Recombinant human phenylalanine hydroxylase (hPAH) was produced in high yields in Escherichia coli using the pET and pMAL expression vectors. In the pMAL system, hPAH was fused through the target sequences of the restriction protease factor Xa (IEGR) or enterokinase (D4K) to the C-terminal end of the highly expressed E. coli maltose-binding protein (MBP). The recombinant hPAH, recovered in soluble forms, revealed a high specific activity even in crude extracts and was detected as a homogeneous band by Western-blot analysis using affinity-purified polyclonal rabbit anti-(rat PAH) antibodies. The enzyme expressed in the pET system was subject to limited proteolysis by host cell proteases and was difficult to purify with a satisfactory yield. By contrast, when expressed as a fusion protein in the pMAL system, hPAH was resistant to cleavage by host cell proteases and was conveniently purified by affinity chromatography on an amylose resin. Catalytically active tetramer-dimer (in equilibrium) forms ...
Mono- and Stereopictres of 5.0 Angstrom coordination sphere of Iron atom in PDB 3pah: Human Phenylalanine Hydroxylase Catalytic Domain Dimer With Bound Adrenaline Inhibitor
TY - JOUR. T1 - Mutational spectrum of phenylalanine hydroxylase deficiency in the population resident in Catalonia. T2 - Genotype-phenotype correlation. AU - Mallolas, Judith. AU - Vilaseca, M. Antònia. AU - Campistol, Jaume. AU - Lambruschini, Nilo. AU - Cambra, Francisco José. AU - Estivill, Xavier P.. AU - Milà, Montserrat. PY - 1999. Y1 - 1999. N2 - Hyperphenylalaninemia (HPA) is a group of diseases characterized by the persistent elevation of phenylalanine levels in tissues and biological fluids. It is an autosomal recessive disorder affecting 1 in 10,000 individuals in Caucasian populations and about 1 in 6600 in Catalonia. We report the mutational spectrum of phenylalanine hydroxylase deficiency in the population living in Catalonia and the genotype-phenotype correlation. The molecular study was performed in 383 samples corresponding to 115 patients from 99 unrelated families and 268 relatives. We have characterized 90% of the mutant alleles; there were 57 different mutations, 49 of ...
Phenylalanine hydroxylase (PAH) (EC 1.14.16.1) is an enzyme that catalyzes the hydroxylation of the aromatic side-chain of phenylalanine to generate tyrosine. PAH is one of three members of the biopterin-dependent aromatic amino acid hydroxylases, a class of monooxygenase that uses tetrahydrobiopterin (BH4, a pteridine cofactor) and a non-heme iron for catalysis. During the reaction, molecular oxygen is heterolytically cleaved with sequential incorporation of one oxygen atom into BH4 and phenylalanine substrate. Phenylalanine hydroxylase is the rate-limiting enzyme of the metabolic pathway that degrades excess phenylalanine. Research on phenylalanine hydroxylase by Seymour Kaufman led to the discovery of tetrahydrobiopterin as a biological cofactor. The enzyme is also interesting from a human health perspective because mutations in PAH, the encoding gene, can lead to phenylketonuria, a severe metabolic disorder. The reaction is thought to proceed through the following steps: formation of a ...
Phenylalanine hydroxylase deficiency is an autosomal recessive disorder caused by pathogenic variants in the gene PAH. While it is found in many different ethnicities, it is particularly prevalent in Sephardic Jewish, Sicilian, Irish, and Turkish individuals, as well as Caucasians. Pathogenic PAH variants result in loss of function of the phenylalanine hydroxylase enzyme, which breaks down the amino acid phenylalanine. The most severe form of the disease is called phenylketonuria. If untreated, buildup of phenylalanine will result in irreversible brain damage and severe intellectual disability. Treatment involves the removal of phenylalanine from the diet. Even with strict adherence to the treatment, some neurologic deficiencies have been noticed in long-term survivors. Psychological problems, including anxiety, depression, phobias and panic attacks may occur in adults who do not comply well to their treatment. Some patients have a milder form of hyperphenylalaninemia and may tolerate higher ...
