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Table Of Contents

Phenylalanine

Phenyalanine

Atom Symbol

MSDS

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Click on the image to go to the page which links to all the other pages on this web site on the subject of "oral chelation." The amino acids are the most important ingredients in an oral chelation formula. Phenylalanine is one of the important amino acids in the formula.

Menu Of Abstracts On Phenylalanine Click On The Number For The Abstract
...1...	White matter abnormalities in phenylketonuria: results of magnetic resonance measurements.	*Definition: Phenylketonuria (PKU)* means that the undigested amino acid, phenylalanine, is showing up in the urine**
...2...	Treatment of phenylalanine hydroxylase deficiency.	*Definition: Hydroxylase* means an enzyme**
...3...	Dopamine precursors and brain function in phenylalanine hydroxylase deficiency.
...4...	MRI characterization of cerebral dysgenesis in maternal PKU.
...5...	Mutations in the phenylalanine hydroxylase gene: genetic determinants for the phenotypic variability of hyperphenylalaninemia.
...6...	Gene therapy for phenylketonuria.
...7...	Science, medicine and phenylketonuria.
...8...	Possible neurologic effects of aspartame, a widely used food additive.
...9...	Mechanism of action of ochratoxin A.
...10...	Phenylketonuria: screening, treatment and maternal PKU.
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...11...	Maternal phenylketonuria: a metabolic teratogen.
...12...	Aspartame: review of recent experimental and observational data.
...13...	Maternal phenylketonuria. Review with emphasis on pathogenesis.
...14...	Aspartame intolerance.
...15...	Pharmacological effects of phenylalanine on seizure susceptibility: an overview.
...16...	Dietary treatment of destructive behavior associated with hyperphenylalaninemia.	*Definition: hyper* means too much, so hyperphenylalaninemia is too much phenylalanine. The ending, "mia," refers to the material being in the blood.**
...17...	Monoamine oxidase and catecholamine metabolism.
...18...	PKU in adolescents: rationale and psychosocial factors in diet continuation.
...19...	Phenylalanine levels of 6-10 mg/dl may not be as benign as once thought.
...20...	Mutations in the phenylalanine hydroxylase gene: methods for their characterization.
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...21...	Population genetics of phenylketonuria.
...22...	The biochemistry and enzymology of amino acid dehydrogenases.
...23...	Protein metabolism in the cancer patient.
...24...	Hsp70s and lysosomal proteolysis.
...25...	The methotrexate story: a paradigm for development of cancer chemotherapeutic agents.
...26...	Dipeptidyl peptidase IV: development, design, synthesis and biological evaluation of inhibitors.
...27...	Dietary amino acids and brain function.
...28...	Long-term follow-up of children with classical phenylketonuria after diet discontinuation: a review.
...29...	Prevention of nephrotoxicity of ochratoxin A, a food contaminant.
...30...	The kinase-dependent function of Lck in T-cell activation requires an intact site for tyrosine autophosphorylation.
Menu Position 30
...31...	Diagnosis and management of tyrosinemia type I.
...32...	Phenylketonuria: contemporary screening and diagnosis.
...33...	Functions of the cystic fibrosis transmembrane conductance regulator protein.
...34...	Postinjury neutrophil priming and activation states: therapeutic challenges [editorial]
...35...	Phenylethylamine modulation of affect: therapeutic and diagnostic implications.
...36...	Painful keratoderma and photophobia: hallmarks of tyrosinemia type II.
...37...	Regulation of the activity of hepatic phenylalanine hydroxylase.
...38...	Formation, nutritional value, and safety of D-amino acids.
...39...	In vitro expression analysis of mutations in phenylalanine hydroxylase: linking genotype to phenotype and structure to function.
...40...	Hydroxylation of salicylate and phenylalanine as assays for hydroxyl radicals: a cautionary note visited for the third time.
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...41...	The effects of high phenylalanine concentration on chick embryonic development.
...42...	Pteridines and mono-amines: relevance to neurological damage.
...43...	White matter abnormalities in patients with treated hyperphenylalaninaemia: magnetic resonance relaxometry and proton spectroscopy findings.
...44...	Tetrahydrobiopterin deficiencies: preliminary analysis from an international survey.
...45...	Amino acid concentrations in cerebrospinal fluid in presenile and senile dementia of Alzheimer type and multi-infarct dementia.
...46...	Nutritional therapy for selected inborn errors of metabolism.
...47...	Amino acid metabolism in uremia.
...48...	Use of cetirizine to investigate non-H1 effects of second-generation antihistamines.
...49...	Nurses' role in preventing birth defects in offspring of women with phenylketonuria [published erratum appears in J Obstet Gynecol Neonatal Nurs 1992 Sep-Oct;21(5):352]
...50...	Enzymology of the phenylalanine-hydroxylating system.
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...51...	Enzymatic catalysis by Friedel-Crafts-type reactions.
...52...	Transport of amino acids by the human placenta: predicted effects thereon of maternal hyperphenylalaninaemia.
...53...	The influence of mutations of enzyme activity and phenylalanine tolerance in phenylalanine hydroxylase deficiency.
...54...	Gene therapy for phenylketonuria.
...55...	Relationship between genotype and phenotype in monogenic diseases: relevance to polygenic diseases.
...56...	Use of aspartame in pregnancy.
...57...	Defects of tetrahydrobiopterin synthesis and their possible relationship to a disorder of purine metabolism (the Lesch-Nyhan syndrome).
...58...	Dysfunction of CFTR bearing the delta F508 mutation.
...59...	The 'cerebral diabetes' paradigm for unipolar depression.
...60...	Congenital adrenal hyperplasia (CAH)--the place for prenatal treatment and neonatal screening.
Menu Position 60
...61...	Mechanical models of pseudopod formation.
...62...	The systemic administration of intravenous melphalan.
...63...	Trace amines and Tourette's syndrome.
...64...	Unraveling prion diseases through molecular genetics.
...65...	The control of aromatic amino acid catabolism and its relationship to neurotransmitter amine synthesis.
...66...	Cytosolic free Ca2+ signals in single adherent human neutrophils: generation and functional role.
...67...	Nutrition in the management of inborn errors of metabolism [published erratum appears in Clin Lab Med 1993 Dec;13(4):following table of contents]
...68...	Mutagenic activity of peptides and the artificial sweetener aspartame after nitrosation.
..69...	Inhibition of in vitro platelet aggregation and release and fibrinolysis.
...70...	Lysosomal degradation of microinjected proteins.
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...71...	Phenylketonuria due to phenylalanine hydroxylase deficiency: an unfolding story. Medical Research Council Working Party on Phenylketonuria.
...72...	Clinical hyperthermia and chemotherapy.
...73...	Cystic fibrosis gene.
...74...	CFTR!
...75...	Guidelines for the treatment of vitiligo.
...76...	Immunonutrition: role of sulfur amino acids, related amino acids, and polyamines.
...77...	In vitro studies indicating antioxidative properties of rebamipide.
...78...	New perspectives and hope for cure-reflecting recent genetic developments in cystic fibrosis.
...79...	Illegitimate transcription: its use in the study of inherited disease.
...80...	Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene.
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...81...	Artificial cells with emphasis on bioencapsulation in biotechnology.
...82...	Present status of boron neutron capture therapy.
...83...	Intestinal mucosal amino acid catabolism.
...84...	The clinical importance of hypochlorhydria (a consequence of chronic Helicobacter infection): its possible etiological role in mineral and amino acid malabsorption, depression, and other syndromes.
...85...	Entero-insular axis and diabetes mellitus.
...86...	Mechanisms by which cancer chemotherapeutic drugs induce emesis.
...87...	Therapeutic uses of microencapsulated genetically engineered cells.
...88...	A review of recent advances in understanding ochratoxicosis.
...89...	Molecular biology of Alzheimer's amyloid--Dutch variant.
...90....	Pharmacotherapy of attention-deficit/hyperactivity disorder in adults.
Menu Position 90
...91...	Treatment of osteoarthritis with aspartame.
...92...	Signal transduction in cells following binding of chemoattractants to membrane receptors.
...93...	Antioxidant potential of ferulic acid.
...94...	Copper, lysyl oxidase, and extracellular matrix protein cross-linking.
...95...	Strategies for correcting the delta F508 CFTR protein-folding defect.
...96...	A summary of mechanistic hypotheses of gabapentin pharmacology.
...97...	Amino acids for the measurement of protein synthesis in vivo by PET.
...98...	Amino acid metabolism in pediatric patients.
...99...	Scleroderma-like skin indurations in a child with phenylketonuria: a clinicopathologic correlation and review of the literature.
...100...	Protein turnover in the kidney and the whole body in humans.

