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In fruit production, the application of the plant growth regulator 1-(2-chloro-4-pyridyl)-3-phenylurea (CPPU) dulls the fruit aroma. Gas chromatography–mass spectrometry and transcriptome analyses were performed on CPPU-treated and pollinated fruits to determine how CPPU affects the production of aroma in melon fruit. The results showed that the contents of two important esters (benzyl acetate and phenethyl acetate) in the CPPU-treated fruits were significantly lower than those in the pollinated fruits. Transcriptome sequencing data revealed that most differentially expressed genes were involved in “phenylalanine metabolism” pathway, and their expression was significantly decreased in the CPPU-treated fruits. Further analysis showed that the phenylalanine content in the CPPU-treated fruits was significantly higher than that in the pollinated fruits. In summary, CPPU application interferes with phenylalanine metabolism in melon fruits and affects the production of aromatic esters.

The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. We demonstrated that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited excessive blood phenylalanine, musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell (hiPSC)-differentiated hepatocytes. Mechanistically, HULC modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-HULC mimics reduced excessive phenylalanine in Pair(−/−) and Pah(R408W/R408W) mice and improved the phenylalanine tolerance of these mice.

Objective: Cage rearing has critical implications for the laying duck industry because it is convenient for feeding and management. However, caging stress is a type of chronic stress that induces maladaptation. Environmental stress responses have been extensively studied, but no detailed information is available about the comprehensive changes in plasma metabolites at different stages of caging stress in ducks. We designed this experiment to analyze the effects of caging stress on performance parameters and oxidative stress indexes in ducks.Methods: Liquid chromatography tandem mass spectrometry (LC/MS-MS) was used to determine the changes in metabolites in duck plasma at 5 (CR5), 10 (CR10), and 15 (CR15) days after cage rearing and traditional breeding (TB). The associated pathways of differentially altered metabolites were analyzed using Kyoto encyclopedia of genes and genomes (KEGG) database.Results: The results of this study indicate that caging stress decreased performance parameters, and the plasma total superoxide dismutase levels were increased in the CR10 group compared with the other groups. In addition, 1,431 metabolites were detected. Compared with the TB group, 134, 381, and 190 differentially produced metabolites were identified in the CR5, CR10, and CR15 groups, respectively. The results of principal component analysis (PCA) show that the selected components sufficiently distinguish the TB group and CR10 group. KEGG analysis results revealed that the differentially altered metabolites in duck plasma from the CR5 and TB groups were mainly associated with ovarian steroidogenesis, biosynthesis of unsaturated fatty acids, and phenylalanine metabolism.Conclusion: In this study, the production performance, blood indexes, number of metabolites and PCA were compared to determine effect of the caging stress stage on ducks. We inferred from the experimental results that caging-stressed ducks were in the sensitive phase in the first 5 days after caging, caging for approximately 10 days was an important transition phase, and then the duck continually adapted.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is frequently found in athletes and those who have experienced repetitive head traumas. CTE is associated with a variety of neuropathologies, which cause cognitive and behavioral impairments in CTE patients. However, currently, CTE can only be diagnosed after death via brain autopsy, and it is challenging to distinguish it from other neurodegenerative diseases with similar clinical features. To better understand this multifaceted disease and identify metabolic differences in the postmortem brain tissues of CTE patients and control subjects, we performed ultra-high performance liquid chromatography–mass spectrometry (UPLC-MS)-based non-targeted metabolomics. Through multivariate and pathway analysis, we found that the brains of CTE patients had significant changes in the metabolites involved in astrocyte activation, phenylalanine, and tyrosine metabolism. The unique metabolic characteristics of CTE identified in this study were associated with cognitive dysfunction, amyloid-beta deposition, and neuroinflammation. Altogether, this study provided new insights into the pathogenesis of CTE and suggested appealing targets for both diagnosis and treatment for the disease.

Objective: This study was conducted to reveal potential metabolic differences of dairy cows fed corn stover (CS) and rice straw (RS) instead of alfalfa hay (AH) as main forage source.Methods: Thirty multiparous mid-late lactation Holstein dairy cows were selected and randomly assigned to three diets, AH, CS, or RS (n = 10). After 13 weeks of the feeding trial, coccygeal arterial and superficial epigastric venous plasma samples were collected before morning feeding for gas chromatography time-of-flight/mass spectrometry analyses.Results: In the artery, 8 and 13 metabolites were detected as differential metabolites between AH and CS, and between AH and RS, respectively. The relative abundance of phenylpropanoate (log2fold change [FC]) = 1.30, 1.09), panthenol (log2FC = 2.36, 2.20), threitol (log2FC = 1.00, 1.07), and 3,7,12-trihydroxycoprostane (log2FC = 0.79, 0.78) were greater in both CS and RS than in AH, and tyrosine (log2FC = –0.32), phenylalanine (log2FC = –0.30), and pyruvic acid (log2FC = –0.30) were lower in RS than in AH. In the vein, 1 and 7 metabolites were detected as differential metabolites between AH and CS, and between AH and RS, respectively. By comparing AH and RS, we found that metabolic pathways of phenylalanine, tyrosine, and tryptophan biosynthesis and phenylalanine metabolism were enriched by integrative artery and vein analysis. Furthermore, AH and RS, arterial phenylpropanoate and 4-hydroxyproline were positively, and phenylalanine was negatively correlated with milk urea nitrogen. Finally, in AH and CS, arterial panthenol was negatively correlated with feed efficiency.Conclusion: Arterial metabolic profiles changed more than those in the veins from animals on three forage diets, differing in amino acids. We found that phenylalanine, tyrosine, and tryptophan biosynthesis and phenylalanine metabolism were restricted when cows were fed low-quality cereal straw diets.