TY - JOUR. T1 - Phenylalanine binding is linked to dimerization of the regulatory domain of phenylalanine hydroxylase. AU - Zhang, Shengnan. AU - Roberts, Kenneth M.. AU - Fitzpatrick, Paul F.. PY - 2014/10/28. Y1 - 2014/10/28. N2 - Analytical ultracentrifugation has been used to analyze the oligomeric structure of the isolated regulatory domain of phenylalanine hydroxylase. The protein exhibits a monomer-dimer equilibrium with a dissociation constant of ∼46 μM; this value is unaffected by the removal of the 24 N-terminal residues or by phosphorylation of Ser16. In contrast, phenylalanine binding (Kd = 8 μM) stabilizes the dimer. These results suggest that dimerization of the regulatory domain of phenylalanine hydroxylase is linked to allosteric activation of the enzyme.. AB - Analytical ultracentrifugation has been used to analyze the oligomeric structure of the isolated regulatory domain of phenylalanine hydroxylase. The protein exhibits a monomer-dimer equilibrium with a dissociation ...
WASHINGTON The Food and Drug Administration has approved Kuvan, by BioMatrin Pharmaceuticals, as the first drug to be approved to slow the effects of Phenylketonuria, a rare genetic disorder that causes mental retardation, smaller brain size, delayed speech and other neurological problems.. PKU is a genetic disorder in which the enzyme phenylalanine hydroxylase, which helps the human body break down phenylalanine, an amino acid found in foods, does not function properly. The result is high levels of phenylalanine in the blood. High levels of phenylalanine hydroxylase are toxic to the brain and can lead to mental retardation, behavioral abnormalities, seizures, an inability to focus and organize information, and other neurologic complications.. Kuvan works by increasing phenylalanine hydroxylase enzyme activity in PKU patients with some residual phenylalanine hydroxylase enzyme function. This then leads to an increased breakdown of phenylalanine, resulting in lower levels of phenylalanine in the ...
A recently described new form of hyperphenylalaninemia is characterized by the excretion of 7-substituted isomers of biopterin and neopterin and 7-oxo-biopterin in the urine of patients. It has been shown that the 7-substituted isomers of biopterin and neopterin derive from L-tetrahydrobiopterin and D-tetrahydroneopterin and are formed during hydroxylation of phenylalanine to tyrosine with rat liver dehydratase-free phenylalanine hydroxylase.,br /,We have now obtained identical results using human phenylalanine hydroxylase. The identity of the pterin formed in vitro and derived from L-tetrahydrobiopterin as 7-(1,2-dihydroxypropyl)pterin was proven by gas-chromatography mass spectrometry. Tetrahydroneopterin and 6-hydroxymethyltetrahydropterin also are converted to their corresponding 7-substituted isomers and serve as cofactors in the phenylalanine hydroxylase reaction. Dihydroneopterin is converted by dihydrofolate reductase to the tetrahydro form which is biologically active as a cofactor ...
TY - JOUR. T1 - Three novel variants (p.Glu178Lys, p.Val245Met, p.Ser250Phe) of the phenylalanine hydroxylase (PAH) gene impair protein expression and function in vitro. AU - Zong, Yanan. AU - Liu, Ning. AU - Ma, Shanshan. AU - Bai, Ying. AU - Guan, Fangxia. AU - Kong, Xiangdong. PY - 2018/8/20. Y1 - 2018/8/20. N2 - Phenylketonuria (PKU) is the most common inherited metabolic disease, an autosomal recessive disorder affecting ,10,000 newborns each year globally. It can be caused by over 1000 different naturally occurring mutations in the phenylalanine hydroxylase (PAH) gene. We analyzed three novel naturally occurring PAH gene variants: p.Glu178Lys (c.532G,A), p.Val245Met (c.733G,A) and p.Ser250Phe (c.749C,T). The mutant effect on the PAH enzyme structure and function was predicted by bioinformatics software. Vectors expressing the corresponding PAH variants were generated for expression in E. coli and in HEK293T cells. The RNA expression of the three PAH variants was measured by quantitative ...
