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Nature Jun 2022Exercise confers protection against obesity, type 2 diabetes and other cardiometabolic diseases. However, the molecular and cellular mechanisms that mediate the...
Exercise confers protection against obesity, type 2 diabetes and other cardiometabolic diseases. However, the molecular and cellular mechanisms that mediate the metabolic benefits of physical activity remain unclear. Here we show that exercise stimulates the production of N-lactoyl-phenylalanine (Lac-Phe), a blood-borne signalling metabolite that suppresses feeding and obesity. The biosynthesis of Lac-Phe from lactate and phenylalanine occurs in CNDP2 cells, including macrophages, monocytes and other immune and epithelial cells localized to diverse organs. In diet-induced obese mice, pharmacological-mediated increases in Lac-Phe reduces food intake without affecting movement or energy expenditure. Chronic administration of Lac-Phe decreases adiposity and body weight and improves glucose homeostasis. Conversely, genetic ablation of Lac-Phe biosynthesis in mice increases food intake and obesity following exercise training. Last, large activity-inducible increases in circulating Lac-Phe are also observed in humans and racehorses, establishing this metabolite as a molecular effector associated with physical activity across multiple activity modalities and mammalian species. These data define a conserved exercise-inducible metabolite that controls food intake and influences systemic energy balance.
Topics: Adiposity; Animals; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Energy Metabolism; Feeding Behavior; Glucose; Lactic Acid; Mice; Obesity; Phenylalanine; Physical Conditioning, Animal
PubMed: 35705806
DOI: 10.1038/s41586-022-04828-5 -
Amino Acids Aug 2021Nα-2-thiophenoyl-D-phenylalanine-2-morpholinoanilide (MMV688845, IUPAC: N-(1-((2-morpholinophenyl)amino)-1-oxo-3-phenylpropan-2-yl)thiophene-2-carboxamide) from the...
Nα-2-thiophenoyl-D-phenylalanine-2-morpholinoanilide (MMV688845, IUPAC: N-(1-((2-morpholinophenyl)amino)-1-oxo-3-phenylpropan-2-yl)thiophene-2-carboxamide) from the Pathogen Box library (Medicines for Malaria Ventures, MMV) is a promising lead compound for antimycobacterial drug development. Two straightforward synthetic routes to the title compound starting from phenylalanine or its Boc-protected derivative are reported. Employing Boc-phenylalanine as starting material and the T3P and PyBOP amide coupling reagents enables racemization-free synthesis, avoiding the need for subsequent separation of the enantiomers. The crystal structure of the racemic counterpart gives insight into the molecular structure and hydrogen bonding interactions in the solid state. The R-enantiomer of the title compound (derived from D-phenylalanine) exhibits activity against non-pathogenic and pathogenic mycobacterial strains, whereas the S-enantiomer is inactive. Neither of the enantiomers and the racemate of the title compound shows cytotoxicity against various mammalian cells.
Topics: Calorimetry, Differential Scanning; Chromatography, High Pressure Liquid; Microbial Sensitivity Tests; Mycobacterium; Phenylalanine; Spectrum Analysis; Stereoisomerism
PubMed: 34259925
DOI: 10.1007/s00726-021-03044-1 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Aug 2020Narcolepsy is the most common cause of excessive daytime sleepiness (EDS) following obstructive sleep apnea. Its treatment aims to reduce EDS and cataplexy, improve... (Review)
Review
Narcolepsy is the most common cause of excessive daytime sleepiness (EDS) following obstructive sleep apnea. Its treatment aims to reduce EDS and cataplexy, improve nighttime sleep disturbance, sleep paralysis and sleep-related hallucinations. Pitolisant (a histamine H3 receptor antagonist) and solriamfetol (a norepinephrine reuptake inhibitor) have recently been approved effective for narcolepsy in the United States and the European Union. Pitolisant has proved to be effective for both EDS and cataplexy. Besides being effective on EDS, solriamfetol seems to have advantages in abuse potential and withdrawal syndrome. As potential treatments for EDS and cataplexy associated with narcolepsy, several new drugs are being developed and tested. These new drugs include new hydroxybutyrate preparations (controlled release sodium hydroxybutyrate FT218, low sodium hydroxybutyrate JZP-258), selective norepinephrine reuptake inhibitor (AXS-12), and modafinil combined with astroglial junction protein inhibitor (THN102). This paper reviews the recently approved drugs and potential treatments for narcolepsy.