Objective Amyotrophic lateral sclerosis (ALS) is an adult‐onset fatal neurodegenerative disease which lacks identified biological markers. A label‐free plasma surface‐enhanced Raman spectroscopy (SERS) method was developed to explore a simple and noninvasive test for ALS. Methods ALS patients were enrolled serially and plasma samples were collected at the time of diagnosis prior to the start of ALS treatment. SERS spectra were recorded using a Renishaw micro‐Raman system. Results To exclude the interference by varying disease severity, we enrolled three groups of ALS patients, including ALS‐1 (n = 60; ALSFRS‐R ≥ 42 and time interval ≤ 12 months), ALS‐2 (n = 61; ALSFRS‐R 12 months). The SERS spectra were analyzed using principal component analysis (PCA), which showed that ALS‐1, ALS‐2, ALS‐3, and control groups were separated significantly. Then, decision tree (DT) models and receiver operating characteristic curves were employed and identified that bands at 722 and 739 cm−1, and ratios of 635–722 cm−1 and 635–739 cm−1 were able to distinguish ALS from controls significantly. Finally, we highlighted six metabolism pathways correlated with ALS, including phenylalanine‐tyrosine‐tryptophan biosynthesis, aminoacyl‐tRNA biosynthesis, phenylalanine metabolism, pantothenate and CoA biosynthesis, porphyrin and chlorophyll metabolism, and pyrimidine metabolism. Interpretation: Plasma SERS could be a promising tool for the detection of ALS. The bands at 722 and 739 cm−1, and the ratios of 635–722 cm−1 and 635–739 cm−1 could serve as potential indicator for ALS.

The article presents the data of research work on the development of technology for the production of low-protein potato products (mashed potatoes, dumplings) for the nutrition of people with impaired phenylalanine metabolism, the results of evaluating the developed products in terms of organoleptic, structuralmechanical, rheological properties. The values of the nutritional value of the prototypes of concentrates of low-protein potato products made according to the developed technology were: protein — from 2.5 to 4 g, phenylalanine — from 120 to 245 mg per 100 g of product, in a portion of the prepared product (100 g) the protein content is 0.5–1 g, phenylalanine 30–48 mg. The article also presents the results of a study of changes in postprandial blood glucose levels when eating low-protein potato products (dumplings and mashed potatoes).

Background Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. Main body In 2017 the first European PKU Guidelines were published. These guidelines contained evidence based and/or expert opinion recommendations regarding diagnosis, treatment and care for patients with PKU of all ages. This manuscript is a supplement containing the practical application of the dietary treatment. Conclusion This handbook can support dietitians, nutritionists and physicians in starting, adjusting and maintaining dietary treatment.

Rapeseed (Brassica napus L.) is an important oilseed crop in the world. Its productivity is significantly influenced by numerous abiotic stresses, including cold stress (CS). Consequently, enhancement in CS tolerance is becoming an important area for agricultural investigation and crop improvement. Therefore, the current study aimed to identify the stress-responsive genes, metabolites, and metabolic pathways based on a combined transcriptome and metabolome analysis to understand the CS responses and tolerance mechanisms in the cold-tolerant (C18) and cold-sensitive (C6) rapeseed varieties. Based on the metabolome analysis, 31 differentially accumulated metabolites (DAMs) were identified between different comparisons of both varieties at the same time points. From the transcriptome analysis, 2,845, 3,358, and 2,819 differentially expressed genes (DEGs) were detected from the comparison of C6-0 vs. C18-0, C6-1 vs. C18-1, and C6-7 vs. C18-7. By combining the transcriptome and metabolome data sets, we found that numerous DAMs were strongly correlated with several differentially expressed genes (DEGs). A functional enrichment analysis of the DAMs and the correlated DEGs specified that most DEGs and DAMs were mainly enriched in diverse carbohydrates and amino acid metabolisms. Among them, starch and sucrose metabolism and phenylalanine metabolism were significantly enriched and played a vital role in the CS adaption of rapeseed. Six candidate genes were selected from the two pathways for controlling the adaption to low temperature. In a further validation, the T-DNA insertion mutants of their Arabidopsis homologous, including 4cl3, cel5, fruct4, ugp1, axs1, and bam2/9, were characterized and six lines differed significantly in levels of freezing tolerance. The outcome of the current study provided new prospects for the understanding of the molecular basis of CS responses and tolerance mechanisms in rapeseed and present a set of candidate genes for use in improving CS adaptability in the same plant.

Background The bacillus Calmette-Guérin (BCG) vaccine protects against tuberculosis and heterologous infections but elicits high inter-individual variation in specific and nonspecific, or trained, immune responses. While the gut microbiome is increasingly recognized as an important modulator of vaccine responses and immunity in general, its potential role in BCG-induced protection is largely unknown. Results Stool and blood were collected from 321 healthy adults before BCG vaccination, followed by blood sampling after 2 weeks and 3 months. Metagenomics based on de novo genome assembly reveals 43 immunomodulatory taxa. The nonspecific, trained immune response is detected by altered production of cytokines IL-6, IL-1β, and TNF-α upon ex vivo blood restimulation with Staphylococcus aureus and negatively correlates with abundance of Roseburia. The specific response, measured by IFN-γ production upon Mycobacterium tuberculosis stimulation, is associated positively with Ruminococcus and Eggerthella lenta. The identified immunomodulatory taxa also have the strongest effects on circulating metabolites, with Roseburia affecting phenylalanine metabolism. This is corroborated by abundances of relevant enzymes, suggesting alternate phenylalanine metabolism modules are activated in a Roseburia species-dependent manner. Conclusions Variability in cytokine production after BCG vaccination is associated with the abundance of microbial genomes, which in turn affect or produce metabolites in circulation. Roseburia is found to alter both trained immune responses and phenylalanine metabolism, revealing microbes and microbial products that may alter BCG-induced immunity. Together, our findings contribute to the understanding of specific and trained immune responses after BCG vaccination.

Introduction:Phenylketonuria is one of the common causes of preventable mental retardation. Therefore, dietary and/or cofactor therapy initiated by early detection of the disease is of great clinical importance. In this study, the specificity and sensitivity of fluorescence immunoassay (FIA), tandem mass spectrometry (MS/MS) and plasma amino acid analysis methods used in the diagnosis of phenylalanine metabolism disorder (PMD) were compared.Methods:Patients who were referred to our clinic with a prediagnosis of PMD disorder (n=163) from primary health care institutions were included in the study.Results:The median age of the patients on admission was 3 months (range: 0-25 months). It was observed that the samples were resent to the newborn screening program at a rate of 68.1%. The sensitivity and specificity of FIA for phenylalanine (Phe) with a cut-off value of 2.95 mg/dL were 73.3% and 78.6%, respectively. The sensitivity and specificity of MS/MS for Phe with a cut-off value of ≥94.94 μmol/L were 93.3% and 92.2%, respectively.Conclusion:A clinical delay was detected in the diagnosis of the cases. Because of this clinical delay, it is considered that the samples in the screening program are repeated frequently and that families do not have enough information about the disease. In our study, it was shown that MS/MS was more effective than FIA. The use of MS/MS instead of FIA for the detection of phenylalanine metabolism disorder in the neonatal screening program may be effective in preventing the diagnostic delay.

