Detection of Hepatic Phenylalanine 4-Hydroxylase in Classical Phenylketonuria

Friedman, Paul A.; Fisher, Daniel B.; Kang, Ellen S.; Kaufman, Seymour

doi:10.1073/pnas.70.2.552

Cited by 61 publications

(17 citation statements)

References 21 publications

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“…Although the complex kinetic behavior of phenylalanine hydroxylase complicated the precise determi nation of its activity [Tourian, 1971;Shiman and Gray, 1980], a good correlation has been reported between blood phenylalanine level and the residual activity of this enzyme in the liver of patients with hyperphenyialaninemia types II and III [Bartliolomecl al., 1975]. The activity found in these patients varied from 1.5 to 34.5% of normal; in severe phenylke tonuria, this value is found at 0.27% of nor mal [Friedman et al, 1973].…”

Section: Phenylketonuriamentioning

confidence: 97%

Partial Enzyme Deficiencies: Residual Activities and the Development of Neurological Disorders

Conzelmann¹,

Sandhoff²

1983

Dev Neurosci

254

138

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Section: Phenylketonuriamentioning

confidence: 97%

Partial Enzyme Deficiencies: Residual Activities and the Development of Neurological Disorders

Conzelmann¹,

Sandhoff²

1983

Dev Neurosci

254

138

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“…It may be calculated that the maximum available activity of phenylalanine hydroxylase in the liver of a normal 70-kg adult would be 110 IOmol tyrosine produced/kg body weight per h, assuming a liver weight of 1.5 kg of which 6% is protein and a maximal in vitro hydroxylase activity of 90 ,mol/h per g liver protein (4). In classical PKU the hepatic enzyme activity is reduced to < 0.5% of normal values (35), so that even under ideal conditions the residual enzyme is capable of hydroxylating < 0.6 ,umol/kg per h of phenylalanine. Tyrosine hydroxylase is known to have the capacity to hydroxylate phenylalanine (36), and at high substrate concentrations this alternate pathway is a plausible mechanism by which phenylalanine could be hydroxylated in PKU.…”

Section: Discussionmentioning

confidence: 99%

Significant phenylalanine hydroxylation in vivo in patients with classical phenylketonuria.

Thompson¹,

Halliday²

1990

J. Clin. Invest.

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;tmol/kg per h (range 0.9-8.4) of phenylalanine to tyrosine and those with HPA 4.4 and 5.3, respectively. These rates were substantial in comparison with those in controls (6.3±1.6, 3.2-8.2). The significant hydroxylation in PKU and HPA subjects is likely to result from induction of activity of tyrosine hydroxylase towards phenylalanine by the greatly elevated phenylalanine concentration. The presence of such activity in PKU suggests that therapy aimed at promotion of this usually latent hydroxylating capacity may be a future alternative to dietary treatment of PKU. (J. Clin. Invest. 1990.86:317-322.)

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“…hepatic phenylalanine hydroxylase (9,15), t h e enzyme which CASE LA converts phenylalanine t o tyrosine. Phenylalanine is metabolized b y alternate minor pathways and significant amounts of A girl, birth weight 3,270 g, first-born of healthy Italian several unusual but not abnormal metabolites are formed and parents, had no family history of phenylketonuria, mental excreted in urine (see reviews in References 2 0 and 27).…”

Section: Methodsmentioning

confidence: 99%

Aromatic Acids in Urine of Healthy Infants, Persistent Hyperphenylalaninemia, and Phenylketonuria, before and after Phenylalanine Load

et al. 1974

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ExtractAromatic acids in urine were studied by gas chromatography and mass spectrometry in 3 premature and 7 full term healthy infants, in 2 patients with persistent hyperphenylalaninemia, and in 11 patients with phenylketonuria. Eleven aromatic acids were determined quantitatively.On a free diet, patients with phenylketonuria excreted large amounts of phenylacetic, mandelic, phenyllactic, o-OHphenylacetic, and phenylpyruvic acids ("phenylketonuria metabolites"), whereas the two patients with persistent hyperphenylalaninemia showed only a slightly abnormal excretion of these compounds. No or only very small amounts of phenylketonuria metabolites were found in healthy infants on normal diet, as well as in patients with persistent hyperphenylalaninemia or phenylketonuria on low phenylalanine diet.After an oral L-phenylalanine load (100 mg/kg) n o or only a slight increase of phenylketonuria metabolites was observed in the urine during the subsequent 24 h r in healthy infants o n normal diet, as well as in the two patients with persistent hyperphenylalaninemia o n low phenylalanine diet; in contrast, the concentration of these metabolites increased markedly in patients with phenylketonuria on low phenylalanine diet. This divergent response of the aromatic acids in urine to an oral phenylalanine load administered during a low phenylalanine diet probably represents a useful criterion for the differential diagnosis of these t w o conditions. SpeculationThe quantitative determination of the aromatic acids in urine before and after phenylalanine load can be considered as an indirect measurement of phenylalanine hydroxylase activity.after birth and remains subsequently mostly between 4 and 15 mg/100 ml. On a normal protein intake, it only rarely rises t o 20 or more mg/100 ml. The urine tests for aromatic acids (FeC13, DNPH, Phenistix) are usually negative and, with few exceptions (1,14,28,36), o-OH-phenylacetic acid as well as phenylpyruvic acid are not detectable by paper chromatography (12,17,29,30) or spectrophotometry (1). However, abnormal amounts of aromatic acids can always be demonstrated after a phenylalanine load (1,17,24,28,30,35,36). Most patients, whether o n or off a diet, perform within the average range of intelligence (3).Persistent hyperphenylalaninemia has t o be distinguished from other disorders of phenylalanine metabolism such as phenylalanine transaminase deficiency and transient hyperphenylalaninemia (see reviews in References 1 3 and 23). Patients with persistent hyperphenylalaninemia probably represent a biochemically and genetically heterogeneous group.In the present study, aromatic acids in urine were determined quantitatively by gas chromatography and identified by mass spectrometry. The investigation was performed in healthy infants, as well as in patients with persistent hyperphenylalaninemia and phenylketonuria, before and after a phenylalanine load. The patients were studied while on and off a low phenylalanine diet. SUBJECTS AND METHODSAromatic acid excretion in urine was studied in 3 h...

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Detection of Hepatic Phenylalanine 4-Hydroxylase in Classical Phenylketonuria

Cited by 61 publications

References 21 publications

Partial Enzyme Deficiencies: Residual Activities and the Development of Neurological Disorders

Partial Enzyme Deficiencies: Residual Activities and the Development of Neurological Disorders

Significant phenylalanine hydroxylation in vivo in patients with classical phenylketonuria.

Aromatic Acids in Urine of Healthy Infants, Persistent Hyperphenylalaninemia, and Phenylketonuria, before and after Phenylalanine Load

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