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HealthGate Documents

Record 1 from database: MEDLINE
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Title: White matter abnormalities in phenylketonuria: results of magnetic resonance measurements.
Author: Ullrich K; Möller H; Weglage J; Schuierer G; Bick U; Ludolph A; Hahn Ullrich H; Fünders B; Koch HG
Address: Department of Paediatrics, University of MÂunster, Germany.
Source: Acta Paediatr Suppl, 1994 Dec, 407:, 78-82
Abstract: In adolescents and adults with PKU, blood phenylalanine levels above 10 mg/dl are generally associated with white matter changes in MRI. The grade of these changes is correlated to most recent blood phenylalanine levels. Based on studies using T2 relaxometry the MRI changes seem to be the consequence of a reversible dysmyelination. The clinical relevance of these white matter changes remains unclear as the extent of MRI alterations did not correlate with IQ, neurological and electrophysiological deficits of the patients. The intracerebral phenylalanine concentration as measured by protonspectroscopy amounts to about 50% of blood phenylalanine concentrations. Preliminary data indicate that brain phenylalanine levels remain constant if blood concentrations exceed 20 mg/dl. This might be of clinical relevance for the treatment of adolescent and adult PKU patients.
Language of Publication: English
Unique Identifier: 95284440

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MeSH Heading (Major): Brain Diseases|ET/*PA; Demyelinating Diseases|ET/*PA; Magnetic Resonance Imaging|*; Phenylketonuria|BL/*CO/DH
MeSH Heading: Brain Chemistry; Case-Control Studies; Electrophysiology; Human; Phenylalanine|AN

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0803-5326
Country of Publication: NORWAY

Record 2 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 3 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 4 from database: MEDLINE
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Title: MRI characterization of cerebral dysgenesis in maternal PKU.
Author: Allen RJ; Brunberg J; Schwartz E; Schaefer AM; Jackson G
Address: Division of Pediatric Neurology, University of Michigan Medical School, Ann Arbor, USA.
Source: Acta Paediatr Suppl, 1994 Dec, 407:, 83-5
Abstract: MPKU pregnancies, with or without dietary treatment to reduce maternal plasma phenylalanine (phe), show variable, increased non-physiologic levels, as the putative cause of fetal teratogenicity. Cerebral dysgenesis with clinical neonatal microcephaly and congenital heart disease indicates altered organ morphogenesis. Although there is not an established precise relationship between maternal phe levels and outcome, dietary restriction before or early in gestation is universally advised. Both human experience and animal research have suggested differential organ responses to high and low phe levels. Structural microencephaly may be due to reduced brain volume or abnormal regional brain development. Infants in MPKU are also at risk to develop PKU. Microencephaly was evident by MRI in 8 of 21 infants born to 12 MPKU mothers; 2 infants of one mother developed PKU. All levels of gestational plasma phe were associated with otherwise structurally normal infant microencephalic brains appropriate for age in myelination. CHD occurred in one microencephalic infant of a classic MPKU treated in the first trimester. Maternal, cord and neonatal plasma phenylalanine at delivery did not correlate with teratogenic effects. Only untreated 'classic' MPKU fetal effects appear predictable.
Language of Publication: English
Unique Identifier: 95284441

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MeSH Heading (Major): Abnormalities, Multiple|*DI/ET; Brain|*AB; Magnetic Resonance Imaging|*; Microcephaly|*DI/ET; Phenylketonuria, Maternal|BL/*CO/DH
MeSH Heading: Female; Heart Defects, Congenital|DI; Human; Phenylalanine|BL; Pregnancy

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, MULTICASE
ISSN: 0803-5326
Country of Publication: NORWAY

Record 5 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 6 from database: MEDLINE
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Title: Gene therapy for phenylketonuria.
Author: Eisensmith RC; Woo SL
Address: Department of Cell Biology, Baylor College of Medicine, Houston, TX.
Source: Acta Paediatr Suppl, 1994 Dec, 407:, 124-9
Abstract: Classical phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH). Three different vector systems have been developed to examine the potential of somatic gene therapy for the treatment of PKU. Recombinant retroviral vectors and DNA/protein complexes can efficiently transduce PAH-deficient hepatocytes in vitro, but their present application is limited by their low transduction efficiency in vivo. In contrast, infusion of a recombinant adenoviral vector expressing the human PAH cDNA into the portal circulation of PAH-deficient mice restores 10-80% of normal hepatic PAH activity and completely normalizes serum phenylalanine levels. At present, this effect is transient and re-administration has no further effect. However, this result suggests that PKU can be completely corrected by somatic gene therapy as more persistent vectors are developed.
Language of Publication: English
Unique Identifier: 95284421