Introduction: Phenylketonuria (PKU) is an inborn error in phenylalanine metabolism that can cause irreversible brain damage if it is untreated. In the last decades, the prognosis of this disease ha...

Psychological suboptimal health state (PSHS), a subtype of suboptimal health status (SHS), seriously threatens the physical and mental health of human beings. Baihe Dihuang Tang (BDT), a traditional Chinese medicine prescription, has been used to improve PSHS in clinical and achieve significant efficacy for a long time. Exploring of the underlying mechanism of BDT improving the state of PSHS is of significant importance. In the present work, all subjects were screened in strict accordance with inclusion and exclusion criteria. the UHPLC-Q Exactive Orbitrap-MS and Trace GC-PolarisQ Mass were performed to analyze the metabolic features of BDT improving the state of PSHS. Combined with the experimental results of metabolomics and the predicted results of network pharmacology, the metabolic biological network was constructed to find the potential targets of BDT intervention on PSHS. Finally, A total of 22 differential metabolites have been identified in PSHS group. 15 plasma biomarkers were significantly regulated by BDT. The results indicated that the BDT decoction is of a significant therapeutic effect on the improvement of PSHS primarily through regulating pyruvate metabolism and phenylalanine metabolism. Moreover, it is possible for BDT to improve PSHS through the functional targets including GLO1, MAOA and MAOB, which are closely related to monoamine neurotransmitters. Here, these approaches provide a tractable, powerful tool for understanding the underlying mechanism elucidating of BDT for PSHS management.

Phenylketonuria (PKU) is an inborn error of phenylalanine metabolism primarily treated through a phenylalanine-restrictive diet that is frequently supplemented with an amino acid formula to maintain proper nutrition. Little is known of the effects of these dietary interventions on the gut microbiome of PKU patients, particularly in adults. In this study, we sequenced the V4 region of the 16S rRNA gene from stool samples collected from adults with PKU (n = 11) and non-PKU controls (n = 21). Gut bacterial communities were characterized through measurements of diversity and taxa abundance. Additionally, metabolic imputation was performed based on detected bacteria. Gut community diversity was lower in PKU individuals, though this effect was only statistically suggestive. A total of 65 genera across 5 phyla were statistically differentially abundant between PKU and control samples (p &lt, 0.001). Additionally, we identified six metabolic pathways that differed between groups (p &lt, 0.05), with four enriched in PKU samples and two in controls. While the child PKU gut microbiome has been previously investigated, this is the first study to explore the gut microbiome of adult PKU patients. We find that microbial diversity in PKU children differs from PKU adults and highlights the need for further studies to understand the effects of dietary restrictions.

Background There is a dearth of drug therapies available for the treatment of acute respiratory distress syndrome (ARDS). Certain metabolites play a key role in ARDS and could serve as potential targets for developing therapies against this respiratory disorder. The present study was designed to determine such “functional metabolites” in ARDS using metabolomics and in vivo experiments in a mouse model. Methods Metabolomic profiles of blood plasma from 42 ARDS patients and 28 healthy controls were captured using Ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) assay. Univariate and multivariate statistical analysis were performed on metabolomic profiles from blood plasma of ARDS patients and healthy controls to screen for “functional metabolites”, which were determined by variable importance in projection (VIP) scores and P value. Pathway analysis of all the metabolites was performed. The mouse model of ARDS was established to investigate the role of “functional metabolites” in the lung injury and mortality caused by the respiratory disorder. Results The metabolomic profiles of patients with ARDS were significantly different from healthy controls, difference was also observed between metabolomic profiles of the non-survivors and the survivors among the ARDS patient pool. Levels of Phenylalanine, D-Phenylalanine and Phenylacetylglutamine were significantly increased in non-survivors compared to the survivors of ARDS. Phenylalanine metabolism was the most notably altered pathway between the non-survivors and survivors of ARDS patients. In vivo animal experiments demonstrated that high levels of Phenylalanine might be associated with the severer lung injury and increased mortality of ARDS. Conclusion Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma Phenylalanine. Trial registration Chinese Clinical Trial Registry, ChiCTR1800015930. Registered 29 April 2018, http://www.chictr.org.cn/edit.aspx?pid=25609&htm=4

We analyzed the transcriptomes of Romalea microptera grasshoppers after 8 years of artificial selection for either long or short thoraces. Evolution proceeded rapidly during the experiment, with a 13.3% increase and a 32.2% decrease in mean pronotum lengths (sexes combined) in the up- and down-selected colonies, respectively, after only 11 generations. At least 16 additional traits also diverged between the two colonies during the selection experiment. Transcriptomic analysis identified 693 differentially expressed genes, with 386 upregulated and 307 downregulated (55.7% vs. 44.3%), including cellular process, metabolic process, binding, general function prediction only, and signal transduction mechanisms. Many of the differentially expressed genes (DEGs) are known to influence animal body size.

There exists a critical link between immunological processes and metabolic changes. Furthermore, it becomes more and more evident that changes in immunometabolic pathways are highly interconnected with psychological processes and the nervous system. Depressive disorders are a major contributor to the overall burden of disease worldwide. Despite extensive research, therapeutic interventions are often not satisfying. This may be due to the yet only partially elucidated pathobiochemistry underlying the development of depression which may be influenced by multiple factors including genetics, environment, lifestyle, and importantly by the immunological status. In this review article, the roles and consequences of the interferon gamma-dependent pathways of tryptophan breakdown and neopterin formation are discussed, as well as phenylalanine metabolism, trying to provide a rational link between immunology, metabolism and mental status. Besides underlining the complexity of the mechanism involved in the development of depression, the knowledge on relevant biomarkers may be useful in orchestrating personalized therapy regimes.

It is well-known that anaerobic treatment has been considered as a utility process to accumulate γ-aminobutyric acid (GABA) in tea leaves. In this article, the nonvolatile differential compounds in picked-tea leaves between filled-N2 treatment and filled-CO2 treatment were compared in metabolic profiles and dynamic changes via ultrahigh performance liquid chromatography linked to a hybrid quadrupole orthogonal time-of-flight mass spectrometer (UPLC-Q-TOF-MS). Multivariate analysis and heat map of hierarchical clustering analysis indicated that filled-N2 treatment resulted in a wider range of metabolic perturbation than filled-CO2 treatment, but GABA accumulates faster and more significantly under filled-CO2 treatment than other treatment. The differential metabolites in anaerobic treatment were mainly reflected in the levels of glucose metabolism and amino acid metabolism, and the main differential pathway included the glyoxylate metabolism pathway, galactose metabolism, and phenylalanine metabolism. These metabolomic analyses were also evaluated to illuminate the physiological adaptive strategies of tea adopted to tolerate certain anaerobic stress types.

