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1.
Pharmacol Rev ; 76(1): 142-193, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37940347

RESUMO

The neutral amino acid transporter subfamily that consists of six members, consecutively SLC6A15-SLC620, also called orphan transporters, represents membrane, sodium-dependent symporter proteins that belong to the family of solute carrier 6 (SLC6). Primarily, they mediate the transport of neutral amino acids from the extracellular milieu toward cell or storage vesicles utilizing an electric membrane potential as the driving force. Orphan transporters are widely distributed throughout the body, covering many systems; for instance, the central nervous, renal, or intestinal system, supplying cells into molecules used in biochemical, signaling, and building pathways afterward. They are responsible for intestinal absorption and renal reabsorption of amino acids. In the central nervous system, orphan transporters constitute a significant medium for the provision of neurotransmitter precursors. Diseases related with aforementioned transporters highlight their significance; SLC6A19 mutations are associated with metabolic Hartnup disorder, whereas altered expression of SLC6A15 has been associated with a depression/stress-related disorders. Mutations of SLC6A18-SLCA20 cause iminoglycinuria and/or hyperglycinuria. SLC6A18-SLC6A20 to reach the cellular membrane require an ancillary unit ACE2 that is a molecular target for the spike protein of the SARS-CoV-2 virus. SLC6A19 has been proposed as a molecular target for the treatment of metabolic disorders resembling gastric surgery bypass. Inhibition of SLC6A15 appears to have a promising outcome in the treatment of psychiatric disorders. SLC6A19 and SLC6A20 have been suggested as potential targets in the treatment of COVID-19. In this review, we gathered recent advances on orphan transporters, their structure, functions, related disorders, and diseases, and in particular their relevance as therapeutic targets. SIGNIFICANCE STATEMENT: The following review systematizes current knowledge about the SLC6A15-SLCA20 neutral amino acid transporter subfamily and their therapeutic relevance in the treatment of different diseases.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros , Aminoácidos Neutros , COVID-19 , Humanos , Sistemas de Transporte de Aminoácidos Neutros/química , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Rim/metabolismo , Aminoácidos/metabolismo , Aminoácidos Neutros/metabolismo , COVID-19/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo
2.
Nutr Hosp ; 40(Spec No2): 12-15, 2023 Nov 22.
Artigo em Espanhol | MEDLINE | ID: mdl-37929912

RESUMO

Introduction: Sleep induction and its quality are issues of growing concern because its deterioration affects a large number of people and poses a risk to their well-being and quality of life and long-term health. There are several factors involved in the problem, but nutrition is one of them and in particular milk consumption has often been linked to sleep habits, sometimes as a promoter and sometimes as an inhibitor. The purpose of this review is to examine the matter further. On reaching the brain, tryptophan is the basis for the synthesis of serotonin and melatonin, which improve the induction and quality of sleep. But there is competition between tryptophan and other long-chain neutral amino acids (LNAA) (valine, leucine, isoleucine, tyrosine and phenylalanine) to cross the blood-brain barrier and reach the brain. In this sense, milk proteins with a high tryptophan content and the highest ratio between tryptophan and LNAA are very useful in promoting sleep. Moreover, milk also provides various micronutrients that help in the transformation of tryptophan into serotonin and melatonin, as well as antioxidant components, anti-inflammatory and bioactive peptides, and recent studies indicate that it favorably modulates the composition of the intestinal microbiota. Studies show that increasing milk consumption, up to the recommended intake and within a correct diet, favors the achievement and maintenance of quality sleep.


Introducción: La inducción del sueño y su calidad son temas de preocupación creciente porque su deterioro afecta a un número elevado de personas y supone un riesgo en su bienestar y calidad de vida y en la salud a largo plazo. Hay diversos factores implicados en el problema, pero la nutrición es uno de ellos y, en concreto, el consumo de leche se ha relacionado frecuentemente con los hábitos de sueño, a veces como factor promotor y otras como inhibidor. Profundizar en el tema es el objeto de la presente revisión. El triptófano, al llegar al cerebro, es la base para la síntesis de serotonina y melatonina, que mejoran la inducción y la calidad del sueño. Pero hay una competencia entre el triptófano y otros aminoácidos neutros de cadena larga (ANCL) (valina, leucina, isoleucina, tirosina y fenilalanina) para cruzar la barrera hematoencefálica y llegar al cerebro. En este sentido, las proteínas de la leche, con elevado contenido en triptófano y la relación más elevada entre triptófano y ANCL, son muy útiles en la promoción del sueño. Por otra parte, la leche también aporta diversos micronutrientes que ayudan en la transformación del triptófano en serotonina y melatonina, así como componentes antioxidantes, antiinflamatorios y péptidos bioactivos, y estudios recientes indican que modula favorablemente la composición de la microbiota intestinal. Los estudios realizados ponen de relieve que aumentar el consumo de leche, hasta el aporte aconsejado y dentro de una alimentación correcta, favorece el conseguir y mantener un sueño de calidad.