TY - JOUR. T1 - Phenylalanine Hydroxylase. T2 - Structural Determination of the Tetrahydropterin Intermediates by 13C NMR Spectroscopy. AU - Lazarus, Robert A.. AU - DeBrosse, Charles W.. AU - Benkovic, Stephen J.. PY - 1982/1/1. Y1 - 1982/1/1. UR - http://www.scopus.com/inward/record.url?scp=0001447533&partnerID=8YFLogxK. UR - http://www.scopus.com/inward/citedby.url?scp=0001447533&partnerID=8YFLogxK. U2 - 10.1021/ja00388a105. DO - 10.1021/ja00388a105. M3 - Article. AN - SCOPUS:0001447533. VL - 104. SP - 6869. EP - 6871. JO - Journal of the American Chemical Society. JF - Journal of the American Chemical Society. SN - 0002-7863. IS - 24. ER - ...
3,4-Dihydroxystyrene (DHS) is a centrally-acting inhibitor of the enzyme phenylalanine hydroxylase (PH). It is likely that DHS and other PH inhibitors will never have clinical applications on account of their capacity for inducing hyperphenylalaninemia and phenylketonuria. Phenylalanine hydroxylase Koizumi S; Matsushima Y; Nagatsu T; Iinuma H; Takeuchi T; Umezawa H (September 1984). "3,4-dihydroxystyrene, a novel microbial inhibitor for phenylalanine hydroxylase and other pteridine-dependent monooxygenases". Biochimica et Biophysica Acta. 789 (2): 111-8. doi:10.1016/0167-4838(84)90194-8. PMID 6148105 ...
Phenylalanine hydroxylase (PAH) is the enzyme that metabolizes phenylalanine, an essential amino acid required for catecholamine synthesis. Rare mutations in PAH are causal to phenylketonuria (PKU), an autosomal recessive disease characterized by neuropsychiatric symptoms including intellectual disability. We examined whether there is an association between common single nucleotide polymorphisms (SNPs) of PAH and memory performance in the Japanese population. Subjects were 599 healthy adults (166 males and 433 females; mean age 43.8 ± 15.5 years). The Wechsler Memory Scale-Revised (WMS-R) was administered to all participants to assess memory performance. Genotyping was performed for 6 selected tagging SNPs of PAH (rs1722387, rs3817446, rs1718301, rs2037639, rs10860936 and rs11111419). Analyses of covariance controlling for sex and education years, indicated a significant association between a SNP (rs2037639) and age-corrected verbal memory index of WMS-R (nominal p = 0.0013) which remained significant
W F Coulson, C M Hughes; Heterotropic co-operative effects between amino acid substrates of phenylalanine hydroxylase. Biochem J 1 July 1971; 123 (4): 22P. doi: https://doi.org/10.1042/bj1230022P. Download citation file:. ...
Semantic Scholar extracted view of The production of meta-tritiotyrosine from p-tritiophenylalanine by phenylalanine hydroxylase. by Gordon Guroff et al.
The adrenergic amines noradrenaline and adrenaline increased flux through phenylalanine hydroxylase by approx. 50%. This effect, which appears to be mediated by an alpha-adrenergic mechanism, was accompanied by a rapid increase in the phosphorylation of phenylalanine hydroxylase. Although ionophore A23187 mimicked the effects of the adrenergic amines, vasopressin was completely without effect on either phenylalanine hydroxylation or enzyme phosphorylation. Flux through phenylalanine hydroxylase in young rats (80 g) was insensitive to alpha-adrenergic, but sensitive to beta-adrenergic, agents. Consistent with previous observations [Fisher & Pogson (1984) Biochem. J. 219, 79-85] the present data indicate a close correlation between phosphorylation state and flux rate (i.e. enzyme activity). ...