Repetitive transcranial magnetic stimulation (rTMS) is used to treat different neuropsychiatric conditions like Parkinson’s disease, essential tremor, stroke, cognitive decline, dementia and depression. rTMS may exert its therapeutic effects by influencing the biochemistry of neurotransmitters. In this exploratory study, safety symptom improvement and changes in the availability of neurotransmitter precursor amino acids were studied following prefrontal cortex (PFC) stimulation using repetitive transcranial stimulation with TheraCell apparatus R (Guth Meditec, Salach, Germany) as an additional treatment in ten patients with late life depression. Treatment was well tolerated with no serious adverse effects being observed. rTMS induced a significant improvement in the symptoms of depression and a significant decrease in the HAMD-7 (p

Although classification of an individual’s Sasang constitution is a key step in the prescription of traditional Korean medicine, the classifying process is complex and not objective. Identification of metabolic-based biomarkers could allow the development of a reliable and sensitive classification technique and even therapeutic management. Our pilot study investigated whether metabolites in plasma are characteristic of Sasang constitutions. Ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry-based metabolic analysis was conducted against 15 Soyangin (SY), 15 Taeeumin (TE), and 18 Soeumin (SE) individuals, as classified according to the Questionnaire for Sasang Constitution Classification II (QSCC II) and specialist diagnosis. Metabolomics data showed that the TE group was significantly separated from the SY and SE groups. Nine canonical pathways related to constitution; phenylalanine metabolism, aminoacyl-tRNA, tyrosine, and tryptophan biosynthesis were activated in the TE group as compared with the other groups. Similar to the results of the metabolomics analysis, the TE group was also significantly separated from the other two groups by lipidomic analysis. On the other hand, the intensity of lipid metabolites was higher in the SY group than in the other groups. Our findings suggest that the combined analysis of metabolomics and lipidomics can provide useful information for characteristics of Sasang constitutions.

Phenylketonuria (PKU) is a hereditary disorder characterized by disrupted phenylalanine metabolism and cognitive impairment. However, the precise nature and developmental trajectory of this cognitive impairment remains unclear. The present study used a verbal fluency task to dissociate executive and verbal processes in children with PKU (n = 23; 7–18 years) and controls (n = 44; 7–19 years). Data were collected at three longitudinal timepoints over a three-year period, and the contributions of age, group, and their interaction to fluency performance were evaluated. Results indicated impairments in executive processes in children with PKU, which were exacerbated by declining metabolic control.

The sea cucumber Apostichopus japonicus is an economically important marine organism, and its aquaculture has rapidly developed in China. The very large market demand puts forward higher requirements for the economically efficient breeding of sea cucumbers. Sex and the associated reproductive processes have been reported to affect the physiological characteristics of sea cucumbers. However, little is known about the metabolism differences that related to sex and the associated reproductive processes and their potential effects on the efficiency of A. japonicus aquaculture. In this study, ultra-performance liquid chromatography was applied to investigate the variations in metabolic profiles in cell-free coelomic fluids (CCFs) of sea cucumbers of different sexes and reproductive states. A total of 4435 metabolites were detected, and the metabolic profiles of A. japonicus were significantly affected by both sexes and reproductive process. The differentially abundant metabolites in CCFs of A. japonicus of different sexes and reproductive states were also screened and analyzed. The findings revealed that unsaturated fatty acid synthesis and phenylalanine metabolism were the most significantly changed pathways. Moreover, the weakest ability to synthesize capsaicin using phenylalanine was found in A. japonicus after spawning. Our study provides new insights into the metabolic response of A. japonicus during the reproductive process, and also provides valuable references for the economically efficient breeding of A. japonicus.

Phenylketonuria (PKU) is an inborn error of phenylalanine metabolism due to mutations in phenylalanine hydroxylase (PAH). Recently, small compounds, known as pharmacological chaperones (PhCs), have been identified that restore the enzymatic activity of mutant PAHs. Understanding the mechanism of the reduction in enzymatic activity due to a point mutation in PAH and its restoration by PhC binding is important for the design of more effective PhC drugs. Thermal fluctuations of an enzyme can alter its activity. Here, molecular dynamics simulation show the thermal fluctuation of PAH is increased by introduction of the A313T mutation. Moreover, a simulation using the A313T-PhC complex model was also performed. Thermal fluctuation of the mutant was found to be reduced upon PhC binding, which contributes to restoring its enzymatic activity.

Prostate cancer (PCa) is the second leading cause of cancer death among men and associated with profound metabolic changes. It is important to discover new biomarkers for the diagnosis of PCa and metabolomics technology has made progress toward identifying metabolic alterations in diseases that may provide clinically useful biomarkers. The purpose of this work was to determine the distinctive metabolic signatures from PCa. Plasma samples from PCa patients and age-matched healthy controls were investigated using high resolution ultrahigh performance liquid chromatography-mass spectrometry (UPLC/MS) and the datasets were analyzed using pattern recognition methods. Metabolic differences among PCa and control subjects were identified based on multivariate statistical analyses. As a result, 19 distinguishable metabolites were detected and 11 metabolic pathways were established. The altered metabolic pathways were associated with synthesis and degradation of ketone bodies, and phenylalanine metabolism, etc. To demonstrate the utility of plasma biomarkers for the diagnosis of PCa, three metabolites comprising sarcosine, acetylglycine and coreximine that contributed to the combined model were selected as candidate biomarkers. Distinctive signature with these metabolites could significantly increase the diagnostic performance of PCa. In this study, metabolomics technology has proved to be a powerful tool for the discovery of new biomarkers for disease and suggest that panels of metabolites may be valuable to translate our findings to clinically useful diagnostic tests.