Assuntos
Aminoácidos Neutros , Melatonina , Humanos , Triptofano , Serotonina , Qualidade de Vida , Sono
3.
Sci Rep ; 13(1): 4976, 2023 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-36973313

RESUMO

Manipulation of intake of serotonin precursor tryptophan has been exploited to rapidly induce and alleviate depression symptoms. While studies show that this latter effect is dependent on genetic vulnerability to depression, the effect of habitual tryptophan intake in the context of predisposing genetic factors has not been explored. Our aim was to investigate the effect of habitual tryptophan intake on mood symptoms and to determine the effect of risk variants on depression in those with high and low tryptophan intake in the whole genome and specifically in serotonin and kynurenine pathways. 63,277 individuals in the UK Biobank with data on depressive symptoms and tryptophan intake were included. We compared two subpopulations defined by their habitual diet of a low versus a high ratio of tryptophan to other large amino acids (TLR). A modest protective effect of high dietary TLR against depression was found. NPBWR1 among serotonin genes and POLI in kynurenine pathway genes were significantly associated with depression in the low but not in the high TLR group. Pathway-level analyses identified significant associations for both serotonin and kynurenine pathways only in the low TLR group. In addition, significant association was found in the low TLR group between depressive symptoms and biological process related to adult neurogenesis. Our findings demonstrate a markedly distinct genetic risk profile for depression in groups with low and high dietary TLR, with association with serotonin and kynurenine pathway variants only in case of habitual food intake leading to low TLR. Our results confirm the relevance of the serotonin hypothesis in understanding the neurobiological background of depression and highlight the importance of understanding its differential role in the context of environmental variables such as complexity of diet in influencing mental health, pointing towards emerging possibilities of personalised prevention and intervention in mood disorders in those who are genetically vulnerable.


Assuntos
Aminoácidos Neutros , Triptofano , Adulto , Humanos , Triptofano/metabolismo , Cinurenina/metabolismo , Depressão/genética , Serotonina , Dieta
4.
Cell ; 186(9): 1950-1967.e25, 2023 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-36996814

RESUMO

Little is known about the critical metabolic changes that neural cells have to undergo during development and how temporary shifts in this program can influence brain circuitries and behavior. Inspired by the discovery that mutations in SLC7A5, a transporter of metabolically essential large neutral amino acids (LNAAs), lead to autism, we employed metabolomic profiling to study the metabolic states of the cerebral cortex across different developmental stages. We found that the forebrain undergoes significant metabolic remodeling throughout development, with certain groups of metabolites showing stage-specific changes, but what are the consequences of perturbing this metabolic program? By manipulating Slc7a5 expression in neural cells, we found that the metabolism of LNAAs and lipids are interconnected in the cortex. Deletion of Slc7a5 in neurons affects the postnatal metabolic state, leading to a shift in lipid metabolism. Additionally, it causes stage- and cell-type-specific alterations in neuronal activity patterns, resulting in a long-term circuit dysfunction.


Assuntos
Aminoácidos Neutros , Transportador 1 de Aminoácidos Neutros Grandes , Feminino , Humanos , Gravidez , Aminoácidos Neutros/genética , Aminoácidos Neutros/metabolismo , Encéfalo/metabolismo , Transportador 1 de Aminoácidos Neutros Grandes/genética , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Mutação , Neurônios/metabolismo , Animais , Camundongos
5.
Life Sci ; 316: 121402, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36669678

RESUMO

AIMS: Despite its high concentration in pancreatic islets of Langerhans and broad range of antihyperglycemic effects, the route facilitating the import of dietary taurine into pancreatic ß-cell and mechanisms underlying its insulinotropic activity are unclear. We therefore studied the impact of taurine on beta-cell function, alongside that of other small neutral amino acids, L-alanine and L-proline. MAIN METHODS: Pharmacological profiling of insulin secretion was conducted using clonal BRIN BD11 ß-cells, the impact of taurine on the metabolic fate of glucose carbons was assessed using NMR and the findings were verified by real-time imaging of Ca2+ dynamics in the cytosol of primary mouse and human islet beta-cells. KEY FINDINGS: In our hands, taurine, alanine and proline induced secretory responses that were dependent on the plasma membrane depolarisation, import of Ca2+, homeostasis of K+ and Na+ as well as on cell glycolytic and oxidative metabolism. Taurine shifted the balance between the oxidation and anaplerosis towards the latter, in BRIN BD11 beta-cells. Furthermore, the amino acid signalling was significantly attenuated by inhibition of Na+-K+-Cl- symporter (NKCC). SIGNIFICANCE: These data suggest that taurine, like L-alanine and L-proline, acutely induces glucose-dependent insulin-secretory responses by modulating electrogenic Na+ transport, with potential role of intracellular K+ and Cl- in the signal transduction. The acute action delineated would be consistent with antidiabetic potential of dietary taurine supplementation.