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MeSH Heading (Major): Gene Therapy|*/MT; Phenylalanine Hydroxylase|*GE; Phenylketonuria|EN/GE/*TH
MeSH Heading: Animal; Disease Models, Animal; DNA, Complementary|GE; Gene Transfer; Human; Mice

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0803-5326
Country of Publication: NORWAY

Record 7 from database: MEDLINE
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Title: Science, medicine and phenylketonuria.
Author: Scriver CR
Address: Department of Pediatrics, McGill University, Montreal, Canada.
Source: Acta Paediatr Suppl, 1994 Dec, 407:, 11-8
Abstract: Science addresses ignorance; medicine uses facts. The scientific approach to phenylketonuria (PKU) led to the discovery of its causes, both ultimate (allelic heterogeneity at the PAH locus) and proximate (dietary phenylalanine), the proximal phenotype (phenylalanine hydroxylase deficiency), the associated metabolic phenotype and the major distal phenotype (impaired cognitive development and neuropsychological function) for which the pathogenesis is still being investigated. By applying knowledge through newborn screening, early diagnosis and treatment, the brain disease of PKU has been greatly ameliorated. The population approach, which converted incidence into cases, revealed genetic heterogeneity in hyperphenylalaninemia involving four other loci, controlling cofactor (BH4) synthesis and recycling, and non-random geographic distribution of mutant PAH alleles of which more than 170 were known in April 1994. Various mechanisms including founder effect, genetic drift, hypermutability and selection (perhaps) explain the polymorphic aggregate frequency (approximately 0.01) and spectrum of PKU mutations in human populations.
Language of Publication: English
Unique Identifier: 95284417

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MeSH Heading (Major): Phenylketonuria|EP/*GE/ME/PC
MeSH Heading: Alleles; Gene Frequency; Genetic Screening; Human; Incidence; Infant, Newborn; Mutation|GE; Neonatal Screening; Phenotype; Polymorphism (Genetics); Support, Non-U.S. Gov't

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0803-5326
Country of Publication: NORWAY

Record 8 from database: MEDLINE
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Title: Possible neurologic effects of aspartame, a widely used food additive.
Author: Maher TJ; Wurtman RJ
Address: Department of Pharmacology, Massachusetts College of Pharmacy, Boston 02115.
Source: Environ Health Perspect, 1987 Nov, 75:, 53-7
Abstract: The artificial sweetener aspartame (L-aspartyl-L-phenylalanyl-methyl ester), is consumed, primarily in beverages, by a very large number of Americans, causing significant elevations in plasma and, probably, brain phenylalanine levels. Anecdotal reports suggest that some people suffer neurologic or behavioral reactions in association with aspartame consumption. Since phenylalanine can be neurotoxic and can affect the synthesis of inhibitory monoamine neurotransmitters, the phenylalanine in aspartame could conceiveably mediate neurologic effects. If mice are given aspartame in doses that elevate plasma phenylalanine levels more than those of tyrosine (which probably occurs after any aspartame dose in humans), the frequency of seizures following the administration of an epileptogenic drug, pentylenetetrazole, is enhanced. This effect is simulated by equimolar phenylalanine and blocked by concurrent administration of valine, which blocks phenylalanine's entry into the brain. Aspartame also potentiates the induction of seizures by inhaled fluorothyl or by electroconvulsive shock. Perhaps regulations concerning the sale of food additives should be modified to require the reporting of adverse reactions and the continuing conduct of mandated safety research.
Language of Publication: English
Unique Identifier: 88082587

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MeSH Heading (Major): Aspartame|*AE/ME; Dipeptides|*AE; Food Additives|*AE; Seizures|*CI
MeSH Heading: Animal; Brain|DE/ME; Human; Phenylalanine|BL; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0091-6765
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Dipeptides); 0 (Food Additives); 22839-47-0 (Aspartame); 3617-44-5 (Phenylalanine)

Record 9 from database: MEDLINE
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Title: Mechanism of action of ochratoxin A.
Author: Dirheimer G; Creppy EE
Address: Institut de Biologie Moléculaire et Cellulaire du Centre National de la Recherche Scientifique, Strasbourg, France.
Source: IARC Sci Publ, 1991, :115, 171-86
Abstract: Ochratoxin A has a number of toxic effects in mammals, the most notable of which is nephrotoxicity. It is also immunosuppressive, teratogenic and carcinogenic. The biochemical and molecular aspects of its action were first studied in bacteria. The appearance of 'magic spots' (ppGpp and pppGpp) pointed to inhibition of the charging of transfer ribonucleic acids (tRNA) with amino acids. This suggestion was confirmed by the demonstration that ochratoxin A inhibits bacterial, yeast and liver phenylalanyl-tRNA synthetases. The inhibition is competitive to phenylalanine and is reversed by an excess of this amino acid. As a consequence, protein synthesis is inhibited, as shown with hepatoma cells in culture, with Madin Darby canine kidney cells (which are much more sensitive) and in vivo in mouse liver, kidney and spleen, the inhibition being more effective in the latter two organs. An excess of phenylalanine also prevents inhibition of protein synthesis in cell cultures and in vivo. Analogues of ochratoxin A in which phenylalanine has been replaced by other amino acids have similar inhibitory effects on the respective amino acid-specific aminoacyl tRNA synthetases. 4R-Hydroxyochratoxin A, a metabolite of ochratoxin A, has a similar action, whereas ochratoxin alpha (the dihydroisocoumarin moiety) and ochratoxin B (ochratoxin A without chlorine) have no effect. Ochratoxin A might act on other enzymes that use phenylalanine as a substrate. We showed recently that it inhibits phenylalanine hydroxylase. In addition, the phenylalanine moiety of ochratoxin A is partially hydroxylated to tyrosine by incubation with hepatocytes and in vivo. This competitive action with phenylalanine might explain why this amino acid prevents the immuno-suppressive effect of ochratoxin A and partially prevents its teratogenic and nephrotoxic actions. The effect of ochratoxin A on protein synthesis is followed by an inhibition of RNA synthesis, which might affect proteins with a high turnover. Ochratoxin A also lowers the level of phosphoenolpyruvate carboxykinase, a key enzyme in gluconeogenesis; this inhibition is reported to be due to a specific degradation of mRNA that codes for this enzyme. Recently, ochratoxin A was also found to enhance lipid peroxidation both in vitro and in vivo. This inhibition might have an important effect on cell or mitochondrial membranes and be responsible for the effects on mitochondria that have been shown by several authors. Finally, the recent results of Pfohl-Leszkowicz et al. (this volume), who showed the formation of DNA adducts mainly in kidney but also in liver and spleen, explain the DNA single-strand breaks observed previously in mice and rats after acute and chronic treatment.
Language of Publication: English
Unique Identifier: 92316600

