Phenylalanine
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- Words in title only: phenylalanine
- Published in 1957 through 1999
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Documents: 1 to 22 of 22
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Record 1 from database: MEDLINE
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- Title
- The influence of mutations of enzyme activity and phenylalanine tolerance
in phenylalanine hydroxylase deficiency.
- Author
- Güttler F; Guldberg P
- Address
- John F. Kennedy Institute, Glostrup, Denmark.
- Source
- Eur J Pediatr, 1996 Jul, 155 Suppl 1:, S6-10
- Abstract
- The phenylalanine hydroxylase (PAH) deficiency trait is heterogeneous with
a continuum of metabolic phenotypes ranging from classical phenylketonuria (PKU)
to mild hyperphenylalaninaemia (MHP). More than 200 mutations in the PAH
gene are associated with PAH deficiency. From theoretical considerations or
in vitro expression studies each mutation has a particular influence on
enzyme activity, which explains the variation in dietary tolerance for
phenylalanine (Phe). This paper gives a summary of the effect of each type
of mutation on PAH activity and illustrates how the combination of mutations
(the genotype) is associated with the Phe tolerance (the metabolic
phenotype). Mutations within a population generally include a few prevalent
mutations and a high number of rare mutations. The particular distribution
of mutations implies that many PAH-deficient patients carry the same
mutation combination, enabling the establishment of genotype-phenotype
correlations by comparing clinical parameters in patients with identical
genotypes. Because certain mutations always cause MHP irrespective of the
mutation on the second allele, mutation typing of hyperphenylalaninaemic
neonates will differentiate between PKU and MHP. In addition, genotyping
will provide a tool for precise diagnosis of the metabolic phenotype of the
neonate with PKU and thereby permit earlier implementation of dietary
therapy better tailored to each individual patient.
- Language of Publication
- English
- Unique Identifier
- 96426306
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- MeSH Heading (Major)
- Amino Acid Metabolism, Inborn Errors|EN/*GE; Mutation|*GE; Phenylalanine
Hydroxylase|*DF/GE/ME; Phenylketonuria|*GE
- MeSH Heading
- Codon|GE; Cognition Disorders|GE; Enzyme Activation|GE; Genotype;
Homeostasis|GE; Human; Phenotype; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0340-6199
- Country of Publication
- GERMANY
Record 2 from database: MEDLINE
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- Title
- The phenylalanine hydroxylase locus: a marker for the history of
phenylketonuria and human genetic diversity. PAH Mutation Analysis
Consortium.
- Author
- Scriver CR; Byck S; Prevost L; Hoang L
- Address
- McGill University-Montreal Children's Hospital Research Institute, Quebec,
Canada.
- Source
- Ciba Found Symp, 1996, 197:, 73-90; discussion 90-6
- Abstract
- Disease-producing allelic variation describes one aspect of human genetic
diversity. Phenylketonuria, the major type of hyperphenylalaninaemia and
formerly a functional genetic lethal, has a 2% carrier frequency in
temperate-zone populations. Newborn screening for hyperphenylalaninaemia
(incidence of 1 in 10000) has made it one of the most widely ascertained
human Mendelian traits; 99% of hyperphenylalaninaemia mutations map to the
PAH (phenylalanine hydroxylase) gene on 12q24.1, and most cause
phenylketonuria. The gene is well characterized. Analysis of 3986 mutant
chromosomes by 81 investigators in 26 countries has identified 243 different
mutations in 788 different associations (with polymorphic intragenic
haplotypes [seven diallelic sites, one short tandem repeat, one variable
number of tandem repeats], populations and regions). These data are compiled
on a database accessible on the World-Wide Web or as a stand-alone software
package. A few phenylketonuria alleles occur at high relative frequencies in
particular populations on one or only a few haplotypes, suggesting positive
selection in the past. Additional mechanisms (founder effect, drift and
recurrent mutation) can explain frequencies and distributions of particular
alleles. Allele stratification in Europeans and Orientals implies that
mechanism(s) accounting for distribution and high frequencies of PAH alleles
were acting before and during demic expansion in Europe and after the
European and Oriental radiations.
- Language of Publication
- English
- Unique Identifier
- 96424918
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- MeSH Heading (Major)
- Phenylalanine Hydroxylase|*GE; Phenylketonuria|*GE; Variation (Genetics)|*
- MeSH Heading
- Genetic Markers; Genetic Screening; Haplotypes; Human; Mutation;
Polymorphism (Genetics); Quebec; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0300-5208
- Country of Publication
- NETHERLANDS
Record 3 from database: MEDLINE
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- Title
- Effects of aspartame and phenylalanine on meal-time food intake of humans.
- Author
- Anderson GH; Leiter LA
- Address
- Department of Nutritional Sciences, University of Toronto, Ontario,
Canada.
- Source
- Appetite, 1988, 11 Suppl 1:, 48-53
- Abstract
- This article reviews data relevant to the hypothesis that aspartame may
have a unique effect on meal-time food intake regulation due to its amino
acid composition and in addition to its effects as a high intensity
sweetener. It is concluded that future studies involving aspartame should be
directed towards developing a fundamental understanding of the effects of
high intensity sweeteners on food intake, and not give undue attention to
putative actions based on its amino acid constituents.