Assuntos
Aminoácidos Neutros , Ilhotas Pancreáticas , Camundongos , Animais , Humanos , Insulina/metabolismo , Taurina/farmacologia , Taurina/metabolismo , Aminoácidos Neutros/metabolismo , Aminoácidos Neutros/farmacologia , Linhagem Celular , Ilhotas Pancreáticas/metabolismo , Alanina/farmacologia , Alanina/metabolismo , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Prolina/metabolismo
6.
Nutr. hosp., Supl ; 40(SUP. 2): 12-15, 2023.
Artigo em Espanhol | IBECS | ID: ibc-228687

RESUMO

La inducción del sueño y su calidad son temas de preocupación creciente porque su deterioro afecta a un número elevado de personas y suponeun riesgo en su bienestar y calidad de vida y en la salud a largo plazo. Hay diversos factores implicados en el problema, pero la nutrición es unode ellos y, en concreto, el consumo de leche se ha relacionado frecuentemente con los hábitos de sueño, a veces como factor promotor y otrascomo inhibidor. Profundizar en el tema es el objeto de la presente revisión.El triptófano, al llegar al cerebro, es la base para la síntesis de serotonina y melatonina, que mejoran la inducción y la calidad del sueño. Pero hayuna competencia entre el triptófano y otros aminoácidos neutros de cadena larga (ANCL) (valina, leucina, isoleucina, tirosina y fenilalanina) paracruzar la barrera hematoencefálica y llegar al cerebro. En este sentido, las proteínas de la leche, con elevado contenido en triptófano y la relaciónmás elevada entre triptófano y ANCL, son muy útiles en la promoción del sueño. Por otra parte, la leche también aporta diversos micronutrientesque ayudan en la transformación del triptófano en serotonina y melatonina, así como componentes antioxidantes, antiinflamatorios y péptidosbioactivos, y estudios recientes indican que modula favorablemente la composición de la microbiota intestinal.Los estudios realizados ponen de relieve que aumentar el consumo de leche, hasta el aporte aconsejado y dentro de una alimentación correcta,favorece el conseguir y mantener un sueño de calidad. (AU)


Sleep induction and its quality are issues of growing concern because its deterioration affects a large number of people and poses a risk to theirwell-being and quality of life and long-term health. There are several factors involved in the problem, but nutrition is one of them and in particularmilk consumption has often been linked to sleep habits, sometimes as a promoter and sometimes as an inhibitor. The purpose of this review isto examine the matter further.On reaching the brain, tryptophan is the basis for the synthesis of serotonin and melatonin, which improve the induction and quality of sleep. Butthere is competition between tryptophan and other long-chain neutral amino acids (LNAA) (valine, leucine, isoleucine, tyrosine and phenylalanine)to cross the blood-brain barrier and reach the brain. In this sense, milk proteins with a high tryptophan content and the highest ratio betweentryptophan and LNAA are very useful in promoting sleep.Moreover, milk also provides various micronutrients that help in the transformation of tryptophan into serotonin and melatonin, as well as antioxidantcomponents, anti-inflammatory and bioactive peptides, and recent studies indicate that it favorably modulates the composition of the intestinalmicrobiota. Studies show that increasing milk consumption, up to the recommended intake and within a correct diet, favors the achievementand maintenance of quality sleep. (AU)


Assuntos
Humanos , Leite , Triptofano , Aminoácidos Neutros , Serotonina , Melatonina , Sono , Qualidade de Vida
7.
J Psychiatry Neurosci ; 47(5): E351-E358, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36195339