TY - JOUR. T1 - A Flexible Loop in Tyrosine Hydroxylase Controls Coupling of Amino Acid Hydroxylation to Tetrahydropterin Oxidation. AU - Colette Daubner, S.. AU - McGinnis, James Thomas. AU - Gardner, Meredith. AU - Kroboth, Stacie L.. AU - Morris, Adam R.. AU - Fitzpatrick, Paul F. PY - 2006/6/2. Y1 - 2006/6/2. N2 - The role of a polypeptide loop in tyrosine hydroxylase (TyrH) whose homolog in phenylalanine hydroxylase (PheH) takes on a different conformation when substrates are bound has been studied using site-directed mutagenesis. The loop spans positions 177 to 191; alanine was introduced into those positions, introducing one alanine substitution per TyrH variant. Mutagenesis of residues in the center of the loop resulted in alterations in the KM values for substrates, the Vmax value for dihydroxyphenylalanine (DOPA) synthesis, and the coupling of tetrahydropterin oxidation to tyrosine hydroxylation. The variant with the most altered KM value for 6-methyltetrahydropterin was TyrH F184A. ...
The IUPHAR/BPS Guide to Pharmacology. L-Phenylalanine hydroxylase - Amino acid hydroxylases. Detailed annotation on the structure, function, physiology, pharmacology and clinical relevance of drug targets.
I am currently investigating the mechanism of the iron-dependent enzyme, phenylalanine hydroxylase (PAH), a liver enzyme that is responsible for maintaining phenylalanine homeostasis in humans. Defects in the PAH gene lead to the genetic defect, phenylketonuria (PKU), which is the most common inborn metabolic genetic disorder of clinical significance. Approximately 1:10,000 individuals suffer from PKU in the United States due to abnormal function of the phenylalanine hydroxylase (PAH) enzyme. PAH and missense mutations that give rise to PKU in the human population can now be readily expressed and investigated in a laboratory setting. Work in the Caradonna laboratory characterizing two missense mutations that cause PKU showed that the mutant forms of the enzyme were more susceptible to an inactivation process than the wildtype enzyme. This inactivation process is thought to be the direct consequence of irreversible specific side-chain oxidation chemistry induced by the nonproductive decay of the ...
Finally, there is the phenomenon of enzyme deficiency, often called inborn errors of metabolism. Some people are made ill by their inability to detoxify or metabolize foods, chemicals and drugs. An example is lactase deficiency, which causes people to suffer unpleasant abdominal symptoms when they drink milk. Children with phenylketonuria lack the enzyme phenylalanine hydroxylase and are unable to dispose of phenylalanine, which thus accumulates and causes mental retardation and neurological damage.. But deficiencies are not confined to such named disease conditions. There are thousands of enzymes in our bodies, all working in concert. Many of them are dependent on vitamin and mineral "co-factors" to function properly (for example alcohol dehydrogenase, the enzyme which breaks down alcohol, needs zinc and vitamin B1 to work efficiently). Considering possible variations in inherited endowment of enzymes, complicated by missing nutrient factors, the reader will be readily aware that enzyme ...
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These reference sequences exist independently of genome builds. Explain. These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above. ...
페닐알라닌 수산화효소(phenylalanine hydroxylase)에 의해 페닐알라닌이 수산화되면 티로신이 만들어진다. (또는 외부 음식으로도 섭취할 수 있다.) 카테콜아민을 분비하는 신경세포 또는 신경내분비세포는 이 티로신을 일련의 생화학적 과정을 거쳐 도파(L-DOPA)로 변환시킨다. 이후 도파는 각각의 효소에 의해 순서대로 도파민, 노르에피네프린, 에피네프린으로 변환되어 소포에 저장된다. 이후 특정 신경자극에 의해 세포외방출(exocytosis)이 일어나면 세포는 카테콜아민을 혈액이나 시냅스후뉴런(postsynaptic neuron)에 분비한다. ...
Phenylalanine 4 Hydroxylase - Phenylalanine 4 hydroxylase or Phenylalanine hydroxylase is an enzyme that catalyzes the hydroxylation of the aromatic side-chain of phenylalanine to generate tyrosine...
The structure of full-length phenylalanine hydroxylase in complex with the cofactor BH4 is presented in the most recent issue of PNAS. As the cofactor is also used as a therapy for PKU, this structure is of medical importance ...