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MeSH Heading (Major): Ochratoxins|*PD/PK/TO; Phenylalanine|AA/*ME; Phenylalanyl T RNA Synthetase|*AI
MeSH Heading: Animal; Antibody Formation|DE; Bacteria|DE; Cells, Cultured; Dogs; DNA Damage; Eukaryotic Cells|DE; Guinea Pigs; Human; Kidney Tubules, Proximal|DE; Lipid Peroxidation|DE; Liver Neoplasms, Experimental|PA; Mice; Mice, Inbred BALB C; Mutagenicity Tests; Mycotoxicosis|ET; Phenylalanine Hydroxylase|AI; Phosphoenolpyruvate Carboxykinases|ME; Protein Synthesis Inhibitors|PD/TO; Rats; Structure-Activity Relationship; Support, Non-U.S. Gov't; Tumor Cells, Cultured|DE

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0300-5038
Country of Publication: FRANCE
CAS Registry/EC Number: EC 1.14.16.1 (Phenylalanine Hydroxylase); EC 4.1.1.32 (Phosphoenolpyruvate Carboxykinases); EC 6.1.1.20 (Phenylalanyl T RNA Synthetase); 0 (Ochratoxins); 0 (Protein Synthesis Inhibitors); 303-47-9 (ochratoxin A); 3617-44-5 (Phenylalanine)

Record 10 from database: MEDLINE
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Title: Phenylketonuria: screening, treatment and maternal PKU.
Author: Matalon R; Michals K
Address: Research Institute, Miami Children's Hospital, FL 33155.
Source: Clin Biochem, 1991 Aug, 24:4, 337-42
Abstract: Phenylketonuria (PKU) has become a paradigm of a disease that can be identified by screening in the newborn period and treated to prevent serious complications. After many years of experience treating PKU, new challenges have emerged. It has become apparent that defective activity of phenylalanine hydroxylase leads to a spectrum of clinical presentations that has led to subclassifications of PKU. Blood phenylalanine greater than 1200 mumol/L usually indicates severe deficiency of phenylalanine hydroxylase and is often called "classical PKU." Blood phenylalanine levels between 600 and 1200 mumol/L lead to "atypical PKU." Cases where blood phenylalanine remains between 120 and 480 mumol/L on a normal diet are termed "benign hyperphenylalaninemia." A deficiency of the cofactor tetrahydrobiopterin (BH4), which is required for phenylalanine hydroxylase activity, leads to hyperphenylalaninemia. This cofactor is also required for the enzymatic hydroxylation of tyrosine and tryptophan. Cofactor defects account for only 1-3% of hyperphenylalaninemia, which has been termed "malignant PKU", but they must be identified so that appropriate treatment can be established. Long-term treatment of PKU is currently advised because loss of IQ, poor school performance, and behavior problems occur when blood phenylalanine levels increase. Therefore, there is reason to continue the diet as patients become older. When blood phenylalanine levels are elevated during pregnancy a "maternal PKU syndrome" may result. Babies born to untreated mothers with PKU are at risk for being small for gestational age with microcephaly, mental retardation and congenital heart defects. A national collaborative study for the treatment of maternal PKU is underway. The characterization of the gene for phenylalanine hydroxylase has added a new exciting chapter to the study of PKU.(ABSTRACT TRUNCATED AT 250 WORDS)
Language of Publication: English
Unique Identifier: 92069901

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MeSH Heading (Major): Neonatal Screening|*; Phenylketonuria|*DI/GE/TH
MeSH Heading: Human; Infant, Newborn; Parents

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0009-9120
Country of Publication: CANADA

Record 11 from database: MEDLINE
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Title: Maternal phenylketonuria: a metabolic teratogen.
Author: Levy HL; Ghavami M
Address: Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Source: Teratology, 1996 Mar, 53:3, 176-84
Abstract: The maternal phenylketonuria (PKU) syndrome refers to the teratogenic effects of PKU during pregnancy. These effects include mental retardation, microcephaly, congenital heart disease, and intrauterine growth retardation. In untreated pregnancies wherein the mother has classic PKU with a blood phenylalanine level > or = 1,200 microM (20 mg/dl), the frequencies of these abnormalities in offspring are exceedingly high, approaching 75-90% for microcephaly and mental retardation and 15% for congenital heart disease. There is a dose response relationship with progressively lower frequencies of these abnormalities at lower phenylalanine levels, both in the pregnancies of women with variants of PKU and in treated classic PKU pregnancies. The pathogenesis of this syndrome is unknown; it may be related to inhibition by phenylalanine of large neutral amino acid transport across the placenta or to direct toxicity of phenylalanine and/or a phenylalanine metabolite in certain fetal organs. A mouse model for PKU now exists, and studies of maternal PKU in this model are in progress. The treatment of maternal PKU consists of biochemical control through a phenylalanine restricted diet during pregnancy. The best results are obtained with diet initiation before conception or no later than the earliest weeks of pregnancy. Women with PKU and their families require much psychosocial support to meet the strict requirements of a maternal PKU pregnancy, including compliance with a difficult diet. With such compliance, however, it seems that bearing normal or near normal offspring is possible.
Language of Publication: English
Unique Identifier: 96354349

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MeSH Heading (Major): Abnormalities, Multiple|*ET; Phenylketonuria|DI/*PC; Pregnancy Complications|DI/*PC
MeSH Heading: Alcoholism|DI; Animal; Diagnosis, Differential; Disease Models, Animal; Face|AB; Female; Fetal Alcohol Syndrome|DI; Fetal Growth Retardation|ET; Genetic Counseling; Heart Defects, Congenital|ET; Human; Infant; Infant, Newborn; Male; Mental Retardation|ET; Mice; Microcephaly|ET; Pregnancy; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0040-3709
Country of Publication: UNITED STATES

Record 12 from database: MEDLINE
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Title: Aspartame: review of recent experimental and observational data.
Author: Janssen PJ; van der Heijden CA
Address: National Institute of Public Health and Environmental Hygiene, Bilthoven, The Netherlands.
Source: Toxicology, 1988 Jun, 50:1, 1-26
Abstract: In this report the neurotoxicity of aspartame and its constituent amino acids aspartic acid and phenylalanine is reviewed. The adverse reactions ascribed to the consumption of aspartame-containing products, as reported in the U.S.A., are discussed and placed in perspective with the results of recent behavioural studies in humans and animals. The issue of common intake levels associated with proposed uses of aspartame is addressed. In brief, the following conclusions can be drawn: When aspartame is consumed at levels within the ADI-limit of 40 mg/kg body wt, there is no significant risk for an aspartate-induced neurotoxic effect in the brain. When aspartame is consumed at levels within the ADI-limit by normal subjects or persons heterozygous for phenylketonuria (PKU) the resultant plasma phenylalanine concentrations are practically always within the normal postprandial range; elevation to plasma concentrations commonly associated with adverse effects has not been observed. Persons suffering from phenylketonuria (PKU-homozygotes) on a phenylalanine-restricted diet should avoid consumption of aspartame. PKU-homozygotes on the (less strict) phenylalanine-liberalized diet should be made aware of the phenylalanine content of aspartame. In the available behavioural studies in humans with acute dosing, no adverse effects were observed. Long-term studies on behaviour and cognitive function in (sensitive) humans are lacking. Analyses of adverse reaction reports made by consumers in the U.S.A. have not yielded a specific constellation of symptoms clearly related to aspartame that would suggest a widespread public health hazard associated with aspartame use. Focussed clinical studies are now being carried out in the U.S.A.; the results should provide additional evidence concerning the interpretation of the reports on adverse reactions ascribed to aspartame. In the regulation of admitted uses for aspartame the possibility of intake levels exceeding the ADI-limit in some groups of consumers should be a point of attention.
Language of Publication: English
Unique Identifier: 88265115