Topics: Carbamates; Cataplexy; Drug Development; Humans; Narcolepsy; Phenylalanine; Piperidines
PubMed: 32985153
DOI: 10.3785/j.issn.1008-9292.2020.08.17 -
The Journal of Nutrition Jun 2007In chronic kidney failure, there is impairment in the conversion of phenylalanine to tyrosine. As a result, tyrosine and the tyrosine/phenylalanine ratio are reduced in... (Review)
Review
In chronic kidney failure, there is impairment in the conversion of phenylalanine to tyrosine. As a result, tyrosine and the tyrosine/phenylalanine ratio are reduced in plasma and many tissues, and phenylalanine concentrations tend to be normal or slightly increased. Although animal studies indicate that the kidney is not a major contributor to the conversion of phenylalanine to tyrosine, human studies conducted in the postabsorptive state suggest that the kidney plays a major role in the uptake of phenylalanine and its hydroxylation and release as tyrosine. The human splanchnic bed in the postabsorptive state also displays net uptake of both phenylalanine and tyrosine and hydroxylation of substantial amounts of phenylalanine to form tyrosine. In chronic renal failure (CRF) patients, splanchnic uptake of tyrosine appears to be reduced in the postabsorptive state. After an amino acid meal, there is net release of phenylalanine from the splanchnic bed in normal subjects and to an even greater degree in CRF patients; tyrosine is released postprandially in both normal subjects and CRF patients. In the postabsorptive state, tyrosine release from the kidney is largely derived from the hydroxylation of phenylalanine. In CRF, the release of tyrosine from the kidney is reduced and this reduction may be marked with advanced CRF. These observations, as well as isotope studies indicating normal phenylalanine flux, reduced tyrosine flux and impaired conversion of phenylalanine to tyrosine in CRF patients, raise the possibility that tyrosine may be an essential amino acid in this condition. Further research will be necessary to answer this question. Oxidative stress, which often increases in CRF patients, may lead to increased formation of chlorotyrosine and nitrotyrosine in plasma proteins and of nitrotyrosine in the brain. Increased nitrotyrosine is also found in kidneys of patients with diabetic nephropathy or allograft nephropathy. Increased serum concentrations of oxidation products of phenylalanine have also been observed in patients with CRF. Impaired urinary excretion also may lead to accumulation of metabolic products of both phenylalanine and tyrosine in CRF. It is not known whether the elevated protein chlorotyrosine or nitrotyrosine or increased oxidative products of phenylalanine cause adverse metabolic or toxic effects in patients with CRF.
Topics: Animals; Carbon Dioxide; Humans; Kidney Failure, Chronic; Kinetics; Models, Animal; Phenylalanine; Rats; Reference Values; Tyrosine
PubMed: 17513431
DOI: 10.1093/jn/137.6.1586S -
Biological Chemistry Jul 2023Soluble nuclear transport receptors and stationary nucleoporins are at the heart of the nucleocytoplasmic transport machinery. A subset of nucleoporins contains... (Review)
Review
Soluble nuclear transport receptors and stationary nucleoporins are at the heart of the nucleocytoplasmic transport machinery. A subset of nucleoporins contains characteristic and repetitive FG (phenylalanine-glycine) motifs, which are the basis for the permeability barrier of the nuclear pore complex (NPC) that controls transport of macromolecules between the nucleus and the cytoplasm. FG-motifs can interact with each other and/or with transport receptors, mediating their translocation across the NPC. The molecular details of homotypic and heterotypic FG-interactions have been analyzed at the structural level. In this review, we focus on the interactions of nucleoporins with nuclear transport receptors. Besides the conventional FG-motifs as interaction spots, a thorough structural analysis led us to identify additional similar motifs at the binding interface between nucleoporins and transport receptors. A detailed analysis of all known human nucleoporins revealed a large number of such phenylalanine-containing motifs that are not buried in the predicted 3D-structure of the respective protein but constitute part of the solvent-accessible surface area. Only nucleoporins that are rich in conventional FG-repeats are also enriched for these motifs. This additional layer of potential low-affinity binding sites on nucleoporins for transport receptors may have a strong impact on the interaction of transport complexes with the nuclear pore and, thus, the efficiency of nucleocytoplasmic transport.