The hyperphenylalaninemias are disorders of phenylalanine hydroxylation. The disease results from the absence of the hepatic phehylalaniene hydrosylase (PAH) and causes mental retardation. The clinical manifestations and consequences of hyperphenylalaninaemia are due to abnormal accumulation of normal metabolites, thus resulting in mental retardation. This can be rectified by early diagnosis of the disease and the dietary treatment there-of. It is unfortunate that in most instances the diagnosis is only made after permanent and irreversible brain damage has occurred. This can be rectified if PKU carrier diagnosis is applied to identify those high risk families. ,br,,br, Metabolite analyses led to the identification of hyperphehylalaninaemia patients. This phase was part of the normal screening program for the identification of amino-acidpathies of severely ill infants referred to ,the Department of Biochemistry at the Potchefstroom University for Christian Higher Education (PU for CHE). ...
An examination of the ratios of the 16 repetitively spotted flavonoid 3 hydroxylase cDNAs using a t test showed that the mean ratio of the repeated cDNAs on replicate 1 (2.424) were statistically significant at a P value of 0.0001 when compared to an expected mean of a 2.0, or a two-fold expression difference. The low P values were also found for replicate 2 and for the mean value (3.245) of both replicates. Thus, the flavonoid 3 hydroxylase cDNAs are statistically significant outliers in the microarray analysis.. The microarray data presented here and showing that the cytoplasmic levels of the flavonoid 3 hydroxylase are higher in the T/T line agree very well with RNA blot data which showed that the flavonoid 3 hydroxylase gene has reduced expression in the seed coats of the t*/t* isoline compared to the T/T lines [13]. In addition to the RNA blot data showing differences in these mutant lines, we have definitively shown that the flavonoid 3 hydroxylase is encoded by the T locus by ...
Goodwill, K.E., Sabatier, C., Marks, C., Raag, R., Fitzpatrick, P.F. and Stevens, R.C. (1997). „Crystal structure of tyrosine hydroxylase at 2.3 Å and its implications for inherited neurodegenerative diseases". Nat. Struct. Biol. 4: 578-585. PMID 9228951 ...
Citations for Abcams Anti-Tyrosine Hydroxylase抗体. References for Ms,大鼠,山羊,Hu,猪,Bat in ICC/IF,IHC,IHC (PFA…
TY - JOUR. T1 - Expression of phenylalanine hydroxylase (PAH) in erythrogenic bone marrow does not correct hyperphenylalaninemia in Pahenu2 mice. AU - Harding, Cary. AU - Neff, Mark. AU - Jones, Kelly. AU - Wild, Krzysztof. AU - Wolff, Jon A.. PY - 2003/11. Y1 - 2003/11. N2 - Background: Treatment of many inherited liver enzyme deficiencies requires the removal of toxic intermediate metabolites from the blood of affected individuals. We propose that circulating toxins can be adequately cleared and disease phenotype influenced by enzyme expressed in tissues other than the liver, such as bone marrow. Our specific hypothesis was that phenylalanine hydroxylase (PAH) expressed in bone marrow would lower blood phenylalanine levels in hyperphenylalaninemic Pahenu2 mice, a model of human phenylketonuria (PKU). Methods: Germline-modified marrow PAH-expressing mice were developed using a transgene that contained the mouse liver PAH cDNA under the transcriptional control of a human β-globin promoter. ...
TY - JOUR. T1 - Mechanism of Metal-Independent Hydroxylation by Chromobacterium violaceum Phenylalanine Hydroxylase. AU - Carr, Robert T.. AU - Balasubramanian, Shankar. AU - Hawkins, Paul C.D.. AU - Benkovic, Stephen. PY - 1995/1/1. Y1 - 1995/1/1. N2 - Phenylalanine hydroxylase converts phenylalanine to tyrosine utilizing a tetrahydrobiopterin cofactor. Several key mechanistic questions have yet to be resolved, specifically the identity of the hydroxylating species and the role of the non-heme iron which is present in all of the mammalian PAHs. Recently, we have demonstrated that a bacterial PAH from Chromobacterium violaceum does not require any redox active metal for activity [Carr, R. T., & Benkovic, S. J. (1993) Biochemistry 32, 14132-14138]. To identify the function of iron in the mammalian PAHs, we have undertaken a series of experiments to compare the mechanisms of this metal-independent PAH with the iron-dependent PAH from rat liver. Using [4-2H]phenylalanine as a substrate gave a ...