- Language of Publication
- English
- Unique Identifier
- 89049110
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- MeSH Heading (Major)
- Aspartame|AD/*PD; Dipeptides|*PD; Eating|*DE; Phenylalanine|AD/BL/*PD
- MeSH Heading
- Amino Acids|ME/PD; Human; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0195-6663
- Country of Publication
- ENGLAND
Record 4 from database: MEDLINE
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- Title
- Pharmacological effects of phenylalanine on seizure susceptibility: an
overview.
- Author
- Sze PY
- Address
- Department of Pharmacology, Chicago Medical School, Illinois 60064.
- Source
- Neurochem Res, 1989 Feb, 14:2, 103-11
- Abstract
- The effects of excessive doses of phenylalanine on seizure susceptibility
were examined in animal models in the past, primarily because of their
relevance to phenylketonuria. It was thought that such effects might involve
brain monoaminergic mechanisms. Recently, this issue has been pursued with a
renewed interest but for a different reason. The dipeptide sweetener,
aspartame, contains a phenylalanine residue. In the last three years, a
number of studies involving as many as nine animal models of seizures have
reexamined the effects of phenylalanine (and aspartame) on seizure
thresholds. Data from these studies are in general agreement that aspartame
at dosage levels below 1,000 mg/kg, or phenylalanine at equimolar doses, is
without an effect on seizure susceptibility in animals. When the dosage
level of aspartame reaches 1,000 mg/kg, the findings between various
laboratories and from different animal models of seizures are inconsistent,
showing either no effect or a proconvulsant effect. The Acceptable Daily
Intake of aspartame in humans set by the Food and Drug Administration is 50
mg/kg/day. Thus, the data from the excessive bolus doses in rodents do not
appear to be relevant to human use. This article provides a detailed review
of the data from both early and recent studies and points out the
methodological problems apparent at such high doses.
- Language of Publication
- English
- Unique Identifier
- 89262433
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- MeSH Heading (Major)
- Aspartame|*PD; Dipeptides|*PD; Phenylalanine|*TO; Seizures|CI/*PP
- MeSH Heading
- Animal; Disease Models, Animal; Disease Susceptibility; Human
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0364-3190
- Country of Publication
- UNITED STATES
Record 5 from database: MEDLINE
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- Title
- Molecular basis of phenylketonuria and related hyperphenylalaninemias:
mutations and polymorphisms in the human phenylalanine hydroxylase gene.
- Author
- Eisensmith RC; Woo SL
- Address
- Howard Hughes Medical Institute, Baylor College of Medicine, Houston,
Texas 77030.
- Source
- Hum Mutat, 1992, 1:1, 13-23
- Abstract
- Mutations in the human phenylalanine hydroxylase gene producing
phenylketonuria or hyperphenylalaninemia have now been identified in many
patients from various ethnic groups. These mutations all exhibit a high
degree of association with specific restriction fragment-length polymorphism
haplotypes at the PAH locus. About 50 of these mutations are single-base
substitutions, including six nonsense mutations and eight splicing
mutations, with the remainder being missense mutations. One splicing
mutation results in a 3 amino acid in-frame insertion. Two or 3 large
deletions, 2 single codon deletions, and 2 single base deletions have been
found. Twelve of the missense mutations apparently result from the
methylation and subsequent deamination of highly mutagenic CpG dinucleotides.
Recurrent mutation has been observed at several of these sites, producing
associations with different haplotypes in different populations. About half
of all missense mutations have been examined by in vitro expression
analysis, and a significant correlation has been observed between residual
PAH activity and disease phenotype. Since continuing advances in molecular
methodologies have dramatically accelerated the rate in which new mutations
are being identified and characterized, this register of mutations will be
updated periodically.
- Language of Publication
- English
- Unique Identifier
- 93244826
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- MeSH Heading (Major)
- Amino Acid Metabolism, Inborn Errors|EN/*GE; Mutation|*;
Phenylalanine|*ME; Phenylalanine Hydroxylase|*GE; Phenylketonuria|EN/*GE;
Polymorphism (Genetics)|*
- MeSH Heading
- Amino Acid Sequence; Base Sequence; Codon|GE; Human; Support, U.S. Gov't,
P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 1059-7794
- Country of Publication
- UNITED STATES
Record 6 from database: MEDLINE
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- Title
- Treating phenylketonuria by a phenylalanine-free diet.
- Author
- Start K
- Address
-
- Source
- Prof Care Mother Child, 1998, 8:4, 109-10
- Abstract
- The phenylalanine-free diet is needed for the treatment of phenylketonuria.
Phenylketonuria is an inherited metabolic condition in which there is a
deficiency of the enzyme phenylalanine hydroxylase. Lack of this enzyme
means the body cannot metabolise the essential amino acid phenylalanine,
which then builds up in the blood and causes mental retardation and other
abnormalities. Retardation can be prevented if phenylketonuria is diagnosed
in the first three weeks of infancy and dietary treatment started
straightaway. There is a universal screening test in the UK (the Guthrie
test). Heel-prick blood samples are taken from all babies between 6-14 days
old and analysed at a regional screening centre. For infants, a
phenylalanine-free formula is needed, either as a supplement before breast
feeds or following a formula feed. The diet must continue during weaning and
childhood, with a low protein diet. Foods such as meat, fish, eggs, milk,
cheese, nuts and pulses are excluded as they contain high levels of
phenylalanine. Vegetables and fruit are allowed in measured amounts only!