Biogenesis of the secondary cell wall in trees involves the massive biosynthesis of the phenylalanine-derived polymer lignin. Arogenate dehydratase (ADT) catalyzes the last, and rate-limiting, step of the main pathway for phenylalanine biosynthesis. In this study, we found that transcript levels for several members of the large ADT gene family, including ADT-A and ADT-D, were enhanced in compression wood of maritime pine, a xylem tissue enriched in lignin. Transcriptomic analysis of maritime pine silenced for PpMYB8 revealed that this gene plays a critical role in coordinating the deposition of lignin with the biosynthesis of phenylalanine. Specifically, it was found that ADT-A and ADT-D were strongly down-regulated in PpMYB8-silenced plants and that they were transcriptionally regulated through direct interaction of this transcription factor with regulatory elements present in their promoters. Another transcription factor, PpHY5, exhibited an expression profile opposite to that of PpMYB8 and also interacted with specific regulatory elements of ADT-A and ADT-D genes, suggesting that it is involved in transcriptional regulation of phenylalanine biosynthesis. Taken together, our results reveal that PpMYB8 and PpHY5 are involved in the control of phenylalanine formation and its metabolic channeling for lignin biosynthesis and deposition during wood formation in maritime pine., Functional genomics unravels the role of two arogenate dehydratases in maritime pine during wood formation, and provides new insights into how lignin biosynthesis and deposition are regulated in conifers.

Phenylketonuria (PKU) is a disorder of phenylalanine metabolism, characterized by a neurotoxic phenylalanine (Phe) accumulation, and treatable with a life-long Phe-restricted diet. Though early and continuously treated PKU (ETPKU) patients exhibit normal IQ, their cognitive outcome remains suboptimal. In this longitudinal study, we aimed at assessing the determinants of IQ subscales and quality of metabolic control in ETPKU children.We collected blood Phe levels, numbers of blood samples for Phe determination, parents' socio-professional categories and school achievement data of 39 classical and moderate ETPKU patients who underwent two cognitive evaluations performed by the same neuropsychologist (at 6.5 and 10y of mean age). We then sought to evaluate the determinants of 1) the changes in their IQ between the two testings (delta IQ) and 2) the quality of metabolic control (evaluated by the median Phe levels during the year before the second test) with multivariate regression analysis.Though in the normal range, mean total IQ slightly decreased between the two evaluations, and we observed a better verbal than performance outcome. Modeling the determining factors of the delta IQ, we found a significant influence of the number of blood samples (β = 0.46, 95%CI = 0.13 to 0.79, p

Training with low-carbohydrate (CHO) availability enhances markers of aerobic adaptation and has become popular to periodize throughout an endurance-training program. However, exercise-induced amino acid oxidation is increased with low muscle glycogen, which may limit substrate availability for postexercise protein synthesis. We aimed to determine the impact of training with low-CHO availability on estimates of dietary protein requirements.Eight endurance-trained males (27 ± 4 yr, 75 ± 10 kg, 67 ± 10 mL·kg body mass·min) completed two trials matched for energy and macronutrient composition but with differing CHO periodization. In the low-CHO availability trial (LOW), participants consumed 7.8 g CHO·kg before evening high-intensity interval training (10 × 5 min at 10-km race pace, 1 min rest) and subsequently withheld CHO postexercise (0.2 g·kg). In the high-CHO availability trial (HIGH), participants consumed 3 g CHO·kg during the day before high-intensity interval training, and consumed 5 g CHO·kg that evening to promote muscle glycogen resynthesis. A 10-km run (~80% HRmax) was performed the following morning, fasted (LOW) or 1 h after consuming 1.2 g CHO·kg (HIGH). Whole-body phenylalanine flux and oxidation were determined over 8 h of recovery via oral [C]phenylalanine ingestion, according to standard indicator amino acid oxidation methodology, while consuming sufficient energy, 7.8 g CHO·kg·d, and suboptimal protein (0.93 g·kg·d).Fat oxidation (indirect calorimetry) during the 10-km run was higher in LOW compared with HIGH (0.99 ± 0.35 g·min vs 0.60 ± 0.26 g·min, P0.05). phenylalanine flux during recovery was not different between trials (P0.05) whereas phenylalanine oxidation (reciprocal of protein synthesis) was higher in LOW compared with HIGH (8.8 ± 2.7 μmol·kg·h vs 7.9 ± 2.4 μmol·kg·h, P0.05), suggesting a greater amino acid requirement to support rates of whole-body protein synthesis.Our findings suggest that performing endurance exercise with low-CHO availability increases protein requirements of endurance athletes.

Styrene can be formed by the microbial metabolism of bacteria and fungi. In our previous study, styrene was determined as a spoilage marker of Fuji apples decayed by Penicillium expansum, which is responsible for postharvest diseases. In the present study, P. expansum was cultivated in potato dextrose broth added with phenylalanine&mdash, which is a precursor of styrene&mdash, using different initial pH values and cultivation times. Volatile compounds were extracted and analyzed using gas chromatography-mass spectrometry (GC-MS) combined with stir-bar sorptive extraction. The 76 detected volatile compounds included 3-methylbutan-1-ol, 3-methyl butanal, oct-1-en-3-ol, geosmin, nonanal, hexanal, and &gamma, decalactone. In particular, the formation of 10 volatile compounds derived from phenylalanine (including styrene and 2-phenylethanol) showed different patterns according to pH and the cultivation time. Partial least square-discriminant analysis (PLS-DA) plots indicated that the volatile compounds were affected more by pH than by the cultivation time. These results indicated that an acidic pH enhances the formation of styrene and that pH could be a critical factor in the production of styrene by P. expansum. This is the first study to analyze volatile compounds produced by P. expansum according to pH and cultivation time and to determine their effects on the formation of styrene.

Context: Drug-induced phospholipidosis is one of the significant concerns in drug development, especially in safety assessment and noninvasive diagnostic tool is highly desirable.Objective: The objective of this study is to explored novel biomarkers for phospholipidosis using a metabolomic approach.Method: NMR spectrometry and LC/MS/MS analyses were applied to urine and plasma of rats administrated cationic amphiphilic drugs.Results: The phenylacetylglycine to hippuric acid ratio in plasma was increased in time and dose-dependent manners; and it was well correlated with histopathological observation.Conclusion: The plasma phenylacetylglycine to hippuric acid ratio is a potential marker in monitoring drug-induced phospholipidosis.

Phenylketonuria is one of the best-known examples of inherited metabolic diseases. It is widely considered as a triumph of western medicine. Untreated phenylketonuria manifests as mental retardation, epilepsy, light complexion, eczema, and a „mousy” odour. This review gives some insight into history of the use of the disease's name, which was probably coined by the biochemist J.H. Quastel and focuses on the contributions of the first medical investigators in the area of abnormal phenylalanine metabolism – I.A. Folling, L.S. Penrose as well as G.A. Jervis. The story of the first family with children diagnosed to have phenylketonuria is presented.