RESUMO

BACKGROUND: It has been suggested that individuals predisposed to or recovered from anorexia nervosa experience a hyperserotonergic state associated with anxiety that might be mitigated by restricted food intake, because diminished levels of the tryptophan precursor lower the central availability of serotonin (5-HT). At the neural level, the salience network is a system of functionally connected brain regions; it has been closely associated with 5-HT functioning and mental disorders (including anorexia nervosa). The aim of the present study was to investigate the effect on the salience network of a temporary dietary manipulation of 5-HT synthesis in patients with anorexia nervosa. METHODS: In this double-blind crossover study, we obtained data on resting-state functional connectivity from 22 weight-recovered female patients with a history of anorexia nervosa, and 22 age-matched female healthy controls. The study procedure included acute tryptophan depletion (a dietary intervention that lowers the central 5-HT synthesis rate) and a sham condition. RESULTS: We identified an interaction of group and experimental condition in resting-state functional connectivity between the salience network and the orbitofrontal cortex extending to the frontal pole (F 1,42 = 12.52; p FWE = 0.026). Further analysis revealed increased resting-state functional connectivity during acute tryptophan depletion in patients recovered from anorexia nervosa, resembling that of healthy controls during the sham condition (T 42 = -0.66; p = 0.51). LIMITATIONS: The effect of acute tryptophan depletion on the central availability of 5-HT can be judged only indirectly using plasma ratios of tryptophan to large neutral amino acids. Moreover, the definition of anorexia nervosa recovery varies widely across studies, limiting comparability. CONCLUSION: Taken together, our findings support the notion of 5-HT dysregulation in anorexia nervosa and indicate that reduced 5-HT synthesis and availability during acute tryptophan depletion (and possibly with food restriction) may balance hyperserotonergic functioning and the associated resting-state functional connectivity of the salience network.


Assuntos
Aminoácidos Neutros , Anorexia Nervosa , Feminino , Humanos , Anorexia Nervosa/diagnóstico por imagem , Mapeamento Encefálico , Estudos Cross-Over , Método Duplo-Cego , Imageamento por Ressonância Magnética , Vias Neurais/diagnóstico por imagem , Serotonina , Triptofano
8.
J Cell Mol Med ; 26(20): 5246-5256, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36071551

RESUMO

L-type amino acid transporter 1 (LAT1; SLC7A5), which preferentially transports large neutral amino acids, is highly upregulated in various cancers. LAT1 supplies cancer cells with amino acids as substrates for enhanced biosynthetic and bioenergetic reactions and stimulates signalling networks involved in the regulation of survival, growth and proliferation. LAT1 inhibitors show anti-cancer effects and a representative compound, JPH203, is under clinical evaluation. However, pharmacological impacts of LAT1 inhibition on the cellular amino acid transport and the translational activity in cancer cells that are conceptually pivotal for its anti-proliferative effect have not been elucidated yet. Here, we demonstrated that JPH203 drastically inhibits the transport of all the large neutral amino acids in pancreatic ductal adenocarcinoma cells. The inhibitory effects of JPH203 were observed even in competition with high concentrations of amino acids in a cell culture medium. The analyses of the nutrient-sensing mTORC1 and GAAC pathways and the protein synthesis activity revealed that JPH203 downregulates the global translation. This study demonstrates a predominant contribution of LAT1 to the transport of large neutral amino acids in cancer cells and the suppression of protein synthesis by JPH203 supposed to underly its broad anti-proliferative effects across various types of cancer cells.


Assuntos
Aminoácidos Neutros , Neoplasias , Aminoácidos , Linhagem Celular Tumoral , Transportador 1 de Aminoácidos Neutros Grandes/genética , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo
9.
Am J Physiol Renal Physiol ; 323(4): F455-F467, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35979966

RESUMO

B0AT1 (Slc6a19) mediates absorption of neutral amino acids in the small intestine and in the kidneys, where it is primarily expressed in early proximal tubules (S1-S2). To determine the role of B0AT1 in nephropathy induced by aristolochic acid (AA), which targets the proximal tubule, littermate female B0AT1-deficient (Slc6a19-/-), heterozygous (Slc6a19+/-), and wild-type (WT) mice were administered AA (10 mg/kg ip) or vehicle every 3 days for 3 wk, and analyses were performed after the last injection or 3 wk later. Vehicle-treated mice lacking Slc6a19 showed normal body and kidney weight and plasma creatinine versus WT mice. The urinary glucose-to-creatinine ratio (UGCR) and urinary albumin-to-creatinine ratio (UACR) were two to four times higher in vehicle-treated Slc6a19-/- versus WT mice, associated with lesser expression of early proximal transporters Na+-glucose cotransporter 2 and megalin, respectively. AA caused tubular injury independently of B0AT1, including robust increases in cortical mRNA expression of p53, p21, and hepatitis A virus cellular receptor 1 (Havcr1), downregulation of related proximal tubule amino acid transporters B0AT2 (Slc6a15), B0AT3 (Slc6a18), and Slc7a9, and modest histological tubular damage and a rise in plasma creatinine. Absence of B0AT1, however, attenuated AA-induced cortical upregulation of mRNA markers of senescence (p16), inflammation [lipocalin 2 (Lcn2), C-C motif chemokine ligand 2 (Ccl2), and C-C motif chemokine receptor 2 (Ccr2)], and fibrosis [tissue inhibitor of metallopeptidase 1 (Timp1), transforming growth factor-ß1 (Tgfb1), and collagen type I-α1 (Col1a1)], associated with lesser fibrosis staining, lesser suppression of proximal tubular organic anion transporter 1, restoration of Na+-glucose cotransporter 2 expression, and prevention of the AA-induced fivefold increase in the urinary albumin-to-creatinine ratio observed in WT mice. The data suggest that proximal tubular B0AT1 is important for the physiology of renal glucose and albumin retention but potentially deleterious for the kidney response following AA-induced kidney injury.NEW & NOTEWORTHY Based on insights from studies manipulating glucose transport, the hypothesis has been proposed that inhibiting intestinal uptake or renal reabsorption of energy substrates has unique therapeutic potential to improve metabolic disease and kidney outcome in response to injury. The present study takes this idea to B0AT1, the major transporter for neutral amino acids in the intestine and kidney, and shows that its absence attenuates aristolochic acid-induced nephropathy.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros , Aminoácidos Neutros , Ácidos Aristolóquicos , Nefropatias , Albuminas/metabolismo , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Animais , Ácidos Aristolóquicos/toxicidade , Creatinina , Feminino , Fibrose , Glucose , Nefropatias/induzido quimicamente , Nefropatias/genética , Camundongos , RNA Mensageiro
10.
J Biol Chem ; 298(8): 102178, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35752361