Topics: Humans; Active Transport, Cell Nucleus; Nuclear Pore Complex Proteins; Binding Sites; Phenylalanine
PubMed: 37210735
DOI: 10.1515/hsz-2023-0155 -
The Journal of Nutrition Jun 2007The initial use of a tracer of phenylalanine was by Moss and Schoenheimer in rats in 1940 to determine that phenylalanine was hydroxylated to tyrosine, defining for the... (Review)
Review
The initial use of a tracer of phenylalanine was by Moss and Schoenheimer in rats in 1940 to determine that phenylalanine was hydroxylated to tyrosine, defining for the first time the primacy of this pathway. Phenylalanine and tyrosine kinetics were not measured in humans until the 1970-80s. The first application was to determine the degree of blockage of phenylalanine hydroxylation in patients with hyperphenylalanemia and phenylketonuria, but this approach was expanded to determination of phenylalanine hydroxylation in normal subjects. Far more uses have been demonstrated for measuring rates of phenylalanine disposal and tyrosine production in relatively normal subjects than in patients with in-born errors of metabolism. Key to use of tracers to determine phenylalanine and tyrosine metabolic rates has been the development of appropriate tracer models. Most applications have used relatively simple models ignoring the intracellular hydroxylation rate component. Because the liver is the primary site of hydroxylation in the body, the intracellular enrichment at the site of hydroxylation can be assessed from the tracer enrichments at isotopic steady state in rapid-turnover plasma proteins, such as Apo-B, made and secreted by the liver. Although there are potential problems with use of deuterated tracers of phenylalanine, suitable tracers are available and have been demonstrated for general measurement of phenylalanine and tyrosine kinetics in humans.
Topics: Humans; Kinetics; Models, Biological; Oxidation-Reduction; Phenylalanine; Reproducibility of Results; Tyrosine
PubMed: 17513423
DOI: 10.1093/jn/137.6.1549S -
ACS Sensors Dec 2019Determination of the amino acid phenylalanine is important for lifelong disease management in patients with phenylketonuria, a genetic disorder in which phenylalanine...
Determination of the amino acid phenylalanine is important for lifelong disease management in patients with phenylketonuria, a genetic disorder in which phenylalanine accumulates and persists at levels that alter brain development and cause permanent neurological damage and cognitive dysfunction. Recent approaches for treating phenylketonuria focus on injectable medications that efficiently break down phenylalanine but sometimes result in detrimentally low phenylalanine levels. We have identified new DNA aptamers for phenylalanine in two formats, initially as fluorescent sensors and then, incorporated with field-effect transistors (FETs). Aptamer-FET sensors detected phenylalanine over a wide range of concentrations (fM to mM). -Chlorophenylalanine, which inhibits the enzyme that converts phenylalanine to tyrosine, was used to induce hyperphenylalaninemia during brain development in mice. Aptamer-FET sensors were specific for phenylalanine versus -chlorophenylalanine and differentiated changes in mouse serum phenylalanine at levels expected in patients. Aptamer-FETs can be used to investigate models of hyperphenylalanemia in the presence of structurally related enzyme inhibitors, as well as naturally occurring amino acids. Nucleic acid-based receptors that discriminate phenylalanine analogs, some that differ by a single substituent, indicate a refined ability to identify aptamers with binding pockets tailored for high affinity and specificity. Aptamers of this type integrated into FETs enable rapid, electronic, label-free phenylalanine sensing.
Topics: Animals; Aptamers, Nucleotide; DNA; Electrochemical Techniques; Fenclonine; Mice; Phenylalanine; Phenylketonurias; Transistors, Electronic
PubMed: 31631652
DOI: 10.1021/acssensors.9b01963 -
The American Journal of Clinical... Feb 2020Phenylalanine is an indispensable amino acid and, via tyrosine, is the precursor for the neurotransmitters dopamine, norepinephrine, and epinephrine. Currently, dietary...
BACKGROUND
Phenylalanine is an indispensable amino acid and, via tyrosine, is the precursor for the neurotransmitters dopamine, norepinephrine, and epinephrine. Currently, dietary requirements for phenylalanine during pregnancy are unknown.
OBJECTIVES
This study's aim was to determine phenylalanine requirements (in the presence of excess tyrosine) during early and late gestation using direct amino acid oxidation (DAAO; with l-[1-13C]phenylalanine) and indicator amino acid oxidation (IAAO; with l-[1-13C]leucine).
METHODS
Twenty-three healthy women (age: 30.4 ± 3.1 y, mean ± SD) were studied at a range of phenylalanine intakes (5.5-30.5 mg · kg-1 · d-1 in early and late pregnancy using DAAO, and 2.5-30.5 mg · kg-1 · d-1 in late pregnancy using IAAO) for a total of 76 study days. Test intakes were provided as 8 isocaloric and isonitrogenous meals with 1.5 g · kg-1 · d-1 protein and energy at 1.7 times the measured resting energy expenditure. Breath samples were analyzed on an isotope ratio mass spectrometer for 13C enrichment. Phenylalanine requirement was determined using a 2-phase linear regression crossover model to identify a breakpoint in 13CO2 production (representing the mean requirement) in response to phenylalanine intakes.