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MeSH Heading (Major): Aspartame|*AE/ME/TO; Dipeptides|*AE; Phenylalanine|BL/*ME
MeSH Heading: Animal; Behavior, Animal|DE; Brain Chemistry|DE; Human; Phenylketonuria|ME

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0300-483X
Country of Publication: NETHERLANDS
CAS Registry/EC Number: 0 (Dipeptides); 22839-47-0 (Aspartame); 3617-44-5 (Phenylalanine)

Record 13 from database: MEDLINE
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Title: Maternal phenylketonuria. Review with emphasis on pathogenesis.
Author: Levy HL
Address: Children's Hospital, Boston, Mass.
Source: Enzyme, 1987, 38:1-4, 312-20
Abstract: Maternal phenylketonuria (PKU) refers to fetal damage from PKU in the pregnant woman. The progeny from such pregnancies are almost always microcephalic and mentally subnormal and have an increased frequency of congenital heart disease and low birth weight. Treatment with a phenylalanine-restricted diet, if begun before conception, seems to protect the fetus. The degree of protection is much less if dietary treatment is delayed until the pregnancy is in progress. The origin of fetal damage in maternal PKU is not known. Due to placental concentration of amino acids, the fetus is exposed to a higher concentration of phenylalanine than that in the mother, but it is not certain that phenylalanine is the toxic agent. Animal models made hyperphenylalaninemic by the administration of phenylalanine, often accompanied by a phenylalanine hydroxylase inhibitor, do not reproduce the full maternal PKU syndrome; but fetuses and newborns from these models have had reduced growth of the body and brain, and offspring later may show evidence of impaired learning ability.
Language of Publication: English
Unique Identifier: 88151861

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MeSH Heading (Major): Abnormalities, Multiple|*ET; Phenylketonuria|*CO/DH/PX; Pregnancy Complications|*DH/PX
MeSH Heading: Animal; Female; Human; Mental Retardation|ET; Pregnancy

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0013-9432
Country of Publication: SWITZERLAND

Record 14 from database: MEDLINE
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Title: Aspartame intolerance.
Author: Garriga MM; Metcalfe DD
Address: Mast Cell Physiology Section, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
Source: Ann Allergy, 1988 Dec, 61:6 Pt 2, 63-9
Abstract: Aspartame is a food additive marketed under the brand name Nutrasweet. Aspartame is a white, odorless, crystalline powder and consists of two amino acids, L-aspartic acid and L-phenylalanine. It is 180 times as sweet as sugar. The Food and Drug Administration (FDA) first allowed its use in dry foods in July 1981 and then approved its use in carbonated beverages in July 1983. It has subsequently been approved for use in a number of materials including multivitamins, fruit juices, stick-type confections, breath mints, and iced tea. The FDA requires the statement "phenylketonurics: contains phenylalanine" on labels of food products containing aspartame because individuals with phenylketonuria (PKU) must restrict their intake of phenylalanine. Aspartame is judged to be free of long-term cancer risks. Aspartame is not stable under certain conditions including baking and cooking, and prolonged exposure to acid conditions. In such situations it loses its sweetness. Products formed from aspartame include its component amino acids (phenylalanine and aspartic acid), methanol, and diketopiperazine (DKP). Animal studies show DKP to be nontoxic. Methanol occurs in small amounts and does not exceed that formed during consumption of many foods including fresh fruits and vegetables. FDA's Center for Food Safety and Applied Nutrition (CFSAN) monitors aspartame's safety in part through reports of adverse reactions. After aspartame was approved for use in carbonated beverages, the FDA received an increased number of reports concerning adverse reactions related to aspartame. The Centers for Disease Control (CDC) reviewed these reports, which included complaints of neurologic, gastrointestinal, andallergic reactions.(ABSTRACT TRUNCATED AT 250 WORDS)
Language of Publication: English
Unique Identifier: 89086740

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MeSH Heading (Major): Aspartame|*AE; Dipeptides|*AE; Product Surveillance, Postmarketing|*
MeSH Heading: Behavior; Female; Headache|ET; Human; Hypersensitivity|ET; Male

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0003-4738
Country of Publication: UNITED STATES
CAS Registry/EC Number: 0 (Dipeptides); 22839-47-0 (Aspartame)

Record 15 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
CAS Registry/EC Number: 0 (Dipeptides); 22839-47-0 (Aspartame); 3617-44-5 (Phenylalanine)

Record 16 from database: MEDLINE
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Title: Dietary treatment of destructive behavior associated with hyperphenylalaninemia.
Author: Baumeister AA; Baumeister AA
Address: Department of Psychology, Louisiana State University, Baton Rouge 70803, USA.
Source: Clin Neuropharmacol, 1998 Jan, 21:1, 18-27
Abstract: Behavior disorders frequently are associated with mental retardation. The most common interventions involve psychotropics, behavior modification, or both. Etiologically based treatments, derived from an understanding of underlying disease pathogeneses, are infrequent. However, several genetic diseases are associated with elevated rates of destructive responding. The hyperphenylalaninemias provide an excellent model for alternative interventions that have clear biological plausibility. A literature review is undertaken that provides the biochemical rationale for treatment with a low-phenylalanine diet. Several phenylalanine dietary control studies designed to manage aberrant responding among patients with hyperphenylalaninemia are summarized. Together they provide strong evidence that dietary phenylalanine restriction is the treatment of choice among patients ranging from classic phenylketonuria to milder hyperphenylalaninemia. Corroborating evidence derived from phenylalanine loading, magnetic resonance imaging, and dietary amino acid supplementation studies is presented.
Language of Publication: English
Unique Identifier: 98240444