RESUMO

The solute carrier 1A family comprises a group of membrane proteins that act as dual-function amino acid transporters and chloride (Cl-) channels and includes the alanine serine cysteine transporters (ASCTs) as well as the excitatory amino acid transporters. ASCT2 is regarded as a promising target for cancer therapy, as it can transport glutamine and other neutral amino acids into cells and is upregulated in a range of solid tumors. The compound L-γ-glutamyl-p-nitroanilide (GPNA) is widely used in studies probing the role of ASCT2 in cancer biology; however, the mechanism by which GPNA inhibits ASCT2 is not entirely clear. Here, we used electrophysiology and radiolabelled flux assays to demonstrate that GPNA activates the Cl- conductance of ASCT2 to the same extent as a transported substrate, whilst not undergoing the full transport cycle. This is a previously unreported phenomenon for inhibitors of the solute carrier 1A family but corroborates a body of literature suggesting that the structural requirements for transport are distinct from those for Cl- channel formation. We also show that in addition to its currently known targets, GPNA inhibits several of the excitatory amino acid transporters. Together, these findings raise questions about the true mechanisms of its anticancer effects.


Assuntos
Aminoácidos Neutros , Neoplasias , Sistema ASC de Transporte de Aminoácidos/genética , Sistema ASC de Transporte de Aminoácidos/metabolismo , Sistemas de Transporte de Aminoácidos , Glutamina/metabolismo , Humanos , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo , Neoplasias/metabolismo
11.
Trends Endocrinol Metab ; 33(7): 463-480, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35508517

RESUMO

5-Aminovaleric acid betaine (5-AVAB) is a trimethylated compound associated with the gut microbiota, potentially produced endogenously, and related to the dietary intake of certain foods such as whole grains. 5-AVAB accumulates within the metabolically active tissues and has been typically found in higher concentrations in the heart, muscle, and brown adipose tissue. Furthermore, 5-AVAB has been associated with positive health effects such as fetal brain development, insulin secretion, and reduced cancer risk. However, it also has been linked with some negative health outcomes such as cardiovascular disease and fatty liver disease. At the cellular level, 5-AVAB can influence cellular energy metabolism by reducing ß-oxidation of fatty acids. This review will focus on the metabolic role of 5-AVAB with respect to both physiology and pathology. Moreover, the analytics and origin of 5-AVAB and related compounds will be reviewed.


Assuntos
Aminoácidos Neutros , Microbioma Gastrointestinal , Betaína/metabolismo , Dieta , Humanos
12.
Nat Commun ; 13(1): 1757, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35365608