Special low protein bread, pasta, biscuits and flour are used to supplement
the diet and ensure adequate calorie intake. Whether the diet can be stopped
at the end of adolescence is debatable. If stopped, it should be re-started
at conception and maintained during pregnancy, as high levels of
phenylalanine in the mother can affect the fetus.
- Language of Publication
- English
- Unique Identifier
- 99031909
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- MeSH Heading (Major)
- Child Nutrition|*/ED; Phenylalanine|*AD; Phenylketonuria|*DH/DI
- MeSH Heading
- Adult; Child; Female; Human; Parents|ED; Pregnancy
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0964-4156
- Country of Publication
- ENGLAND
- CAS Registry/EC Number
- 3617-44-5 (Phenylalanine)
Record 7 from database: MEDLINE
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- Title
- Phenylalanine levels of 6-10 mg/dl may not be as benign as once thought.
- Author
- Diamond A
- Address
- Department of Psychology, University of Pennsylvania, Philadelphia
19104-6196, USA.
- Source
- Acta Paediatr Suppl, 1994 Dec, 407:, 89-91
- Abstract
- Results of a longitudinal study of children treated early and continuously
for phenylketonuria (PKU) indicated that those children whose plasma
phenylalanine (Phe) levels were approximately 3-5 times normal (6-10 mg/dl;
levels previously considered safe in the US) were impaired in cognitive
functions dependent on prefrontal cortex. In particular, the children had
difficulty when required to hold information in the mind and, at the same
time, exercise inhibitory control to resist doing what might be their first
inclination. The deficits were evident in relation to each of several
comparison groups and at all three age ranges (infants, toddlers and young
children). The deficits appeared to be selective in that the same children
who were impaired on the prefrontal cortex tests performed normally on the
control tests. Since most of the control tasks tap functions dependent on
parietal cortex or the medial temporal lobe, these results suggest that
those functions are spared. To investigate the biological mechanism causing
these cognitive deficits, we created an animal model of early-treated PKU.
The results indicated that rats whose plasma Phe levels were mildly, but
chronically, elevated had cognitive deficits (impaired performance on a
behavioral task dependent on frontal cortex (delayed alternation)) and
neurochemical changes (most notably, reduced dopamine metabolism in frontal
cortex).
- Language of Publication
- English
- Unique Identifier
- 95284443
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- MeSH Heading (Major)
- Cognition Disorders|BL/*ET/PP; Phenylalanine|*BL; Phenylketonuria|*BL/CO/DH
- MeSH Heading
- Animal; Case-Control Studies; Cerebral Cortex|PP; Contrast Sensitivity;
Cross-Sectional Studies; Disease Models, Animal; Human; Longitudinal
Studies; Rats
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0803-5326
- Country of Publication
- NORWAY
Record 8 from database: MEDLINE
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- Title
- Dopamine precursors and brain function in phenylalanine hydroxylase
deficiency.
- Author
- Lou HC
- Address
- John F Kennedy Institute, Glostrup, Denmark.
- Source
- Acta Paediatr Suppl, 1994 Dec, 407:, 86-8
- Abstract
- Phenylalanine and tyrosine constitute the two initial steps in the
biosynthesis of dopamine, which, in its turn, is the metabolic precursor of
noradrenaline and adrenaline. The extracellular phenylalanine concentration
influences brain function in phenylalanine deficiency (PHD) by decreased
dopamine synthesis. It has been shown to induce EEG slowing, and prolonged
the performance time on neuropsychological tests. The tyrosine concentration
in the CNS is reduced in PHD, possibly implying insufficient substrate (=
tyrosine) for catecholamine synthesis due to competition inhibition, for
instance across the blood brain barrier. In experimental studies it has been
shown that the synthesis and release of dopamine can be influenced by an
increase in the availability of tyrosine. In PHD an extra dietary intake of
three doses of tyrosine (160 mg/kg/24h) induced a shortening of reaction
time and decreased variability, and in a double-blind crossover study a
similar dose has been reported to induce an improvement on psychological
tests. In a study with lower doses of tyrosine (110 mg/kg/24 h) no effect
was found on reaction time tests. These findings need to be substantiated,
and more detailed information should be obtained.
- Language of Publication
- English
- Unique Identifier
- 95284442
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- MeSH Heading (Major)
- Dopamine|*BI; Phenylalanine|*ME; Phenylketonuria|DH/*ME; Tyrosine|*ME/TU
- MeSH Heading
- Brain Chemistry; Clinical Trials; Cross-Over Studies; Double-Blind Method;
Electroencephalography; Human; Neuropsychological Tests; Phenylalanine
Hydroxylase|DF
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0803-5326
- Country of Publication
- NORWAY
Record 9 from database: MEDLINE
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- Title
- Treatment of phenylalanine hydroxylase deficiency.