Calmodulin (CaM) is a ubiquitous Ca2+-binding receptor that modulates diverse target proteins and biological processes in all eukaryotes.1,6,7 CaM-binding proteins have been extensively studied in yeasts, plants and animals, but little is known regarding CaM target proteins in the filamentous fungi.1,6,7 Recently, our studies have shown that CaM plays an important role in the secondary metabolism of Beauveria bassiana (a filamentous fungus) through the regulation of BbKIVR and BbPAL.3,4 In this way, the isolation and characterization of CaM-binding proteins involved in the fungal secondary metabolism will provide novel aspects of the CaM-mediated signaling pathway unique to filamentous fungi.

Phenylalanine hydroxylase catalyzes a critical step in the phenylalanine catabolic pathway, and impairment of the human enzyme is linked to phenylketonuria. Phenylalanine is also a positive allosteric regulator of the enzyme, and the allosteric binding site has been determined by crystallography. However, the allosteric activation mechanism remains unclear. Using large-scale simulations to explore how phenylalanine binds to the regulatory site, Ge et al. discovered gating motions of the protein that suggest a conformational selection mechanism.

Background Phenylketonuria (PKU) is an autosomal recessive disorder caused by deficiency of hepatic phenylalanine hydroxylase (PAH) leading to increased levels of phenylalanine in the plasma. Phenylalanine levels and phenylalanine hydroxylase (PAH) activity monitoring are currently limited to conventional blood dot testing. 1- 13 C-phenylalanine, a stable isotope can be used to examine phenylalanine metabolism, as the conversion of phenylalanine to tyrosine occurs in vivo via PAH and subsequently releases the carboxyl labeled 13 C as 13 CO 2 in breath. Objective Our objective was to examine phenylalanine metabolism in children with PKU using a minimally-invasive 1- 13 C-phenylalanine breath test ( 13 C-PBT). Design Nine children (7M: 2F, mean age 12.5±2.87y) with PKU participated in the study twice: once before and once after sapropterin supplementation. Children were provided 6mg/kg oral dose of 1- 13 C-phenylalanine and breath samples were collected at 20min intervals for a period of 2h. Rate of CO 2 production was measured at 60min post-oral dose using indirect calorimetry. The percentage of 1- 13 C-phenylalanine exhaled as 13 CO 2 was measured over a 2h period. Prior to studying children with PKU, we tested the study protocol in healthy children (n=6; 4M: 2F, mean age 10.2±2.48y) as proof of principle. Results Production of a peak enrichment (C max ) of 13 CO 2 (% of dose) in all healthy children occurred at 20min ranging from 17–29% of dose, with a subsequent return to ~5% by the end of 2h. Production of 13 CO 2 from 1- 13 C-phenylalanine in all children with PKU prior to sapropterin treatment remained low. Following sapropterin supplementation for a week, production of 13 CO 2 significantly increased in five children with a subsequent decline in blood phenylalanine levels, suggesting improved PAH activity. Sapropterin treatment was not effective in three children whose 13 CO 2 production remained unchanged, and did not show a reduction in blood phenylalanine levels and improvement in dietary phenylalanine tolerance. Conclusions Our study shows that the 13 C-PBT can be a minimally invasive, safe and reliable measure to examine phenylalanine metabolism in children with phenylketonuria. The breath data are corroborated by blood phenylalanine levels in children who had increased responses in 13 CO 2 production, as reviewed post-hoc from clinical charts.

Phenylketonuria (PKU) is an inborn error in phenylalanine metabolism due to deficiency of the enzyme, phenylalanine hydroxylase (PAH). Treatment includes restriction of dietary phenylalanine, and in some individuals, supplementation with the PAH cofactor, tetrahydrobiopterin (sapropterin dihydrochloride). A survey was conducted among patients with PKU who had been prescribed sapropterin to assess reasons for continuing or discontinuing the drug. The primary reason that sapropterin responders discontinued the drug was because of side effects, followed by insufficient reduction of blood phenylalanine and insurance issues. Conversely, those who remained on therapy cited increased tolerance for dietary protein as the main reason for continuation, along with lower blood phenylalanine concentrations and feeling better. This study suggests that adherence to sapropterin therapy is mainly dependent upon the increase in dietary protein allowed when on the drug.

Covering: 1936 to 2013 Epidithiodioxopiperazine alkaloids possess an astonishing array of molecular architecture and generally exhibit potent biological activity. Nearly twenty distinct families have been isolated and characterized since the seminal discovery of gliotoxin in 1936. Numerous biosynthetic investigations offer a glimpse at the relative ease with which Nature is able to assemble this class of molecules, while providing synthetic chemists inspiration for the development of more efficient syntheses. Herein, we discuss the isolation and characterization, proposed fungal biogeneses, and total syntheses of epidithiodioxopiperazines.

Phenylketonuria (PKU) is one of the most widespread dysfunctions caused by an inheritable problem in the phenylalanine metabolism. In this metabolic disease, gene mutations in phenylalanine hydroxylase (PAH) result in phenylalanine accumulation that causes varying degrees of mental retardation. The most effective treatment is restriction of phenylalanine in diet provided through different strategies including combination of low-protein foods, hydrolyzing of protein-rich foods, or use of protein substitutes. Meat and meat products, sea foods, milk and infant formula, cereal products, and beans are among the modified foods for PKU management. Elimination of phenylalanine from food presents major technological, nutritional, and organolleptic challenges because protein, as an essential structure-building and nutritional element, is removed. In addition, following this program is laborious, boring, and restrictive for both patients and their families. This paper reviews the current findings about PKU and the recent developments in the production of phenylalanine-free foods. Also, the nutritional requirements and challenges encountered by PKU individuals and food technologists are finally discussed.

Response monitoring (post-error slowing) and inhibitory control (commission errors) were examined in children with phenylketonuria (PKU) and controls (6-18 years) using Go/No-Go tasks with higher (PKU n = 37; control n = 55) versus lower (PKU n = 24; control n = 25) non-target expectancy. On both tasks children with PKU exhibited impaired monitoring and inhibitory control, but the post-error slowing pattern was different. With higher expectancy children with PKU slowed more (less efficient monitoring) and with lower expectancy slowed less (less monitoring) than controls. No effects of age or phenylalanine level were noted. These results indicate that expectancy differentially effects monitoring and inhibitory control in PKU.