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MeSH Heading (Major): Amino Acid Metabolism, Inborn Errors|*DT/*PX; Mental Disorders|*DH/*PX; Mental Retardation|*PX; Phenylalanine|*ME
MeSH Heading: Adult; Case Report; Female; Human; Male; Middle Age; Phenylketonuria|DH/PX

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0362-5664
Country of Publication: UNITED STATES

Record 17 from database: MEDLINE
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Title: Monoamine oxidase and catecholamine metabolism.
Author: Kopin IJ
Address: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
Source: J Neural Transm Suppl, 1994, 41:, 57-67
Abstract: The enzyme which has come to be known as monoamine oxidase was discovered in liver over 60 years ago as tyramine oxidase (Hare, 1928). Almost 10 years later, Blaschko et al. (1957a,b) established that epinephrine, norepinephrine and dopamine were also substrates for this enzyme. Zeller (1938) distinguished monoamine oxidase as different from several other amine oxidases, such as diamine oxidase. Although it was generally assumed that catecholamines were metabolized by MAO, this was not established until isotopically labelled epinephrine and an MAO inhibitor became available. Schayer (1951) found that after administration of N-methyl-14C-epinephrine, only about 50% of the radioactivity appeared in the urine, whereas when the 14C label was incorporated into the beta-position on the side chain, almost all of the radioactivity could be recovered. One year later, Zeller et al. (1952) discovered that isonicotinic acid hydrazide (iproniazid) inhibited MAO. When animals pretreated with the MAO inhibitor were administered N-methyl-14C-epinephrine, almost all of the radioactivity was recovered (Schayer et al., 1955), indicating that the enzyme was responsible for the metabolism of about half of the administered catecholamine. Schayer et al. (1952, 1953) had found that five urinary metabolite products of beta-labelled-14C-norepinephrine could be separated by paper chromatography, but the chemical structures of these compounds were not known. Armstrong et al. (1957) showed that 3-methoxy-4-hydroxymandelic acid (vanillyl mandelic acid, VMA) was the major metabolite of norepinephrine and Shaw et al. (1957) demonstrated that large amounts of homovanillic acid (HVA) were excreted in urine after administration of 3,4-dihydroxy-phenylalanine (DOPA). These observations led Axelrod to examine the possibility that O-methylation might precede deamination and to his discovery of catechol-O-methyl transferase (Axelrod, 1957, 1959). At that time it became apparent that there were two possible routes for metabolism of norepinephrine to VMA--either deamination followed by O-methylation or O-methylation and subsequent deamination. The relative roles of these two pathways in terminating the physiological actions of catecholamines then became a focus of attention. Biochemical methods were used to access directly the relative importance of the two metabolic pathways. Physiological methods, based on the effects of drugs which alter metabolism of the catecholamine, were used to examine the role of MAO and COMT in terminating the actions of administered or endogenously released catecholamines.
Language of Publication: English
Unique Identifier: 95016639

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MeSH Heading (Major): Catecholamines|*ME; Monoamine Oxidase|*PH
MeSH Heading: Animal; Catechol O-Methyltransferase|PH; Human; Isoenzymes|PH; Monoamine Oxidase Inhibitors|TU; Parkinson Disease|DT; Selegiline|TU

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0303-6995
Country of Publication: AUSTRIA

Record 18 from database: MEDLINE
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Title: PKU in adolescents: rationale and psychosocial factors in diet continuation.
Author: Levy HL; Waisbren SE
Address: Biochemical Genetics Unit of the Division of Genetics, Children's Hospital, Boston, MA 02115, USA.
Source: Acta Paediatr Suppl, 1994 Dec, 407:, 92-7
Abstract: Follow-up of early-treated children with PKU has shown that diet discontinuation in childhood presents risks of cognitive and emotional dysfunction in a substantial number of adolescents and young adults. This dysfunction includes IQ loss, mental processing abnormalities, learning difficulties, anxiety and personality disorders. In addition, neurologic deterioration has been reported in several such individuals. As a consequence of this current understanding of PKU, diet continuation, at least through adolescence and in the young adult years, is now recommended. Many centers are extending this to a policy of "diet for life". This represents a major challenge to adolescents and their families. Metabolic control using the criteria applied during childhood is virtually impossible to achieve past 12 years of age. Time constraints, social pressures, financial limitations and growing independence from the family combine to interfere with dietary control. Added to these difficulties are the biological changes during teenage years which reduce phenylalanine tolerance. To meet these challenges, we have identified a number of psychosocial factors that interfere with adherence to medical recommendations. The factors most highly related to metabolic control were social support for the diet and positive perceptions of treatment. This information has led to the development of support programs for adolescents and young adults with PKU.(ABSTRACT TRUNCATED AT 250 WORDS)
Language of Publication: English
Unique Identifier: 95284444

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MeSH Heading (Major): Adolescent Psychology|*; Cognition Disorders|*ET; Mental Disorders|*ET; Phenylketonuria|CO/*DH/ME/*PX
MeSH Heading: Adolescence; Attitude to Health; Follow-Up Studies; Human; Patient Compliance; Patient Education; Self-Help Groups; Social Support; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0803-5326
Country of Publication: NORWAY

Record 19 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 20 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 21 from database: MEDLINE
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Title: Population genetics of phenylketonuria.
Author: Eisensmith RC; Woo SL
Address: Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Source: Acta Paediatr Suppl, 1994 Dec, 407:, 19-26
Abstract: Phenylketonuria (PKU) is an autosomal recessive disorder caused by a large number of mutations at the phenylalanine hydroxylase (PAH) locus, most of which are strongly associated with specific RFLP or VNTR haplotypes. One of the major questions remaining in PKU research is why this apparently maladaptive disorder has been maintained at a frequency of approximately 1 in 10,000 among Caucasians. A growing number of studies have provided evidence that both the relatively high frequency of PKU and the strong mutation/haplotype associations might reflect the existence of multiple founding populations for PKU. Examples of putative founding populations for PKU in both Europe and Asia will be presented. Some PAH mutations are associated with multiple haplotypes, suggesting recurrence. Evidence for and against recurrence as the mechanism responsible for the association of the R408W mutation with RFLP haplotypes 1 and 2 will be discussed.
Language of Publication: English
Unique Identifier: 95284422

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MeSH Heading (Major): Founder Effect|*; Gene Frequency|*GE; Mutation|*GE; Phenylketonuria|*EP/*GE
MeSH Heading: Asia|EP; Epidemiology, Molecular; Europe|EP; Haplotypes|GE; Human

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0803-5326
Country of Publication: NORWAY