- Author
- Smith I
- Address
- Medical Unit, Institute of Child Health, London, UK.
- Source
- Acta Paediatr Suppl, 1994 Dec, 407:, 60-5
- Abstract
- In phenylalanine hydroxylase deficiency detected by screening treatment in
early life, both age at start of treatment and phenylalanine control during
treatment are the major determinants of eventual psychological status. The
influence of phenylalanine control declines with age but executive
performance is influenced by hyperphenylalaninaemia at all ages. In a few
subjects neurological deterioration has been reported years after relaxing
or stopping treatment. MRI changes in brain white matter are present in most
subjects no longer on a strict diet. These changes are usually reversible
and closely related to phenylalanine status at the time of investigation.
Whether or not the changes point to a specific vulnerability of white matter
remains uncertain, although MRI changes were particularly prominent in
subjects with neurological disability and may be irreversible in such
subjects. Policies on treatment have to take account of these findings.
- Language of Publication
- English
- Unique Identifier
- 95284434
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- MeSH Heading (Major)
- Phenylalanine Hydroxylase|*DF; Phenylketonuria|*DH/DI/EN
- MeSH Heading
- Adult; Age Factors; Child; Child, Preschool; Counseling; Decision Trees;
Human; Infant, Newborn; Magnetic Resonance Imaging; Neonatal Screening;
Patient Selection
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0803-5326
- Country of Publication
- NORWAY
Record 10 from database: MEDLINE
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- Title
- Mutations in the phenylalanine hydroxylase gene: genetic determinants for
the phenotypic variability of hyperphenylalaninemia.
- Author
- Güttler F; Guldberg P
- Address
- Danish Center for Human Genome Research, John F Kennedy Institute,
Glostrup.
- Source
- Acta Paediatr Suppl, 1994 Dec, 407:, 49-56
- Abstract
- Phenylalanine hydroxylase (PAH) deficiency is a heterogeneous disease at
the phenotype level. The spectrum of clinical and metabolic phenotypes spans
from the potential pathogenic disease classical phenylketonuria (PKU) to the
benign condition non-PKU hyperphenylalaninemia (non-PKU HPA). This review
provides an introduction to the clinical variants of PAH deficiency, and
summarizes our attempts to define the disease at the molecular level and to
relate mutation genotype to clinical outcome. Complete genotype
determination in a large number of patients with PAH-deficient
hyperphenylalaninemia demonstrates that clinical heterogeneity can be
explained by a multiplicity of mutations in the PAH gene. Some combinations
of mutations are associated with phenylalanine levels fluctuating around the
border between PKU and non-PKU HPA. However, certain mutations seem always
to cause non-PKU HPA irrespective of the mutation on the second allele and
can, therefore, unambiguously be designated as being associated with the
non-PKU HPA phenotype. Our results suggest that mutation analysis in
newborns presenting with hyperphenylalaninemia can be used for rapid and
highly efficient differential diagnosis of PAH deficiency, and for
predicting the severity of the disease. These possibilities may facilitate
and optimize the management of hyperphenylalaninemia and thereby improve
prognosis.
- Language of Publication
- English
- Unique Identifier
- 95284432
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- MeSH Heading (Major)
- Mutation|*GE; Phenylalanine Hydroxylase|DF/*GE; Phenylketonuria|DI/EP/*GE/TH;
Variation (Genetics)|*GE
- MeSH Heading
- Denmark|EP; Genotype; Human; Infant, Newborn; Phenotype; Phenylalanine|BL;
Severity of Illness Index; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0803-5326
- Country of Publication
- NORWAY
Record 11 from database: MEDLINE
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- Title
- Mutations in the phenylalanine hydroxylase gene: methods for their
characterization.
- Author
- Guldberg P; Güttler F
- Address
- Danish Center for Human Genome Research, John F Kennedy Institute,
Glostrup.
- Source
- Acta Paediatr Suppl, 1994 Dec, 407:, 27-33
- Abstract
- Mutations in the phenylalanine hydroxylase (PAH) gene represent the root
cause of PAH-deficient hyperphenylalaninemia. To date, more than 160
different mutations have been reported. Single-base substitutions and
microdeletions account for the majority of molecular defects. This review
provides a brief general introduction to various strategies for detection of
PAH mutations, and summarizes our own methodological developments. We have
established a method based on PCR in combination with denaturing gradient
gel electrophoresis (DGGE) for mutation scanning of the entire coding
sequence and all exon/intron boundaries of the PAH. Systematic application
of this method to the study of a large number of mutant chromosomes from
hyperphenylalaninemic patients demonstrated a 98% diagnostic efficiency and
a 100% mutation detection efficiency. We have created compromised PCR and
DGGE conditions for simultaneous amplification and simultaneous mutation
scanning of all PAH-coding fragments. This technique is convenient in a
diagnostic setting and allows "same-day" DNA-based diagnosis of
newborns with hyperphenylalaninemia. A further modification of the method
allows unambiguous identification of known mutations, circumventing the
cumbersome step of nucleotide sequencing.
