A synopsis of the unconjugated acidic transamination metabolites of phenylalanine in phenylketonuria

Langenbeck, U.; Behbehani, A. W.; Mench-Hoinowski, A.

doi:10.1007/bf01800355

Cited by 8 publications

(10 citation statements)

References 34 publications

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“…Rey et al (1974) first described the influence of age on excretion of OHPAA in children with PKU and found adult threshold values only after 2 years. Accordingly, metabolic data of PKU children older than 2 years conform with respective findings in juvenile patients (Langenbeck et al 1980(Langenbeck et al , 1992, and phe tolerance at 10 years of age can be predicted reliably from the respective data at 2 years (van Spronsen et al 2009). …”

Section: Discussionsupporting

confidence: 72%

“…The child with the higher phe tolerance at 42 months (600 vs. 350 mg phe/day) excreted higher amounts of phe transamination metabolites into urine (10.9 vs. 4.9 mmol/kg Â h), whereas the sibling with much lower excretion had plasma metabolite levels in the toxic range (220 vs. 134 mmol/L; cf. Langenbeck et al 1992).…”

Section: Discussionmentioning

confidence: 99%

“…The urinary levels of the phe transamination metabolites phenylpyruvic acid (PPA), phenyllactic acid (PLA) and 2-hydoxyphenylacetic acid (OHPAA) are linearly related in older children to the logarithm of their corresponding plasma levels (Langenbeck et al 1992). Analytically valid quantitative urine data of these metabolites may therefore be taken as proxy of the endogenous phe transamination capacity.…”

Section: Urinary Phenylalanine Metabolitesmentioning

confidence: 99%

“…Besides PLA, which attains urinary concentrations in the range of PPA only after prolonged phe loads (Langenbeck et al 1992), OHPAA is established as the analytically most stable phe transamination metabolite in urine (Dhondt et al 1974) when gas chromatography with traditional derivatives is applied (Langenbeck et al 1980). Therefore, urinary OHPAA is taken in the present communication as an indicator of phe transamination during the protein loading tests.…”

Section: Urinary Phenylalanine Metabolitesmentioning

confidence: 99%

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Development of Metabolic Phenotype in Phenylketonuria: Evaluation of the Blaskovics Protein Loading Test at 5 Years of Age

et al. 2015

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Background: As part of the German Collaborative Study on Phenylketonuria (PKU)/Hyperphenylalaninaemia (HPA) Study Protocol, a Blaskovics protein loading test (180 mg phenylalanine (phe) protein equivalent per kg body weight and day for 72 h) had been applied to 145 children at the age of 6 months. For investigating possible age-related changes of metabolic phenotype, 51 of them received a 2nd loading test at 5 years of age.Methods: Besides the analysis of blood phe levels, acidic phe transamination metabolites were quantified in urine.Results: Compared to the 6-month data, the mean blood phe level 72 h after start of loading (Phe72) was found to be decreased by 7% (P ¼ 0.06), whereas the mean urinary excretion (per 1.73 m 2 body surface and day) of 2-hydroxyphenylacetic acid was increased 1.9-fold (P < 0.01). Corresponding with these analytical data, the kinetic model constant k out of metabolic plus renal phe disposal was found increased 1.3-fold in mean (P < 0.01).In 3 of the 51 patients, Phe72 was very high at 6 months while in the medium range at 5 years, suggesting that catabolic states may mimic a more severe metabolic defect.The blood phe level response of mild PKU (type II) was assigned identically at both ages in 7/9 patients. Diverging results were (i) response type III (mild hyperphenylalaninaemia) at 6 months and type II at 5 years and (ii) type II at 6 months and type III at age 5.Conclusion: Renal elimination of OHPAA and phe tolerance increase significantly between the age of 6 months and 5 years, suggesting that, at least in childhood, formation and/or renal disposal of phe transamination metabolites may be major distal determinants of phe tolerance.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Urinary Phenylalanine Metabolitesmentioning

confidence: 99%

Section: Urinary Phenylalanine Metabolitesmentioning

confidence: 99%

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Development of Metabolic Phenotype in Phenylketonuria: Evaluation of the Blaskovics Protein Loading Test at 5 Years of Age

et al. 2015

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“…The approach adopted in estimating a value for V max for the human transaminating enzyme was to use data on the sum of all transamination-derived metabolites (i.e., phenylpyruvate, phenyllactate, and o-hydroxyphenylacetate) excreted by a group of classical PKU patients as a function of their plasma phenylalanine levels. The maximum amount excreted, expressed as mmol͞mol creatinine, was 1,370, a level that appeared to plateau at plasma phenylalanine levels between 1,200 and 2,400 mol͞liter (22).…”

Section: ϫDphe͞dt ϭ ϫVmentioning

confidence: 97%

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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Effect of phenylalanine and its metabolites on ATP diphosphohydrolase activity in synaptosomes from rat cerebral cortex

et al. 1994

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The in vitro effects of phenylalanine and some of its metabolites on ATP diphosphohydrolase (apyrase, EC 3.6.1.5) activity in synaptosomes from rat cerebral cortex were investigated. The enzyme activity in synaptosomes from rats subjected to experimental hyperphenylalaninemia (alpha-methylphenylalanine plus phenylalanine) was also studied. In the in vitro studies, a biphasic effect of phenylalanine on both enzyme substrates (ATP and ADP) was observed, with maximal inhibition at 2.0 mM and maximal activation at 5.0 mM. Inhibition of the enzyme activity was not due to calcium chelation. Moreover, phenylpyruvate, when compared with phenylalanine showed opposite effects on the enzyme activity, suggesting that phenylalanine and phenylpyruvate bind to two different sites on the enzyme. The other tested phenylalanine metabolites phenyllactate, phenylacetate and phenylethylamine) had no effect on ATP diphosphohydrolase activity. In addition, we found that ATP diphosphohydrolase activity in synaptosomes from cerebral cortex of rats with chemically induced hyperphenylalaninemia was significantly enhanced by acute or chronic treatment. Since it is conceivable that ATPase-ADPase activities play an important role in neurotransmitter (ATP) metabolism, it is tempting to speculate that our results on the deleterious effects of phenylalanine and phenylpyruvate on ATP diphosphohydrolase activity may be related to the neurological dysfunction characteristics of naturally and chemically induced hyperphenylalaninemia.

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A synopsis of the unconjugated acidic transamination metabolites of phenylalanine in phenylketonuria

Cited by 8 publications

References 34 publications

Development of Metabolic Phenotype in Phenylketonuria: Evaluation of the Blaskovics Protein Loading Test at 5 Years of Age

Development of Metabolic Phenotype in Phenylketonuria: Evaluation of the Blaskovics Protein Loading Test at 5 Years of Age

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

Effect of phenylalanine and its metabolites on ATP diphosphohydrolase activity in synaptosomes from rat cerebral cortex

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