Record 22 from database: MEDLINE
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Title: The biochemistry and enzymology of amino acid dehydrogenases.
Author: Brunhuber NM; Blanchard JS
Address: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461.
Source: Crit Rev Biochem Mol Biol, 1994, 29:6, 415-67
Abstract: This review is an exhaustive description of the biochemistry and enzymology of all 17 known NAD(P)(+)-amino acid dehydrogenases. These enzymes catalyze the oxidative deamination of an amino acid to its keto acid and ammonia, with the concomitant reduction of either NAD+ or NADP+. These enzymes have many important applications in industrial and medical settings and have been the object of prodigious enzymological research. This article describes all that is known about the poorly characterized members of the family and contains detailed information on the better characterized enzymes, including valine, phenylalanine, leucine, alanine, and glutamate dehydrogenases. The latter three enzymes have been the subject of extensive enzymological experimentation, and, consequently, their chemical mechanisms are discussed. The three-dimensional structure of the Clostridium symbiosum glutamate dehydrogenase has been determined recently and remains the only structure known of any amino acid dehydrogenase. The three-dimensional structure and its implications to the chemical mechanisms and rate-limiting steps of the amino acid dehydrogenase family are discussed.
Language of Publication: English
Unique Identifier: 95220046

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MeSH Heading (Major): Amino Acid Oxidoreductases|*CH/*ME
MeSH Heading: Animal; Human; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 1040-9238
Country of Publication: UNITED STATES

Record 23 from database: MEDLINE
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Title: Protein metabolism in the cancer patient.
Author: Garlick PJ; McNurlan MA
Address: Department of Surgery, State University of New York, Health Sciences Center, Stony Brook 11794-8191, USA.
Source: Biochimie, 1994, 76:8, 713-7
Abstract: The 'flooding' method has been widely used for measuring protein synthesis in animal tissues in vivo and in vitro, employing radioactively labelled amino acids, because it minimises errors in determining the specific radioactivity of the direct precursor of protein synthesis. This approach has now been modified for measuring protein synthesis rates in tumours and healthy tissues of humans by injection of the stable isotopic labels, [1(-13)C]leucine or [2H5]phenylalanine, followed by tissue sampling during surgery. Based on the observation that rates of protein synthesis correlate with changes in the expression of cell proliferation markers, we have suggested that changes in protein synthesis in tumours can be used as indices of changes in tumour growth. Measurements in colorectal cancer patients have shown that protein synthesis is stimulated 80% by feeding, suggesting that the tumour is not a pure parasite, but responds to exogenous nutrients. Moreover, when the composition of the amino acids given to the patient was changed from a balanced mixture to one supplemented with branched chain amino acids, the response of the tumour to feeding was significantly diminished, suggesting that tumour growth might be modulated by diet composition. Dietary supplements of arginine have been shown previously to inhibit tumour growth in animals, probably by activating the immune system. However, in breast cancer patients arginine stimulated tumour protein synthesis, suggesting that arginine might have separate stimulatory effects on the tumour and the immune system, the outcome depending on which effect predominates.
Language of Publication: English
Unique Identifier: 95201034

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MeSH Heading (Major): Neoplasms|DH/*ME; Proteins|*BI
MeSH Heading: Amino Acids, Branched-Chain|AD/ME; Animal; Arginine|AD/ME; Carbon Isotopes; Deuterium; Fasting; Human

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0300-9084
Country of Publication: FRANCE

Record 24 from database: MEDLINE
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Title: Hsp70s and lysosomal proteolysis.
Author: Terlecky SR
Address: Department of Biology, University of California, San Diego, La Jolla 92093-0322.
Source: Experientia, 1994 Nov, 50:11-12, 1021-5
Abstract: Confluent cultured cells activate a lysosomal pathway of polypeptide breakdown in response to withdrawal of serum growth factors. The substrates for this proteolytic pathway are a restricted class of cytosolic polypeptides containing peptide sequences biochemically related to lysine-phenylalanine-glutamate-arginine-glutamine, or, in single amino acid abbreviations, KFERQ. The heat shock cognate protein of 73 kD (hsc73) binds to a variety of polypeptides via this molecular determinant and facilitates their lysosomal import and degradation. In addition, a portion of intracellular hsc73 resides within the lysosome and appears to be an essential component of the proteolytic machinery. Several potential mechanisms by which hsc73 mediates selective lysosomal import and degradation of polypeptides are discussed.
Language of Publication: English
Unique Identifier: 95080363

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MeSH Heading (Major): Heat-Shock Proteins 70|*PH; Lysosomes|*ME; Proteins|*ME
MeSH Heading: Amino Acid Sequence; Animal; Biological Transport; Human; Molecular Sequence Data; Oligopeptides|ME

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0014-4754
Country of Publication: SWITZERLAND

Record 25 from database: MEDLINE
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Title: The methotrexate story: a paradigm for development of cancer chemotherapeutic agents.
Author: Huennekens FM
Address: Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA 92037.
Source: Adv Enzyme Regul, 1994, 34:, 397-419
Abstract: Methotrexate (MTX), one of the earliest cancer chemotherapy agents, continues to be used extensively in the treatment of leukemia and a variety of other tumors. The efficacy of this drug results from its facile uptake by cells, rapid polyglutamylation and virtually stoichiometric inhibition of dihydrofolate reductase (DHFR), a key enzyme in cell replication. From the work of a multitude of biochemists, molecular biologists, organic chemists and pharmacologists, much is known about the mode of action of MTX and the mechanisms by which tumors exhibit inherent or acquired resistance to this drug. MTX enters cells primarily by a carrier-mediated active transport system whose principal substrate is 5-methyltetrahydrofolate, and additional glutamates are added to the gamma-position of the parent glutamate moiety. The tight binding of MTX to DHFR is defined from NMR and X-ray crystallographic studies of the enzyme and its drug or substrate complexes, supplemented by site-directed mutagenesis to confirm specific interactions. Resistance to the drug, encountered in cell culture model systems or in cancer patients, can result from an increased level of DHFR (due to gene amplification), mutant DHFR with reduced affinity for MTX, or decreased uptake or polyglutamylation of the drug. Although DHFR is an extremely well-studied enzyme, there is still some uncertainty about its kinetics, mechanism for reduction of folate, multiple forms, and activation by a diverse group of agents. Prodrug forms of MTX, e.g., MTX alpha-phenylalanine, which can be activated by carboxypeptidase A-monoclonal antibody conjugates, offer promise for improved efficacy of the drug by selective targeting to tumors. The large body of information summarized above has aided in the development of other folate antagonists, provides a paradigm for assessing the status of other cancer chemotherapeutic agents in current use, and offers a platform from which to speculate about the future of the field.
Language of Publication: English
Unique Identifier: 95028763

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MeSH Heading (Major): Antimetabolites, Antineoplastic|*PD/TU; Methotrexate|AA/ME/*PD/TU; Neoplasms|*DT; Tetrahydrofolate Dehydrogenase|*AI
MeSH Heading: Drug Resistance; Human; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
ISSN: 0065-2571
Country of Publication: ENGLAND