- Language of Publication
- English
- Unique Identifier
- 95284423
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- MeSH Heading (Major)
- Mutation|*GE; Phenylalanine Hydroxylase|DF/*GE; Phenylketonuria|DI/*GE
- MeSH Heading
- DNA Mutational Analysis; Electrophoresis, Polyacrylamide Gel|MT; Genetic
Screening|MT; Human; Infant, Newborn; Neonatal Screening|MT; Polymerase
Chain Reaction|MT; Sensitivity and Specificity; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0803-5326
- Country of Publication
- NORWAY
Record 12 from database: MEDLINE
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- Title
- Enzymology of the phenylalanine-hydroxylating system.
- Author
- Kaufman S
- Address
- Laboratory of Neurochemistry, National Institute of Mental Health,
Bethesda, Md.
- Source
- Enzyme, 1987, 38:1-4, 286-95
- Abstract
- The phenylalanine-hydroxylating system consists of 3 essential components,
phenylalanine hydroxylase (PAH), dihydropteridine reductase (DHPR) and the
coenzyme, tetrahydrobiopterin (BH4). DHPR and BH4 are also essential
components of the trosine- and tryptophan-hydroxylating systems. During the
hydroxylation reaction, BH4 is converted to the quinonoid dihydrobiopterin.
The reduction of this latter compound back to BH4 is catalyzed by the
reductase in the presence of NADH. In addition to the classic form of
phenylketonuria, which is caused by a lack of PAH, a form is caused by a
lack of DHPR and another by a deficiency of BH4 caused by the lack of an
enzyme involved in its de novo biosynthesis. Besides hyperphenylalaninemia,
these variant forms are characterized by neurological deterioration.
- Language of Publication
- English
- Unique Identifier
- 88151858
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- MeSH Heading (Major)
- Amino Acid Metabolism, Inborn Errors|*EN/TH; Biopterin|*AA/DF;
Hydroxylases|*; Phenylalanine|*ME; Phenylalanine Hydroxylase|*DF/ME
- MeSH Heading
- Human; Hydroxylation
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0013-9432
- Country of Publication
- SWITZERLAND
Record 13 from database: MEDLINE
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- Title
- Hydroxylation of salicylate and phenylalanine as assays for hydroxyl
radicals: a cautionary note visited for the third time.
- Author
- Halliwell B; Kaur H
- Address
- Neurodegenerative Disease Research Centre, King's College, London, UK.
- Source
- Free Radic Res, 1997 Sep, 27:3, 239-44
- Abstract
- Hydroxylation of salicylate to 2,3- and 2,5-dihydroxy-benzoates (DHBs) is
widely used as an index of hydroxyl radical (OH.) formation in vivo and in
vitro. Several recent studies indicate that peroxynitrite can lead to
generation of DHBs from salicylate and it is uncertain as to whether or not
OH. is involved. A similar problem may occur in the use of phenylalanine as
an OH. detector. Hence formation of hydroxylation products from salicylate
(or phenylalanine) may not in itself be a definitive index of OH.
generation, especially in cases where such generation in physiological
systems is decreased by inhibitors of nitric oxide synthase. Determination
of salicylate (or phenylalanine) nitration products can allow distinction
between peroxynitrite-dependent aromatic hydroxylation and that involving
"real" OH..
- Language of Publication
- English
- Unique Identifier
- 98011512
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- MeSH Heading (Major)
- Hydroxyl Radical|*AN/ME; Phenylalanine|AA/*CH/ME; Salicylic Acids|*CH/ME
- MeSH Heading
- Animal; Chromatography, High Pressure Liquid|MT; Human; Hydroxylation;
Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 1071-5762
- Country of Publication
- SWITZERLAND
Record 14 from database: MEDLINE
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- Title
- The phenylketonuria locus: current knowledge about alleles and mutations
of the phenylalanine hydroxylase gene in various populations.
- Author
- Konecki DS; Lichter Konecki U
- Address
- UniversitÂats-Kinderklinik, Heidelberg, Federal Republic of Germany.
- Source
- Hum Genet, 1991 Aug, 87:4, 377-88
- Abstract
- The hyperphenylalaninemic disorders of classic phenylketonuria (PKU), mild
phenylketonuria, and hyperphenylalaninemia (HPA), result from a deficiency
of the hepatic enzyme phenylalanine hydroxylase (PAH) or its cofactor (tetrahydrobiopterin).
Use of the complementary DNA of this enzyme has allowed the establishment of
a restriction fragment length polymorphism (RFLP) haplotype-analysis system.
This haplotype analysis system provides the means for determination of
mutant PAH alleles in most affected families and is the basis for mutational
analysis of the PKU locus. This review is focused on two major areas of
current PKU research: (1) the use of DNA haplotype analysis in the study of
the population genetics of PAH deficiency, and (2) the study of genotypes,
and their various combinations, as a means of explaining and predicting the
phenotypic variability observed for the disorders of PAH deficiency.
- Language of Publication
- English
- Unique Identifier
- 91348681
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- MeSH Heading (Major)
- Alleles|*; Genetics, Population|*; Mutation|*; Phenylalanine
Hydroxylase|DF/*GE; Phenylketonuria|*GE
- MeSH Heading
- Chromosome Mapping; Haplotypes; Human; Polymorphism, Restriction Fragment
Length; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0340-6717
- Country of Publication
- GERMANY
Record 15 from database: MEDLINE
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- Title
- Phenylketonuria and the phenylalanine hydroxylase gene.