RESULTS
Phenylalanine requirement during early pregnancy was determined to be 15 mg · kg-1 · d-1 (95% CI: 10.4, 19.9 mg · kg-1 · d-1); during late pregnancy, it was determined to be 21 mg · kg-1 · d-1 by DAAO (95% CI: 17.4, 24.7 mg · kg-1 · d-1) and IAAO (95% CI: 10.5, 32.2 mg · kg-1 · d-1).
CONCLUSIONS
Our results suggest a higher requirement (40%) for phenylalanine during late pregnancy than during early pregnancy. Moreover, the early pregnancy requirements are higher than the previous adult male requirement (9.1 mg · kg-1 · d-1; 95% CI: 4.6, 13.6 mg · kg-1 · d-1), although the 95% CIs overlap. Both DAAO and IAAO methods provided similar breakpoints in late pregnancy, showing that the DAAO method was appropriate even though low phenylalanine intakes could not be tested. These results have potential implications for gestation stage-specific dietary phenylalanine recommendations in future.This trial was registered at clinicaltrials.gov as NCT02669381.
Topics: Adult; Amino Acids; Carbon Dioxide; Carbon Isotopes; Dose-Response Relationship, Drug; Female; Humans; Linear Models; Meals; Nutritional Requirements; Oxidation-Reduction; Phenylalanine; Pregnancy
PubMed: 31758682
DOI: 10.1093/ajcn/nqz288 -
Expert Opinion on Investigational Drugs Oct 2020The overall survival of patients with multiple myeloma has improved with the advent of novel agents; however, multiple myeloma remains incurable. Combinations of... (Review)
Review
INTRODUCTION
The overall survival of patients with multiple myeloma has improved with the advent of novel agents; however, multiple myeloma remains incurable. Combinations of standard-of-care agents such as immunomodulators, proteasome inhibitors, and anti-CD38 monoclonal antibodies are increasingly used in earlier lines of therapy. Patients with disease that is refractory to multiple novel agents represent a population with high unmet medical need and for whom therapies with new mechanisms of action could be beneficial. Melphalan flufenamide (melflufen) has demonstrated encouraging activity in patients with relapsed and refractory multiple myeloma.
AREAS COVERED
This review provides an overview of the mechanism of action of melflufen, a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly delivers alkylating agents into tumor cells. It reviews key Phase I and II clinical trial data for melflufen in combination with dexamethasone as well as in triplet combinations with daratumumab or bortezomib. The safety profile of melflufen, which is characterized primarily by clinically manageable hematologic adverse events, is described.
EXPERT OPINION
Melflufen has potential to fill a gap in the myeloma treatment landscape by providing a new mechanism of action with clinically meaningful efficacy and a favorable safety profile in patients refractory to multiple novel agents.
Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Humans; Melphalan; Multiple Myeloma; Phenylalanine; Recurrence; Survival Rate
PubMed: 32924646
DOI: 10.1080/13543784.2020.1808884 -
Molecules (Basel, Switzerland) Oct 2018Two synthetic protocols for the introduction of fluorine atoms into resorcinarene-based cavitands, at the lower and upper rim, respectively, are reported. Cavitand ,...
Two synthetic protocols for the introduction of fluorine atoms into resorcinarene-based cavitands, at the lower and upper rim, respectively, are reported. Cavitand , bearing four fluorocarbon tails, and cavitand , which presents a fluorine atom on the position of a diester phosphonate phenyl substituent, were synthesized and their complexation abilities toward the model guest sarcosine methyl ester hydrochloride were evaluated via NMR titration experiments. The effect of complexation on the F NMR resonance of the probe is evident only in the case of cavitand , where the inset of the cation-dipole and H-bonding interactions between the P=O bridges and the guest is reflected in a sizable downfield shift of the fluorine probe.
Topics: Calixarenes; Cations; Ethers, Cyclic; Fluorine; Halogenation; Hydrogen Bonding; Magnetic Resonance Spectroscopy; Molecular Structure; Organophosphonates; Phenylalanine; Resorcinols; Sarcosine
PubMed: 30336589
DOI: 10.3390/molecules23102670