Record 26 from database: MEDLINE
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Title: Dipeptidyl peptidase IV: development, design, synthesis and biological evaluation of inhibitors.
Author: Borloo M; De Meester I
Address: Universitaire Instelling Antwerpen, Departement Farmaceutische Wetenschappen, Wilrijk, BelgiÂe.
Source: Verh K Acad Geneeskd Belg, 1994, 56:1, 57-88
Abstract: Dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5) is a highly specific serine protease which cleaves off N-terminal dipeptides from peptides with a penultimate proline or alanine. The enzyme is widely distributed in mammalian cells and tissues, but specific activities differ greatly. In the hematopoietic system it is found almost exclusively on T cells, where it is identified as CD26, a T cell activation molecule. DPP IV may be involved in the metabolism of peptides, intestinal assimilation and cell adhesion and it plays an integral role in T cell activation. DPP IV inhibitors may provide help during the further elucidation of the biological function(s) of this enzyme. Moreover, because of the integral role the enzyme plays in T cell activation, specific inhibition of DPP IV may constitute a new way of immune modulation. N-Peptidyl-O-acylhydroxylamines and boronic acid analogues of proline and alanine are two known DPP IV inhibitors. The major drawbacks for their therapeutic use are for the hydroxylamines, the toxicity and for the boronic acid derivatives, the chemical liability. A low toxicity, acceptable stability and a high specificity are essential criteria for the design of inhibitors that are suitable, not only for experimental, but also for therapeutic use. Therefore we proposed 5 types of potential DPP IV inhibitors: azapeptides, azetidines, Michael substrates, reduced peptides and phosphonic acids. All the synthesized compounds possess a substrate-like structure, which is a pre-requisite for recognition by the enzyme. We choose for a modified proline or alanine at the penultimate position, substituted with glycine, alanine, valine, isoleucine or phenylalanine at the N-terminus. The prepared compounds were screened biologically at a 5 mM concentration with a fluorometric method using Gly-Pro-4-Me-2NA as substrate.
Language of Publication: English
Unique Identifier: 94270022

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MeSH Heading (Major): Dipeptidyl Peptidases|AI/*CS/PD
MeSH Heading: Aza Compounds|CS; Azetidines|CS; Human; Phosphonic Acids|CS; Substrate Specificity

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0372-610X
Country of Publication: BELGIUM

Record 27 from database: MEDLINE
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Title: Dietary amino acids and brain function.
Author: Fernstrom JD
Address: University of Pittsburgh School of Medicine, PA 15213.
Source: J Am Diet Assoc, 1994 Jan, 94:1, 71-7
Abstract: Two groups of amino acids--the aromatic and the acidic amino acids--are reputed to influence brain function when their ingestion in food changes the levels of these amino acids in the brain. The aromatic amino acids (tryptophan, tyrosine, phenylalanine) are the biosynthetic precursors for the neurotransmitters serotonin, dopamine, and norepinephrine. Single meals, depending on their protein content, can rapidly influence uptake of aromatic amino acid into the brain and, as a result, directly modify their conversion to neurotransmitters. Such alterations in the production of transmitters can directly modify their release from neurons and, thus, influence brain function. The acidic amino acids glutamate and aspartate are themselves brain neurotransmitters. However, they do not have ready access to the brain from the circulation or the diet. As a result, the ingestion of proteins, which are naturally rich in aspartate and glutamate, has no effect on the level of acidic amino acid in the brain (or, thus, on brain function by this mechanism). Nevertheless, the food additives monosodium glutamate and aspartame (which contains aspartate) have been reputed to raise the level of acidic amino acid in the brain (when ingested in enormous amounts), to modify brain function, and even to cause neuronal damage. Despite such claims, a substantial body of published evidence clearly indicates that the brain is not affected by ingestion of aspartame and is affected by glutamate only when the amino acid is administered alone in extremely large doses. Therefore, when consumed in the diet neither compound presents a risk to normal brain function.
Language of Publication: English
Unique Identifier: 94095800

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MeSH Heading (Major): Amino Acids|*AD/ME; Brain|*PH; Neurotransmitters|*BI
MeSH Heading: Affect; Animal; Cholesterol|BL; Dietary Carbohydrates|ME; Dietary Fats|ME; Dietary Proteins|ME; Human; Serotonin|BI/PH

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0002-8223
Country of Publication: UNITED STATES

Record 28 from database: MEDLINE
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Title: Long-term follow-up of children with classical phenylketonuria after diet discontinuation: a review.
Author: Potocnik U; Widhalm K
Address: Department of Pediatrics, University of Vienna, Austria.
Source: J Am Coll Nutr, 1994 Jun, 13:3, 232-6
Abstract: The age at which children suffering from classical phenylketonuria can safely discontinue their dietary therapy has been constantly disputed over the past decades. Recently, most phenylketonuria centers have begun to recommend a life-long diet, especially for female patients. Male patients are also advised to continue their diet until at least well into adult age. As a result of this new outlook in therapy management, we reviewed the existing literature and summarized all relevant long-term follow-up data of children who discontinued their debts at an early age, focusing on intellectual and neurological performance. The abilities of these children are compared during dietary treatment and again several years after diet discontinuation. Results show clearly that children maintaining their diets into their teens have fewer deficits than do those terminating their diets before 10 years of age. It seems essential to initiate diet early, and to keep blood phenylalanine levels < 600 mumol/L and well controlled to at least age 10 to ensure satisfactory long-term development of the patient. Furthermore, it seems highly justified to maintain a life-long diet which can be liberalized, but not completely discontinued in adulthood.
Language of Publication: English
Unique Identifier: 94358313

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MeSH Heading (Major): Phenylketonuria|*DH/PP/PX
MeSH Heading: Adolescence; Child; Child, Preschool; Female; Follow-Up Studies; Human; Infant; Infant, Newborn; Intelligence; Longitudinal Studies; Male; Nervous System|PP; Phenylalanine|BL

Publication Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
ISSN: 0731-5724
Country of Publication: UNITED STATES

Record 29 from database: MEDLINE
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Title: Prevention of nephrotoxicity of ochratoxin A, a food contaminant.
Author: Creppy EE; Baudrimont I; Betbeder AM
Address: Toxicology Department, University of Bordeaux, France.
Source: Toxicol Lett, 1995 Dec, 82-83:, 869-77
Abstract: Ochratoxin A (OTA) is a mycotoxin produced by ubiquitous Aspergilli, mainly by Aspergillus ochraceus and also by Penicilium verrucosum. It was found all over the world in feed and human food and blood as well as in animal blood and tissues. The most threatening effects of OTA are its nephrotoxicity and carcinogenicity, since this mycotoxin is nephrotoxic to all anim