- Author
- Eisensmith RC; Woo SL
- Address
- Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX
77030.
- Source
- Mol Biol Med, 1991 Feb, 8:1, 3-18
- Abstract
- The application of the tools of molecular biology has led to a profound
increase in our current understanding of the nature of the disease states
associated with defects in the phenylalanine hydroxylase (PAH) gene. Over
the past decade, the PAH cDNA has been cloned and the primary structure of
the PAH protein has been determined. The PAH cDNA clone has served as an
invaluable probe to define the molecular structure and chromosomal location
of the PAH locus in both man and other organisms. Southern analysis using
the PAH cDNA as a hybridization probe has revealed the presence of numerous
restriction fragment-length polymorphisms (RFLPs) in the PAH gene, which
have permitted the classification of normal and mutant PAH chromosomes. RFLP
analysis has also permitted the implementation of prenatal diagnosis of
phenylketonuria (PKU) and other related hyperphenylalaninemic disorders.
Through the use of molecular cloning and polymerase chain reaction
methodologies, many molecular lesions have now been identified in the PAH
gene, and their association with different PAH haplotypes and disease
phenotypes can now be addressed in a rational manner. Finally, the
characterization of PAH mutations has enabled the population dynamics of
phenylketonuria to be examined in several different populations.
- Language of Publication
- English
- Unique Identifier
- 92048466
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- MeSH Heading (Major)
- Phenylalanine Hydroxylase|*GE; Phenylketonuria|DH/*GE/ME
- MeSH Heading
- Animal; Base Sequence; DNA|GE; DNA Mutational Analysis; Genetics,
Population; Human; Infant, Newborn; Neonatal Screening; Phenylalanine|ME;
Rats; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0735-1313
- Country of Publication
- ENGLAND
Record 16 from database: MEDLINE
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- Title
- In vitro expression analysis of mutations in phenylalanine hydroxylase:
linking genotype to phenotype and structure to function.
- Author
- Waters PJ; Parniak MA; Nowacki P; Scriver CR
- Address
- Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
- Source
- Hum Mutat, 1998, 11:1, 4-17
- Abstract
- Mutations in the human phenylalanine hydroxylase gene (PAH) altering the
expressed cDNA nucleotide sequence (GenBank U49897) can impair activity of
the corresponding enzyme product (hepatic phenylalanine hydroxylase, PAH)
and cause hyperphenylalaninemia (HPA), a metabolic phenotype for which the
major disease form is phenylketonuria (PKU; OMIM 261600). In vitro
expression analysis of inherited human mutations in eukaryotic, prokaryotic,
and cell-free systems is informative about the mechanisms of mutation
effects on enzymatic activity and their predicted effect on the metabolic
phenotype. Corresponding analysis of site-directed mutations in rat Pah cDNA
has assigned critical functional roles to individual amino acid residues
within the best understood species of phenylalanine hydroxylase. Data on in
vitro expression of 35 inherited human mutations and 22 created rat
mutations are reviewed here. The core data are accessible at the PAH
Mutation Analysis Consortium Web site (http://www.mcgill.ca/pahdb).
- Language of Publication
- English
- Unique Identifier
- 98111373
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- MeSH Heading (Major)
- Gene Expression Regulation, Enzymologic|*; Mutation|*; Phenylalanine
Hydroxylase|*CH/*GE/PH
- MeSH Heading
- Animal; DNA Mutational Analysis; Genotype; Human; Phenotype;
Structure-Activity Relationship; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 1059-7794
- Country of Publication
- UNITED STATES
Record 17 from database: MEDLINE
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- Title
- Crystal structure of the catalytic domain of human phenylalanine
hydroxylase reveals the structural basis for phenylketonuria [letter]
- Author
- Erlandsen H; Fusetti F; Martinez A; Hough E; Flatmark T; Stevens RC
- Address
-
- Source
- Nat Struct Biol, 1997 Dec, 4:12, 995-1000
- Abstract
- The 2.0 A crystal structure of the catalytic domain of human phenylalanine
hydroxylase reveals a fold similar to that of tyrosine hydroxylase. It
provides the first structural view of where mutations occur and a rationale
to explain molecular mechanisms of the enzymatic phenotypes in the autosomal
recessive disorder phenylketoneuria.
- Language of Publication
- English
- Unique Identifier
- 98069646
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- MeSH Heading (Major)
- Phenylalanine Hydroxylase|*CH/GE; Phenylketonuria|*EN/GE
- MeSH Heading
- Amino Acid Sequence; Animal; Binding Sites|GE; Comparative Study;
Crystallization; Human; Models, Molecular; Molecular Sequence Data;
Mutation; Protein Folding; Support, Non-U.S. Gov't; Tyrosine
3-Monooxygenase|CH/GE
- Publication Type
- LETTER; REVIEW; REVIEW, TUTORIAL
- ISSN
- 1072-8368
- Country of Publication
- UNITED STATES
Record 18 from database: MEDLINE
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- Title
- The effects of high phenylalanine concentration on chick embryonic
development.