TY - JOUR. T1 - X-ray Absorption Studies of the Cu-Dependent Phenylalanine Hydroxylase from Chromobacterium violaceum. Comparison of the Copper Coordination in Oxidized and Dithionite-Reduced Enzymes. AU - Blackburn, Ninian J.. AU - Strange, Richard W.. AU - Carr, Robert T.. AU - Benkovic, Stephen J.. PY - 1992/2/1. Y1 - 1992/2/1. N2 - The coordination chemistry of the Cu sites of phenylalanine hydroxylase (PAH) from Chromobacterium violaceum has been studied by X-ray absorption spectroscopy (XAS). The EXAFS of the Cu(II) form of the enzyme resembles that of other non-blue copper proteins such as plasma amine oxidases and dopamines-hydroxylase and is characteristic of a mixed N/O coordination shell containing histidine ligation. Detailed simulations of the raw EXAFS data have been carried out using full curved-wave restrained refinement methodologies which allow imidazole ligands to be treated as structural units. The results suggest a Cu(II) coordination of two histidines and two additional ...
Phenylketonuria is the most prevalent disorder caused by an inborn error in aminoacid metabolism. It results from mutations in the phenylalanine hydroxylase gene. Phenotypes can vary from a very mild increase in blood phenylalanine concentrations to a severe classic phenotype with pronounced hyperphenylalaninaemia, which, if untreated, results in profound and irreversible mental disability. Neonatal screening programmes identify individuals with phenylketonuria. The initiation of a phenylalanine-restricted diet very soon after birth prevents most of the neuropsychological complications. However, the diet is difficult to maintain and compliance is often poor, especially in adolescents, young adults, and pregnant women. Tetrahydrobiopterin stimulates phenylalanine hydroxylase activity in about 20% of patients, and in those patients serves as a useful adjunct to the phenylalanine-restricted diet because it increases phenylalanine tolerance and allows some dietary freedom. Possible future treatments ...
GIUGLIANI, Luciana et al. Tetrahydrobiopterin responsiveness of patients with phenylalanine hydroxylase deficiency. J. Pediatr. (Rio J.) [online]. 2011, vol.87, n.3, pp.245-251. ISSN 0021-7557. http://dx.doi.org/10.2223/JPED.2090.. OBJECTIVE: To identify patients responsive to tetrahydrobiopterin (BH4) in a sample of Brazilians with hyperphenylalaninemia due to phenylalanine hydroxylase deficiency (HPA-PAH). METHODS: Interventional study, convenience sampling. The inclusion criteria were: diagnosis of HPA-PAH; age , 7 years; phenylalanine-restricted diet and phenylalanine (Phe) levels , 6 mg/dL in all blood tests 1 year before inclusion. Blood samples were obtained the day before (day 1) and at 0, 4, 8 (day 2) and 24 h (day 3) after BH4 intake. Phe levels were measured using tandem mass spectrometry. The criteria used to define responsiveness to BH4 were: criterion 1- Phe reduction , 30% 8 h after BH4 administration; criterion 2 - Phe reduction , 30% 24 h after BH4 administration. RESULTS: ...
