. 1990

Pediatr Res

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ABSTRACT. Animal and in vitro studies have implicated decreased protein synthesis in the pathogenesis of tissue damage in phenylketonuria (PKU) and of growth failure in Lesch-Nyhan syndrome. Protein turnover was measured in vivo in ten young adult subjects with classical PKU, two subjects with hyperphenylalaninemia, and three children with Lesch-Nyhan syndrome using techniques based on continuous infusions of ['3C]leucine and, in Lesch-Nyhan subjects, [2Hs]phenylalanine. The PKU subjects had various degrees of dietary phenylalanine restriction and plasma phenylalanine levels at the time of study ranged from 450-1540 pmol/L (mean 1106). Plasma phenylalanine in the two hyperphenylalaninemic subjects was 533 and 402 pmol/L. Rates of protein synthesis in all PKU subjects (mean 3.71 g/kg/24 h, range 2.68-5.10, ['3C]leucine as tracer) were in a range similar to or above control values (mean 2.97, range 2.78-3.22, n = 6), as were rates of protein catabolism (PKU mean 4.23 g/kg/24 h, range 3.15-5.45; controls 3.64, 3.50-3.91). Protein turnover values in hyperphenylalaninemia were also similar to those in controls. With ['3C]leucine as tracer, both mean protein synthesis and catabolism values in Lesch-Nyhan subjects (mean 4.80 and 5.64 g/kg/24 h, respectively) were higher than values in control children matched for protein intake (synthesis 4.32 + 0.74 (SD) and catabolism 4.85 + 0.57 (g/kg/24 h, n = 5). Similar results were obtained in LeschNyhan subjects using [2Hs]phenylalanine as tracer. These results suggest that protein turnover is not decreased in either PKU or Lesch-Nyhan syndrome. This conclusion is inconsistent with the hypothesis that tissue damage in PKU results from impaired protein synthesis. The findings also indicate that growth failure in Lesch-Nyhan syndrome is unlikely to be due to decreased protein synthesis resulting from impaired energy metabolism. (Pediatr Res 28: 240-246,1990) Abbreviations PKU, phenylketonuria HPRT, hypoxanthine-guanine phosphoribosyltransferase KIC, a-ketoisocaproic acid BMI, body mass index GTP, guanosine 5'-triphosphate APE, atoms percent excessThe cause of tissue damage in PKU is still a matter of debate.A number of studies have demonstrated reduced protein synthe-

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Significant phenylalanine hydroxylation in vivo in patients with classical phenylketonuria.

Cited by 30 publications

References 34 publications

A model of human phenylalanine metabolism in normal subjects and in phenylketonuric patients

A model of human phenylalanine metabolism in normal subjects and in phenylketonuric patients

In vivo disposal of phenylalanine in phenylketonuria: A study of two siblings

Protein Metabolism in Phenylketonuria and Lesch-Nyhan Syndrome

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