- Author
- Kirby ML; Miyagawa ST
- Address
- Department of Anatomy, Medical College of Georgia, Augusta 30912-2000.
- Source
- J Inherit Metab Dis, 1990, 13:4, 634-40
- Abstract
- Cells from a particular portion of the cranial neural crest (cardiac
neural crest) migrate from the neural fold into pharyngeal arches 3, 4 and
6, where they provide the support for the endothelium of the aortic arch
arteries, and by migration into the outflow tract become involved in
septation of the truncus arteriosus. Ablation of the premigratory cardiac
neural crest results in persistent truncus arteriosus and other defects
reminiscent of the DiGeorge syndrome in man. Removal of a small area of the
cardiac neural crest causes a spectrum of heart defects classified together
as dextraposed aorta including changes like that of Fallot's tetralogy in
man. Some inflow tract anomalies have also been found. Pilot studies
injecting phenylalanine into developing chick embryos at a very early stage
had little effect on embryo viability or on the incidence of congenital
heart defects. However, sham-treated animals produced predominantly small
simple ventricular septal defects but phenylalanine-treated embryos had more
serious and complex heart anomalies. It is not possible to say yet that
congenital heart disease in the offspring of mothers with untreated
phenylketonuria is due to phenylalanine-induced damage to the neural crest,
but the pilot studies in chick suggest that this idea is worth pursuing.
- Language of Publication
- English
- Unique Identifier
- 91040687
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- MeSH Heading (Major)
- Heart Defects, Congenital|CO/*DT/PA; Neural Crest|DE/*ME/PA;
Phenylalanine|*PD; Phenylketonuria|CO/*DT/PA
- MeSH Heading
- Animal; Chick Embryo; Human; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0141-8955
- Country of Publication
- NETHERLANDS
Record 19 from database: MEDLINE
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- Title
- Mortality, major amputation rates, and leukopenia after isolated limb
perfusion with phenylalanine mustard for the treatment of melanoma.
- Author
- Taber SW; Polk HC Jr
- Address
- Department of Surgery, University of Louisville School of Medicine,
Kentucky 40292, USA.
- Source
- Ann Surg Oncol, 1997 Jul, 4:5, 440-5
- Abstract
- BACKGROUND: Isolated limb perfusion (ILP) is a treatment for cutaneous
melanoma performed by several centers worldwide. The final data analysis of
the World Health Organization and European Organization for Research and
Treatment of Cancer in the use of ILP as adjuvant treatment for cutaneous
melanoma is pending. ILP is effective to treat recurrent cutaneous melanoma.
We determined the published rates of morbidity and mortality of ILP and put
that component of the procedure into contemporary perspective. METHODS: A
MEDLINE search was conducted of the English-language literature from 1980 to
1995 for all publications reporting perfusion with phenylalanine mustard
alone or combined with other agents. Patients treated by staged perfusion or
fractional doses of chemotherapy were excluded. All published series were
analyzed for the rate of mortality, number of major amputations, and
presence of leukopenia. RESULTS: The 30-day mortality rate for > 2,000
patients was 0.6%. Death often resulted from cardiopulmonary complications
or overwhelming sepsis from leukopenia. Leukopenia occurred in 0.7% of
patients reviewed, caused by leakage of chemotherapeutic agents into the
systemic circulation. Major amputations occurred in 0.8% of patients, and
most were of the lower extremity. CONCLUSIONS: The definition of efficacy of
ILP in the treatment of extremity melanomas remains to be clearly defined.
However, based on this review of worldwide publications, the risk of death,
amputation, and leukopenia is low.
- Language of Publication
- English
- Unique Identifier
- 97406533
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- MeSH Heading (Major)
- Amputation|*; Antineoplastic Agents, Alkylating|*AD/AE; Extremities|*/SU;
Leukopenia|*CI; Melanoma|*DT/MO/SU; Melphalan|*AD/AE; Perfusion,
Regional|*/MT; Skin Neoplasms|*DT/MO/SU
- MeSH Heading
- Human; Survival Rate
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 1068-9265
- Country of Publication
- UNITED STATES
Record 20 from database: MEDLINE
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- Title
- Phenylketonuria due to phenylalanine hydroxylase deficiency: an unfolding
story. Medical Research Council Working Party on Phenylketonuria.
- Address
-
- Source
- BMJ, 1993 Jan, 306:6870, 115-9
- Abstract
- Efficient neonatal screening for phenylketonuria and the availability of
complex diets for lifelong use have virtually eliminated severe mental
handicap from the disease. Nevertheless, there remains a high risk of fetal
damage in offspring of women with the disease, and the possibility that the
diets themselves may be harmful cannot be excluded. Search for a preventive
treatment for the disease has been greatly aided by advances in molecular
genetics. For example, in mice modified liver cells have been implanted,
which have not only corrected the phenylalanine defect but have remained
healthy for the normal life span of the animal. Overall, however, prevention
and treatment have not progressed as quickly as was hoped, and research and
development must be pursued vigorously to take account of contemporary
perceptions of the disorder.