RESUMO

Numerous studies found intestinal microbiota alterations which are thought to affect the development of various diseases through the production of gut-derived metabolites. However, the specific metabolites and their pathophysiological contribution to cardiac hypertrophy or heart failure progression still remain unclear. N,N,N-trimethyl-5-aminovaleric acid (TMAVA), derived from trimethyllysine through the gut microbiota, was elevated with gradually increased risk of cardiac mortality and transplantation in a prospective heart failure cohort (n = 1647). TMAVA treatment aggravated cardiac hypertrophy and dysfunction in high-fat diet-fed mice. Decreased fatty acid oxidation (FAO) is a hallmark of metabolic reprogramming in the diseased heart and contributes to impaired myocardial energetics and contractile dysfunction. Proteomics uncovered that TMAVA disturbed cardiac energy metabolism, leading to inhibition of FAO and myocardial lipid accumulation. TMAVA treatment altered mitochondrial ultrastructure, respiration and FAO and inhibited carnitine metabolism. Mice with γ-butyrobetaine hydroxylase (BBOX) deficiency displayed a similar cardiac hypertrophy phenotype, indicating that TMAVA functions through BBOX. Finally, exogenous carnitine supplementation reversed TMAVA induced cardiac hypertrophy. These data suggest that the gut microbiota-derived TMAVA is a key determinant for the development of cardiac hypertrophy through inhibition of carnitine synthesis and subsequent FAO.


Assuntos
Microbioma Gastrointestinal , Aminoácidos Neutros , Animais , Cardiomegalia/metabolismo , Ácidos Graxos/metabolismo , Humanos , Camundongos , Estudos Prospectivos , Valeratos
13.
Biomed Pharmacother ; 149: 112845, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35339828

RESUMO

There has been a renewed interest in the potential use of psychedelics for the treatment of psychiatric conditions. Nevertheless, little is known about the mechanism of action and molecular pathways influenced by ayahuasca use in humans. Therefore, for the first time, our study aims to investigate the human metabolomics signature after consumption of a psychedelic, ayahuasca, and its connection with both the psychedelic-induced subjective effects and the plasma concentrations of ayahuasca alkaloids. Plasma samples of 23 individuals were collected both before and after ayahuasca consumption. Samples were analysed through targeted metabolomics and further integrated with subjective ratings of the ayahuasca experience (i.e., using the 5-Dimension Altered States of Consciousness Rating Scale [ASC]), and plasma ayahuasca-alkaloids using integrated network analysis. Metabolic pathways enrichment analysis using diffusion algorithms for specific KEGG modules was performed on the metabolic output. Compared to baseline, the consumption of ayahuasca increased N-acyl-ethanolamine endocannabinoids, decreased 2-acyl-glycerol endocannabinoids, and altered several large-neutral amino acids (LNAAs). Integrated network results indicated that most of the LNAAs were inversely associated with 9 out of the 11 subscales of the ASC, except for tryptophan which was positively associated. Several endocannabinoids and hexosylceramides were directly associated with the ayahuasca alkaloids. Enrichment analysis confirmed dysregulation in several pathways involved in neurotransmission such as serotonin and dopamine synthesis. In conclusion, a crosstalk between the circulating LNAAs and the subjective effects is suggested, which is independent of the alkaloid concentrations and provides insights into the specific metabolic fingerprint and mechanism of action underlying ayahuasca experiences.


Assuntos
Aminoácidos Neutros , Banisteriopsis , Endocanabinoides/farmacologia , Alucinógenos , Banisteriopsis/química , Endocanabinoides/química , Alucinógenos/farmacologia , Humanos , Metabolômica
14.
Mol Genet Metab ; 135(1): 27-34, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34974973

RESUMO

BACKGROUND: Large neutral amino acid (LNAA) treatment has been suggested as alternative to the burdensome severe phenylalanine-restricted diet. While its working mechanisms and optimal composition have recently been further elucidated, the question whether LNAA treatment requires the natural protein-restricted diet, has still remained. OBJECTIVE: Firstly, to determine whether an additional liberalized natural protein-restricted diet could further improve brain amino acid and monoamine concentrations in phenylketonuria mice on LNAA treatment. Secondly, to compare the effect between LNAA treatment (without natural protein) restriction and different levels of a phenylalanine-restricted diet (without LNAA treatment) on brain amino acid and monoamine concentrations in phenylketonuria mice. DESIGN: BTBR Pah-enu2 mice were divided into two experimental groups that received LNAA treatment with either an unrestricted or semi phenylalanine-restricted diet. Control groups included Pah-enu2 mice on the AIN-93 M diet, a severe or semi phenylalanine-restricted diet without LNAA treatment, and wild-type mice receiving the AIN-93 M diet. After ten weeks, brain and plasma samples were collected to measure amino acid profiles and brain monoaminergic neurotransmitter concentrations. RESULTS: Adding a semi phenylalanine-restricted diet to LNAA treatment resulted in lower plasma phenylalanine but comparable brain amino acid and monoamine concentrations as compared to LNAA treatment (without phenylalanine restriction). LNAA treatment (without phenylalanine restriction) resulted in comparable brain monoamine but higher brain phenylalanine concentrations compared to the severe phenylalanine-restricted diet, and significantly higher brain monoamine but comparable phenylalanine concentrations as compared to the semi phenylalanine-restricted diet. CONCLUSIONS: Present results in PKU mice suggest that LNAA treatment in PKU patients does not need the phenylalanine-restricted diet. In PKU mice, LNAA treatment (without phenylalanine restriction) was comparable to a severe phenylalanine-restricted diet with respect to brain monoamine concentrations, notwithstanding the higher plasma and brain phenylalanine concentrations, and resulted in comparable brain phenylalanine concentrations as on a semi phenylalanine-restricted diet.