PKU is an autosomal recessive trait caused by the absence of phenylalanine hydroxylase. Phenylalanine hydroxylase is an enzyme involved in the metabolism of phenylalanine (Phe). When phenylalanine hydroxylase is absent or defective, Phe levels rise and toxic Phe metabolites accumulate, causing central nervous system injury. PKU is a treatable disease. Affected individuals must adhere to a diet low in Phe during childhood. Women with PKU should also adhere to a low Phe diet before and during pregnancy to avoid fetal damage. The offspring of women with untreated maternal hyperphenylalaninemia (HPA) usually exhibit mental retardation, microcephaly, growth retardation, and other congenital anomalies. This study will examine the effect of a restricted Phe diet on reproductive outcome in women with maternal HPA.. Participants in this study will be women with HPA whose blood Phe values are persistently greater than 4 mg/dl. Those women with blood Phe values consistently greater than 8 mg/dl will be ...
PKU : Phenylketonuria (PKU) is the most frequent inherited disorder of amino acid metabolism (about 1:10,000-1:15,000) and was the first successfully treated inborn error of metabolism. It is inherited in an autosomal recessive manner and is caused by a defect in the enzyme phenylalanine hydroxylase (PAH), which converts the essential amino acid phenylalanine to tyrosine. Deficiency of PAH results in decreased levels of tyrosine and an accumulation of phenylalanine in blood and tissues. Untreated, PKU leads to severe brain damage with intellectual impairment, behavior abnormalities, seizures, and spasticity. The level of enzyme activity differentiates classic PKU (PAH activity |1%) from other milder forms; however, all are characterized by increased levels of phenylalanine (hyperphenylalaninemia). Treatment includes the early introduction of a diet low in phenylalanine. Tetrahydrobiopterin (BH4) is a cofactor of not only PAH, but also of the tyrosine and tryptophan hydroxylases. Approximately 2% of
Phenylketonuria or PKU has an important place in medical history as the first congenital metabolic disorder. It is a genetic defect in the phenylalanine hydroxylase enzyme existing in the liver and kidneys which is responsible for the conversion of phenylalanine to tyrosine. Deficiency of the enzyme results in accumulation of phenylalanine and its metabolites in the blood and other tissues. If left untreated, mental retardation, speech delays, eczema, seizures, behavioral abnormalities, etc would be expected. In PKU, proper nutrition is the only treatment of choice to prevent complications. The treatment is based on a low-protein diet, and elimination of all protein-rich foods to prevent severe mental retardation. Dietary changes in PKU are permanent through the life. By controlling the diet, we reach disease control too. The metabolic control in childhood and adolescence is related to patients quality of life, and their mental status. Even in patients who resume treatment after a period of free diet,
Hyperphenylalaninemia (HPA) is a rare metabolic disorder caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH). Elevated plasma levels of phenylalanine (phe) cause mental retardation, microcephaly, delayed speech, seizures, eczema, and behavior problems. Adequate control of the plasma levels of phe by a phe-restricted diet can prevent the developmental and behavioral problems.. The foundation of this diet is a phe-free medical product/formula made from free amino acids. Based on longitudinal studies, it has been reported that the most benefit is attained by individuals who maintain a phe-restricted diet throughout life. Despite the obvious benefits of the diet, it has been suggested that the dietary restrictions may be associated with poor bone health in these patients. However, data supporting this has been reported in studies with small sample sizes and/or inadequate sample populations that include children. There is a paucity of data on bone health in adults with HPA.. The ...
Queuosine is a modified pyrrolopyrimidine nucleoside found in the anticodon loop of transfer RNA acceptors for the amino acids tyrosine, asparagine, aspartic acid, and histidine. Since it is exclusively synthesised by bacteria, higher eukaryotes must salvage queuosine or its nucleobase queuine from food and the gut microflora. Previously, animals made deficient in queuine died within 18 days of withdrawing tyrosine-a non-essential amino acid-from the diet [Marks T, Farkas WR (1997) Biochem Biophys Res Commun 230:233-7]. Here we show that human HepG2 cells deficient in queuine and mice made deficient in queuosine modified transfer RNA, by disruption of the tRNA guanine transglycosylae (TGT) enzyme, are compromised in their ability to produce tyrosine from phenylalanine. This has similarities to the disease phenylketonuria, which arises from mutation in the enzyme phenylalanine hydroxylase or from a decrease in the supply of its cofactor tetrahydrobiopterin (BH4). Immunoblot and kinetic analysis ...