- Language of Publication
- English
- Unique Identifier
- 93169184
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- MeSH Heading (Major)
- Phenylalanine Hydroxylase|*DF/*GE; Phenylketonuria|CO/*GE/TH
- MeSH Heading
- Adolescence; Adult; Animal; Central Nervous System Diseases|ET; Child;
Female; Great Britain; Health Services Needs and Demand; Human; Mice;
Phenylketonuria, Maternal|CO; Pregnancy
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0959-8138
- Country of Publication
- ENGLAND
Record 21 from database: MEDLINE
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- Title
- Regulation of the activity of hepatic phenylalanine hydroxylase.
- Author
- Kaufman S
- Address
-
- Source
- Adv Enzyme Regul, 1986, 25:, 37-64
- Abstract
- Rat liver phenylalanine hydroxylase catalyzes the tetrahydropterin-dependent
oxidation of phenylalanine to tyrosine, according to equation 1. In addition
to the naturally-occurring coenzyme, tetrahydrobiopterin (BH4), certain
synthetic analogs of BH4 such as 6-methyltetrahydropterin (6MPH4) have high
cofactor activity. (formula; see text) The hydroxylase can be activated by a
variety of reversible and irreversible modifications, including those caused
by partial proteolysis, by interaction with phospholipids such as
lysolecithin, by alkylation of a single sulfhydryl group, by phosphorylation
catalyzed by cAMP-dependent protein kinase, and by preincubation with its
substrate, phenylalanine. All of these modes of activation greatly increase
the hydroxylase activity in the presence of BH4, whereas the activity in the
presence of 6MPH4 is increased only slightly. The ratio of hydroxylase
activity in the presence of BH4 compared to the activity in the presence of
6MPH4, therefore, is a useful index of the state of activation of the
enzyme. Of the various activation mechanisms listed above, only
phosphorylation of the enzyme and phenylalanine-activation appear to operate
in vivo. The evidence indicates that these two regulatory mechanisms act
synergistically. Thus, phosphorylation of the enzyme by cAMP-dependent
protein kinase is stimulated by phenylalanine, especially in the presence of
BH4, (which by itself inhibits), whereas phosphorylation sensitizes the
enzyme to activation by phenylalanine. One of the consequences of these
interlocking control mechanisms is to enhance the responsiveness of the
activity of the hydroxylase to alterations in tissue levels of
phenylalanine. As a result, elevated concentrations of phenylalanine can be
rapidly metabolized, thereby protecting the fetal and neonatal brain from
possible damage by excess phenylalanine.
- Language of Publication
- English
- Unique Identifier
- 87123881
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- MeSH Heading (Major)
- Liver|DE/*EN; Phenylalanine Hydroxylase|*ME
- MeSH Heading
- Animal; Biopterin|AA/ME; Diet; Enzyme Activation; Glucagon|PD; Human;
Ligands; Phenylalanine|ME; Phosphoprotein Phosphatase|ME; Phosphorylation;
Rats
- Publication Type
- JOURNAL ARTICLE; REVIEW
- ISSN
- 0065-2571
- Country of Publication
- ENGLAND
Record 22 from database: MEDLINE
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- Title
- Trace metal requirements in total parenteral nutrition (TPN). 5. Formation
constants for the copper(II)--histidine ternary complexes with threonine,
lysine, glycine, phenylalanine, valine, and cystine, and discussion of their
implications regarding the copper distribution in blood plasma during TPN
and the evaluation of the daily dose of copper.
- Author
- Berthon G; Blais MJ; Piktas M; Houngbossa K
- Address
-
- Source
- J Inorg Biochem, 1984 Feb, 20:2, 113-30
- Abstract
- Specific metal deficiencies have been reported to affect patients
receiving total parenteral nutrition (TPN). Our previous studies on the
topic were devoted to the computer-based interpretation of the extra urinary
excretion of zinc; a theoretical approach was also proposed, with a view to
compensating for the extra losses of this metal. Similarly, the present work
deals with the problem of TPN-induced copper deficiency and its remedy. As
is the case for zinc, the TPN-induced excretion of copper clearly stems from
the relative mobilization of the plasma protein-bound pool of this metal
into its diffusable low-molecular-weight fraction; this phenomenon being due
to the competitive complexation of copper by the amino acids of the
nutritive solution. The computer simulation of this effect thus required
that first the equilibrium constants be experimentally determined for the
main complexes of copper that might form in the solution as well as in
plasma during the infusion. Accordingly, complex formation in the
copper-histidine ternary systems with threonine, lysine, glycine,
phenylalanine, valine, and cystine was investigated by potentiometry at 37
degrees C in NaCIO4 0.15 mol X dm-3. The implications of the results
obtained are discussed with regard to the interpretation of the copper
excretion and the estimation of the desirable daily dose of this metal for
the TPN mixture under consideration.
- Language of Publication
- English
- Unique Identifier
- 84187542
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- MeSH Heading (Major)
- Amino Acids|*BL; Copper|AD/*BL/DF; Parenteral Nutrition|*/AE; Parenteral
Nutrition, Total|*/AE
- MeSH Heading
- Comparative Study; Computers; Human; Ligands; Models, Biological;
Nutritional Requirements; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE; REVIEW
- ISSN
- 0162-0134
- Country of Publication
- UNITED STATES
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