A serum metabonomic profiling method based on ultra-performance liquid chromatography/time-of-flight mass spectrometry (UHPLC/TOF-MS) was applied to investigate the metabolic changes in hypothyroid rats induced by propylthiouracil (PTU). With Significance Analysis of Microarray (SAM) for classification and selection of biomarkers, 13 potential biomarkers in rat serum were screened out. Furthermore, Ingenuity Pathway Analysis (IPA) was introduced to deeply analyze unique pathways of hypothyroidism that were primarily involved in sphingolipid metabolism, fatty acid transportation, phospholipid metabolism and phenylalanine metabolism. Our results demonstrated that the metabonomic approach integrating with IPA was a promising tool for providing a novel methodological clue to systemically dissect the underlying molecular mechanism of hypothyroidism.

We aimed to assess the reliability of the single biopsy approach for calculating muscle protein synthesis rates compared with the well described sequential muscle biopsy approach following a primed continuous infusion of L-[ ring-2H5]phenylalanine and GC-MS analysis in older men. Two separate experimental infusion protocols, with differing stable isotope amino acid incorporation times, were employed consisting of n = 27 ( experiment 1) or n = 9 ( experiment 2). Specifically, mixed muscle protein FSR were calculated from baseline plasma protein enrichments and muscle protein enrichments obtained at 90 min or 50 min (1BX SHORT), 210 min or 170 min (1BX LONG), and between the muscle protein enrichments obtained at 90 and 210 min or 50 min and 170 min (2BX) of the infusion for experiments 1 and 2, respectively. In experiment 2, we also assessed the error that is introduced to the single muscle biopsy approach when nontracer naive subjects are recruited for participation in a primed continuous infusion of isotope-labeled amino acids. In experiment 1, applying the individual plasma protein enrichment values to the single muscle biopsy approach resulted in no differences in muscle protein FSR between the 1BX SHORT (0.031 ± 0.003%·h−1), 1BX LONG (0.032 ± 0.002%·h−1), or the 2BX approach (0.034 ± 0.002%·h−1). A significant correlation in muscle protein FSR was observed only between the 1BX LONG and 2BX approach ( r = 0.8; P < 0.001). Similar results were observed in experiment 2. In addition, using the single biopsy approach in nontracer naïve state results in a muscle protein FSR that is negative for both the 1BX SHORT (−0.67 ± 0.051%·h−1) and 1BX LONG (−0.19 ± 0.051%·h−1) approaches. This is the first study to demonstrate that the single biopsy approach, coupled with the background enrichment of L-[ ring-2H5]-phenylalanine of mixed plasma proteins, generates data that are similar to using the sequential muscle biopsy approach in the elderly population.

In this work, two types of traditional Italian dry fermented sausages (Felino-type and Milano-type), were analyzed as a case study. The aim was to evaluate the effect of different environmental conditions in the drying chambers and different starter cultures on the characteristics of the industrially produced sausages. At the end of ripening, the sausages obtained were analyzed to determine microbial counts, biogenic amines (BA) accumulation and volatile aroma profile by using SPME-GC analysis. These profiles were compared with the results of a trained panel group. Felino-type sausages, inoculated only with Staphylococci, were characterized by a slow pH drop and by the presence of higher BA contents. Moreover, specific enzymatic activities of Staphylococci, such as phenylalanine metabolism, were observed and these drastically modified product volatile profiles. Also the different drying conditions applied were able to affect some sensory characteristics of the final products such as hardness and chewiness reflecting different water loss kinetics.

Phenylketonuria (PKU), an inborn error in phenylalanine metabolism, requires lifelong nutrition management with a low-phenylalanine diet, which includes a phenylalanine-free amino acid-based medical formula to provide the majority of an individual's protein needs. Compliance with this diet is often difficult for older children, adolescents, and adults with PKU. The whey protein glycomacropeptide (GMP) is ideally suited for the PKU diet because it is naturally low in phenylalanine. Nutritionally complete, acceptable medical foods and beverages can be made with GMP to increase the variety of protein sources for the PKU diet. As an intact protein, GMP improves protein use and increases satiety compared with amino acids. Thus, GMP provides a new, more physiologic source of low-phenylalanine dietary protein for people with PKU.

Ustilago maydis(옥수수깜부기균)에 있어서 동포자 melanin의 구성성분으로 catecol 계 알려진바 이 물질의 전구체인 benzoic acid의 생성 여부와 그 유래 원천을 추적하고자 phenylalanine의 분해 과정을 조사하였다. 방사성 동위원소가 표지된 L- $^{14}C$ -phenylalanine 및 $^{14}C$ -trans-cinnamic acid를 첨가한 액체배지에서 균체와 배양액을 대상으로 대사산물을 추적 조사한 결과 trans-cinnamic acid, benzoic acid, 4-hydroxybenzoic acid와 hydroxybenzoic acid derivatives 추정되는 물질 등이 검출되었다. 또한 L- $^{14}C$ -phenylalanine을 대사하여 매우 천천히 공기 중으로 $^{14}CO_2$ 를 방출함을 확인하여 phenylalanine을 완전히 분해 할 수 있음을 밝혔다. 결론적으로 본 연구는 옥수수깜부기균이 benzoic acid를 생성하고 그 유래는 phenylalanine의 분해에서 만들어지는 증거를 제시하였다. 【Cetecol has been known as a component of melanin in teliospores of the corn smut fungus Ustilago maydis. Its metabolic precursor has been assumed to be benzoic acid but it has not been proven yet. This study was carried out to verify the synthesis of benzoic acid and to chase its metabolic origin in U. maydis. For this aim, the catabolic process of phenylalanine was investigated by culturing the fungus in the complete medium containing L- $^{14}C$ -phenylalanine and $^{14}C$ -trans-cinnamic acid. We detected trans-cinnamic acid, benzoic acid, 4-hydroxybenzoic acid and hydroxybenzoic acid derivatives from the extracts of the fungus cells and cultural filtrates by thin layered chromatography analysis. We also observed that the fungus could completely catabolize L- $^{14}C$ -phenylalanine and produce $^{14}CO_2$ in the air. Conclusively, this study provided an evidence that U. maydis could produce benzoic acid through catabolic process of phenylalanine.】

Fil: Dallagnol, Andrea Micaela. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnologico Conicet - Tucuman. Centro de Referencia Para Lactobacilos; Argentina

A longitudinal experimental design in combination with metabolomics and multiway data analysis is a powerful approach in the identification of metabolites whose correlation with bioproduct formation shows a shift in time. In this paper, a strategy is presented for the analysis of longitudinal microbial metabolomics data, which was performed in order to identify metabolites that are likely inducers of phenylalanine production by Escherichia coli. The variation in phenylalanine production as a function of differences in metabolism induced by the different environmental conditions in time was described by a validated multiway statistical model. Notably, most of the metabolites showing the strongest relations with phenylalanine production seemed to hardly change in time. Apparently, potential bottlenecks in phenylalanine seem to hardly change in the course of a batch fermentation. The approach described in this study is not limited to longitudinal microbial studies but can also be applied to other (biological) studies in which similar longitudinal data need to be analyzed.