Phenylketonuria (PKU) is an autosomal recessive metabolic disorder occurring in 1 in 10,000 to 20,000 births. The absence of phenylalanine hydroxylase results in the accumulation of phenylalanine, its precursors, and its metabolites while at the same time causing tyrosine, the next step in the enzymatic pathway, to become an essential amino acid. The metabolic defect leads to reduced synthesis of a variety of neurotransmitters, serotonin being the most severely affected. Melanin synthesis also is inhibited, so that infants who have PKU are characteristically (though not always) fair-haired, fair-skinned, and blue-eyed.. Early in life, these infants may be asymptomatic or may present with severe vomiting, irritability, eczema, or a musty or mousy odor of the urine. When untreated, the disorder results in profound mental retardation, with intelligence quotient (IQ) scores below 30. Neurologic impairment ranges from neurologically intact (one third of cases) to some hypertonicity (one third) to ...
The main phenylketonuria treatment is a strict diet with very limited intake of phenylalanine, which is mostly found in foods containing protein. Doctors used to believe it was OK for a person with PKU to stop the diet in adolescence, but today, doctors recommend sticking to the diet and PKU formula for life. Without PKU formula, your body cant get enough of essential nutrients called amino acids that are crucial for growth and general health. For example, the amino acid tyrosine is usually a byproduct of phenylalanine metabolism, a process that doesnt occur in people with PKU.. A safe amount of phenylalanine differs for each person. Your doctor will determine a safe amount through regular review of diet records, growth charts and blood levels of phenylalanine. Frequent blood tests will monitor PKU levels as they change over time, especially during childhood growth spurts and pregnancy. In general, the idea is to consume only the amount of phenylalanine thats necessary for normal growth and ...
A genetic disorder that, through a deficiency in a liver enzyme, phenylalanine hydroxylase, causes severe mental retardation unless phenylalanine can be largely restricted from the diet until the age of six. Abbreviated to PKU.
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ABSTRACT: Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine (Phe) metabolism characterized by deficient activity of the hepatic enzyme, phenylalanine hydroxylase. Increased blood Phe levels are toxic to a variety of tissues, particularly the developing fetal brain. The mainstay of treatment for PKU is the dietary restriction of Phe, which results in decreased blood Phe levels. Lifelong dietary restriction and therapy improves quality of life in patients with PKU and should be encouraged. Genetic counseling is recommended for all reproductive-aged women with PKU, and sh... ...
1LTV: Structural comparison of bacterial and human iron-dependent phenylalanine hydroxylases: similar fold, different stability and reaction rates.
1LTV: Structural comparison of bacterial and human iron-dependent phenylalanine hydroxylases: similar fold, different stability and reaction rates.
Mutations in the phenylalanine hydroxylase (PAH) gene which result in lower activities of the enzyme will cause the metabolic disease phenylketonuria. SNPs in this gene include: ...
Despite early and ongoing dietary management with a phe-restricted diet, suboptimal neuropsychological function has been observed in PKU. The restrictive nature of the PKU diet may expose patients to sub-optimal nutritional intake and deficiencies which may impact normal brain function. A systematic review of the published literature was carried out, where possible with meta-analysis, to compare the status of nutrients (Nutrients: DHA, EPA phospholipids, selenium, vitamins B6, B12, E, C, A, D, folic acid, choline, uridine, calcium, magnesium, zinc, iron, iodine and cholesterol) known to be important for brain development and functioning between individuals with PKU and healthy controls. Of 1534 publications identified, 65 studies met the entry criteria. Significantly lower levels of DHA, EPA and cholesterol were found for PKU patients compared to healthy controls. No significant differences in zinc, vitamins B12, E and D, calcium, iron and magnesium were found between PKU patients and controls. Because
Phenylketonuria Phenylketonuria (PKU) is a rare condition in which a baby is born without the ability to properly break down an amino acid called phenylalanine. Causes, incidence, and risk factors Phenylketonuria (PKU) is inherited, which means it is passed down through families. Both parents must pass on the defective gene in order for a baby…
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