Assuntos
Aminoácidos Neutros , Fenilcetonúrias , Animais , Suplementos Nutricionais , Modelos Animais de Doenças , Humanos , Camundongos , Fenilalanina , Fenilcetonúrias/tratamento farmacológico , Fenilcetonúrias/metabolismo
15.
Protein J ; 41(1): 79-87, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35064867

RESUMO

In our previous study, a 3D structure of LNAA66 model protein containing 4-5 α-helices, high large neutral amino acids (LNAA) and lacking phenylalanine was designed, refined, expressed in Pichia pastoris and confirmed by Western blotting. Here the study is focused on the characterization of the expressed and purified recombinant LNAA66 protein. The results revealed that the expressed protein had 68.59% of LNAA enrichment, containing 41.6% of α-helix, 50.4% turns and 8% ß-sheet, which are as per the in silico designed protein. The LC-ESI-MS/MS results confirmed the recombinant protein by identifying the first 30 N-terminal amino acids with a sequence coverage of ~ 29%. The protein was digested entirely into smaller molecular weight fragments when treated with digestive enzymes mimicking the human GI tract digestion, which indicated complete digestibility of the protein. These results suggest that the protein can be utilized for the envisioned application of dietary treatment for phenylketonuria.


Assuntos
Aminoácidos Neutros , Fenilcetonúrias , Humanos , Fenilalanina , Fenilcetonúrias/genética , Fenilcetonúrias/metabolismo , Pichia/genética , Proteínas Recombinantes/genética , Espectrometria de Massas em Tandem
16.
Proc Natl Acad Sci U S A ; 118(49)2021 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-34848541

RESUMO

Despite having similar structures, each member of the heteromeric amino acid transporter (HAT) family shows exquisite preference for the exchange of certain amino acids. Substrate specificity determines the physiological function of each HAT and their role in human diseases. However, HAT transport preference for some amino acids over others is not yet fully understood. Using cryo-electron microscopy of apo human LAT2/CD98hc and a multidisciplinary approach, we elucidate key molecular determinants governing neutral amino acid specificity in HATs. A few residues in the substrate-binding pocket determine substrate preference. Here, we describe mutations that interconvert the substrate profiles of LAT2/CD98hc, LAT1/CD98hc, and Asc1/CD98hc. In addition, a region far from the substrate-binding pocket critically influences the conformation of the substrate-binding site and substrate preference. This region accumulates mutations that alter substrate specificity and cause hearing loss and cataracts. Here, we uncover molecular mechanisms governing substrate specificity within the HAT family of neutral amino acid transporters and provide the structural bases for mutations in LAT2/CD98hc that alter substrate specificity and that are associated with several pathologies.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/fisiologia , Especificidade por Substrato/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sistemas de Transporte de Aminoácidos/metabolismo , Sistemas de Transporte de Aminoácidos/fisiologia , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Aminoácidos/metabolismo , Aminoácidos Neutros/metabolismo , Transporte Biológico/fisiologia , Microscopia Crioeletrônica/métodos , Cadeia Pesada da Proteína-1 Reguladora de Fusão/metabolismo , Células HeLa , Humanos , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Domínios Proteicos , Relação Estrutura-Atividade
17.
Nutrients ; 13(11)2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34836270

RESUMO

The mainstay of phenylketonuria treatment is a low protein diet, supplemented with phenylalanine (Phe)-free protein substitutes and micronutrients. Adhering to this diet is challenging, and even patients with good metabolic control who follow the dietary prescriptions in everyday life ignore the recommendations occasionally. The present study explores the ability of slow-release large neutral amino acids (srLNAAs) to prevent Phe increase following a Phe dietary load. Fourteen phenylketonuric patients aged ≥13 years were enrolled in a 6-week protocol. Oral acute Phe loads of 250 and 500 mg were added to the evening meal together with srLNAAs (0.5 gr/kg). Phe and tyrosine were dosed before dinner, 2h-after dinner, and after the overnight fast. After oral Phe loads, mean plasma Phe remained stable and below 600 µmol/L. No Phe peaks were registered. Tyrosine levels significantly increased, and Phe/Tyrosine ratio decreased. No adverse events were registered. In conclusion, a single oral administration of srLNAAs at the dose of 0.5 gr/kg is effective in maintaining stable plasma Phe during acute oral loads with Phe-containing food and may be added to the dietetic scheme in situations in which patients with generally good adherence to diet foresee a higher than prescribed Phe intake due to their commitments.