SUMMARY Considerable efforts have been directed towards the elucidation of the phenol compounds in the pathogenesis of phenylketonuria, but relatively little has been done towards denning the role of the indole compounds. Observations have been made regarding the levels of 5-hydroxy tryptamine, 5-hydroxy indoleacetic acid, and 5-hydroxy tryptophane decarboxylase in phenylketonuria, and their possible role in causing mental deficiency in the developing infant is discussed. RESUME Metabolisme des composes de l'indole dans la phenylcetonurie On a fait des efforts considerables pour elucider la question des composes du phenol dans la pathogenie de la phenylcetonurie mais on n'a relativement pas fait grand chose pour preciser le role des composes de l'indole. Nous trouvons ici des observations relatives aux taux de la 5-hydroxy tryptamine, de l'acide 5-hydroxy indoleacetique et de la 5-hydroxy tryptophane decarboxylase dans la phenylcetonurie et une discussion de leur role eventuel dans les causes de deficience mentale chez les enfants en cours de croissance. ZUSAMMENFASSUNG Stoffwechsel der Indoherbindungen bei Phenylketonuria Erhebliche Bemuhungen sind auf die Aufklarung der Rolle der Phenolverbindungen in der Pathogenie der Phenylketonuria gelenkt worden aber es ist verhaltnismassig wenig getan worden, urn die Rolle der Indolverbindungen zu erklaren. Hier findet man Beobachtungen hinsichtlich des Gehalts an 5-Hydroxytryptamin, 5-hydroxyindol-essigsaure und 5-Hydroxytryptophan decarboxylase bei Phenylketonuria und Erorterung uber ihre eventuelle Rolle in den Ursachen des Schwaschsinns bei aufwachsenden Kindern.

Radioactive amino-acids accumulate in gliomas even with an intact blood-brain-barrier. L-3-[(123)I]-iodo-alpha-methyl-tyrosine (IMT) is well established for SPECT imaging of gliomas. Recently, we introduced p-[(123)I]-iodo-L-phenylalanine (IPA) for the characterisation of brain lesions. This study compares both tracers in glioma patients.Eleven patients with gliomas (1 WHO grade 1, 5 grade 2, 1 grade 3, 2 grade 4 gliomas, 1 unconfirmed upgrading and 1 post-therapeutic non-neoplastic lesion) underwent SPECT imaging with IPA (early and delayed acquisitions at 30 min and 3 h) and IMT (early only). Maximum tumour-to-brain ratios (TBR) were calculated using region-of-interest analysis to assess uptake of IMT and IPA. Imaging results were compared to histopathological findings.Early TBRs of IMT and IPA were strongly correlated (r = 0.828, p = 0.002). TBRs were higher for IMT than IPA (1.95+/-0.50 versus 1.79+/-0.42; p0.05), but independent from tumour cell density (p0.1). Visual interpretation by different observers was more concordant for IMT-SPECT than IPA-SPECT (kappa 1.0 versus 0.774). No differences in early TBRs were observed between low-grade and high-grade gliomas for IMT (1.97+/-0.53 versus 2.21+/-0.44, p0.5) or IPA (1.70+/-0.23 versus 2.21+/-0.56, p = 0.167) with a trend to higher TBRs in low-grade tumours for IMT (p = 0.093). In contrast to the known wash-out of IMT, we observed persistent accumulation of IPA in gliomas.IPA shows lower TBRs than IMT, especially in low-grade tumours, so IMT should be preferred for the delineation of low-grade gliomas by SPECT imaging. Due to its prolonged retention, however, IPA remains promising for therapeutic use in gliomas after labelling with I-131.

Phenylketonuria was amongst the first of the metabolic disorders to be characterised, exhibiting an inborn error in phenylalanine metabolism due to a functional deficit of the enzyme phenylalanine hydroxylase. It affects around 700,000 people around the globe. Mutations in the gene coding for hepatic phenylalanine hydroxylase cause this deficiency resulting in elevated plasma phenylalanine concentrations, leading to cognitive impairment, neuromotor disorders and related behavioural symptoms. Inception of low phenylalanine diet in the 1950s marked a revolution in the management of phenylketonuria and has since been a vital element of all therapeutic regimens. However, compliance to dietary therapy has been found difficult and newer supplement approaches are being examined. The current development of gene therapy and enzyme replacement therapeutics may offer promising alternatives for the management of phenylketonuria. This review outlines the pathological basis of phenylketonuria, various treatment regimes, their associated challenges and the future prospects of each approach. Briefly, novel drug delivery systems which can potentially deliver therapeutic strategies in phenylketonuria have been discussed.

Background The daily requirement for phenylalanine is not known with certainty. Earlier 24-h tracer studies have suggested that the requirement is between 30 and 40 mg . kg(-1) . d(-1). Objective The objective was to assess the phenylalanine requirement in healthy well-nourished Indians with the use of 8 test phenylalanine intakes (19, 23, 27, 31, 35, 38, 43, and 47 mg . kg(-1) . d(-1)) and the 24-h indicator amino acid oxidation (24-h IAAO) and 24-h indicator amino acid balance (24-h IAAB) methods. Design Thirty-two healthy, well-nourished Indian men were studied during each of 2 randomly assigned 6-d diet periods in which phenylalanine intakes of 19, 23, 27, 31, 35, 38, 43, and 47 mg . kg(-1) . d(-1) were supplied; the diet was devoid of tyrosine. A 24-h [13C]leucine tracer infusion was used to measure 24-h IAAO and 24-h IAAB on day 7. The breakpoint in the relation between these values and the phenylalanine intake was determined. Results Two-phase linear regression of daily leucine oxidation and balance against phenylalanine intake estimated a breakpoint in the response curve at phenylalanine intakes of 37 and 38 mg . kg(-1) . d(-1) (95% CI for both: 31, >47 mg . kg(-1) . d(-1)), respectively. Conclusion On the basis of the 24-h IAAO and 24-h IAAB methods, a mean phenylalanine requirement of 38 mg . kg(-1) . d(-1) is proposed for healthy well-nourished Indian adults in the absence of tyrosine intake. This finding is similar to that in Western adults.