Assuntos
Aminoácidos Neutros/administração & dosagem , Suplementos Nutricionais , Fenilalanina/administração & dosagem , Fenilcetonúrias/tratamento farmacológico , Adolescente , Adulto , Aminoácidos/administração & dosagem , Aminoácidos Neutros/sangue , Aminoácidos Neutros/uso terapêutico , Dieta , Feminino , Humanos , Itália , Masculino , Micronutrientes/uso terapêutico , Fenilalanina/sangue , Fenilalanina/uso terapêutico , Fenilcetonúrias/sangue , Tirosina/sangue , Tirosina/uso terapêutico , Adulto Jovem
18.
Function (Oxf) ; 2(4): zqab027, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34847569

RESUMO

The SARS-CoV-2 receptor, angiotensin-converting enzyme-2 (ACE2), is expressed at levels of greatest magnitude in the small intestine as compared with all other human tissues. Enterocyte ACE2 is coexpressed as the apical membrane trafficking partner obligatory for expression and activity of the B0AT1 sodium-dependent neutral amino acid transporter. These components are assembled as an [ACE2:B0AT1]2 dimer-of-heterodimers quaternary complex that putatively steers SARS-CoV-2 tropism in the gastrointestinal (GI) tract. GI clinical symptomology is reported in about half of COVID-19 patients, and can be accompanied by gut shedding of virion particles. We hypothesized that within this 4-mer structural complex, each [ACE2:B0AT1] heterodimer pair constitutes a physiological "functional unit." This was confirmed experimentally by employing purified lyophilized enterocyte brush border membrane vesicles exposed to increasing doses of high-energy electron radiation from a 16 MeV linear accelerator. Based on radiation target theory, the results indicated the presence of Na+-dependent neutral amino acid influx transport activity functional unit with target size molecular weight 183.7 ± 16.8 kDa in situ in intact apical membranes. Each thermodynamically stabilized [ACE2:B0AT1] heterodimer functional unit manifests the transport activity within the whole ∼345 kDa [ACE2:B0AT1]2 dimer-of-heterodimers quaternary structural complex. The results are consistent with our prior molecular docking modeling and gut-lung axis approaches to understanding COVID-19. These findings advance understanding the physiology of B0AT1 interaction with ACE2 in the gut, and thereby contribute to translational developments designed to treat or mitigate COVID-19 variant outbreaks and/or GI symptom persistence in long-haul postacute sequelae of SARS-CoV-2.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros , Aminoácidos Neutros , COVID-19 , Humanos , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Simulação de Acoplamento Molecular , Peptidil Dipeptidase A/metabolismo , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Sistemas de Transporte de Aminoácidos
20.
Fish Physiol Biochem ; 47(5): 1507-1525, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34338990

RESUMO

System b0,+ absorbs lysine, arginine, ornithine, and cystine, as well as some (large) neutral amino acids in the mammalian kidney and intestine. It is a heteromeric amino acid transporter made of the heavy subunit SLC3A1/rBAT and the light subunit SLC7A9/b0,+AT. Mutations in these two genes can cause cystinuria in mammals. To extend information on this transport system to teleost fish, we focused on the slc3a1 and slc7a9 genes by performing comparative and phylogenetic sequence analysis, investigating gene conservation during evolution (synteny), and defining early expression patterns during zebrafish (Danio rerio) development. Notably, we found that slc3a1 and slc7a9 are non-duplicated in the zebrafish genome. Whole-mount in situ hybridization detected co-localized expression of slc3a1 and slc7a9 in pronephric ducts at 24 h post-fertilization and in the proximal convoluted tubule at 3 days post-fertilization (dpf). Notably, both the genes showed co-localized expression in epithelial cells in the gut primordium at 3 dpf and in the intestine at 5 dpf (onset of exogenous feeding). Taken together, these results highlight the value of slc3a1 and slc7a9 as markers of zebrafish kidney and intestine development and show promise for establishing new zebrafish tools that can aid in the rapid screening(s) of substrates. Importantly, such studies will help clarify the complex interplay between the absorption of dibasic amino acids, cystine, and (large) neutral amino acids and the effect(s) of such nutrients on organismal growth.


Assuntos
Sistemas de Transporte de Aminoácidos Básicos , Aminoácidos Neutros , Peixe-Zebra/fisiologia , Sistemas de Transporte de Aminoácidos Básicos/genética , Animais , Cistina/metabolismo , Glicoproteínas , Filogenia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
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