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Cancer Cell Feb 2020Metabolic pathways must be adapted to support cell processes required for transformation and cancer progression. Amino acid metabolism is deregulated in many cancers,... (Review)
Review
Metabolic pathways must be adapted to support cell processes required for transformation and cancer progression. Amino acid metabolism is deregulated in many cancers, with changes in branched-chain amino acid metabolism specifically affecting cancer cell state as well as systemic metabolism in individuals with malignancy. This review highlights key concepts surrounding the current understanding of branched-chain amino acid metabolism and its role in cancer.
Topics: Amino Acids, Branched-Chain; Epigenomics; Humans; Intracellular Signaling Peptides and Proteins; Isoleucine; Leucine; Neoplasms
PubMed: 32049045
DOI: 10.1016/j.ccell.2019.12.011 -
Pharmacological Research Jan 2023Fibrosis is a common pathological feature of organ diseases resulting from excessive production of extracellular matrix, which accounts for significant morbidity and... (Review)
Review
Fibrosis is a common pathological feature of organ diseases resulting from excessive production of extracellular matrix, which accounts for significant morbidity and mortality. However, there is currently no effective treatment targeting fibrogenesis. Recently, metabolic alterations are increasingly considered as essential factors underlying fibrogenesis, and especially research on metabolic regulation of amino acids is flourishing. Among them, branched-chain amino acids (BCAAs) are the most abundant essential amino acids, including leucine, isoleucine and valine, which play significant roles in the substance and energy metabolism and their regulation. Dysregulation of BCAAs metabolism has been proven to contribute to numerous diseases. In this review, we summarize the metabolic regulation of fibrosis and the changes in BCAAs metabolism secondary to fibrosis. We also review the effects and mechanisms of the BCAAs intervention, and its therapeutic targeting in hepatic, renal and cardiac fibrosis, with a focus on the fibrosis in liver and associated hepatocellular carcinoma.
Topics: Humans; Amino Acids, Branched-Chain; Isoleucine; Valine; Leucine; Fibrosis
PubMed: 36503000
DOI: 10.1016/j.phrs.2022.106604 -
Aging Cell Jun 2022The proportion of humans suffering from age-related diseases is increasing around the world, and creative solutions are needed to promote healthy longevity. Recent work... (Review)
Review
The proportion of humans suffering from age-related diseases is increasing around the world, and creative solutions are needed to promote healthy longevity. Recent work has clearly shown that a calorie is not just a calorie-and that low protein diets are associated with reduced mortality in humans and promote metabolic health and extended lifespan in rodents. Many of the benefits of protein restriction on metabolism and aging are the result of decreased consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we discuss the emerging evidence that BCAAs are critical modulators of healthy metabolism and longevity in rodents and humans, as well as the physiological and molecular mechanisms that may drive the benefits of BCAA restriction. Our results illustrate that protein quality-the specific composition of dietary protein-may be a previously unappreciated driver of metabolic dysfunction and that reducing dietary BCAAs may be a promising new approach to delay and prevent diseases of aging.
Topics: Amino Acids, Branched-Chain; Diet, Protein-Restricted; Isoleucine; Leucine
PubMed: 35526271
DOI: 10.1111/acel.13626 -
International Journal of Molecular... Nov 2020The molecular design of short peptides to achieve a tailor-made functional architecture has attracted attention during the past decade but remains challenging as a...
The molecular design of short peptides to achieve a tailor-made functional architecture has attracted attention during the past decade but remains challenging as a result of insufficient understanding of the relationship between peptide sequence and assembled supramolecular structures. We report a hybrid-resolution model to computationally explore the sequence-structure relationship of self-assembly for tripeptides containing only phenylalanine and isoleucine. We found that all these tripeptides have a tendency to assemble into nanofibers composed of laterally associated filaments. Molecular arrangements within the assemblies are diverse and vary depending on the sequences. This structural diversity originates from (1) distinct conformations of peptide building blocks that lead to different surface geometries of the filaments and (2) unique sidechain arrangements at the filament interfaces for each sequence. Many conformations are available for tripeptides in solution, but only an extended β-strand and another resembling a right-handed turn are observed in assemblies. It was found that the sequence dependence of these conformations and the packing of resulting filaments are determined by multiple competing noncovalent forces, with hydrophobic interactions involving Phe being particularly important. The sequence pattern for each type of assembly conformation and packing has been identified. These results highlight the importance of the interplay between conformation, molecular packing, and sequences for determining detailed nanostructures of peptides and provide a detailed insight to support a more precise design of peptide-based nanomaterials.
Topics: Amino Acid Sequence; Drug Design; Hydrophobic and Hydrophilic Interactions; Isoleucine; Microscopy, Electron, Scanning; Molecular Dynamics Simulation; Nanofibers; Nanotechnology; Oligopeptides; Phenylalanine; Protein Conformation; Protein Engineering; Protein Multimerization
PubMed: 33182629
DOI: 10.3390/ijms21228431 -
Chemical & Pharmaceutical Bulletin Nov 2023D-Amino acids, which are present in small amounts in living organisms, are responsible for a variety of physiological functions. Some bioactive/biomolecular peptides...
D-Amino acids, which are present in small amounts in living organisms, are responsible for a variety of physiological functions. Some bioactive/biomolecular peptides also contain D-amino acids in their sequences; such peptides express different functions than peptides composed only of L-form amino acids. Among the 20 amino acids that make up proteins, threonine (Thr) and isoleucine (Ile) have two chiral carbons and thus have two enantiomers and diastereomers. These stereoisomers have been previously analyzed through HPLC using chiral columns or chiral resolution labeling reagents. However, the separation and identification of these stereoisomers are highly laborious and complicated. Herein, we propose an analytical method for the separation and identification of Ile stereoisomers through LC-MS using our original chiral resolution labeling reagent, 1-fluoro-2,4-dinitrophenyl-5-L-valine-N,N-dimethylethylenediamine-amide (L-FDVDA) and a PBr column packed with pentabromobenzyl-modified silica gel. Twenty DL-amino acids including Thr stereoisomers (41 amino acids including glycine) were separated and identified using C column. Ile stereoisomers could be separated using not a C column but a PBr column. Additionally, we showed that peptides containing Thr and Ile stereoisomers can be accurately detected through labeling with L-FDVDA.
Topics: Isoleucine; Stereoisomerism; Indicators and Reagents; Amino Acids; Chromatography, High Pressure Liquid; Amines; Peptides
PubMed: 37612063
DOI: 10.1248/cpb.c23-00439 -
Frontiers in Immunology 2022Immunometabolism has been the focus of extensive research over the last years, especially in terms of augmenting anti-tumor immune responses. Regulatory T cells (Tregs)... (Review)
Review
Immunometabolism has been the focus of extensive research over the last years, especially in terms of augmenting anti-tumor immune responses. Regulatory T cells (Tregs) are a subset of CD4 T cells, which have been known for their immunosuppressive roles in various conditions including anti-tumor immune responses. Even though several studies aimed to target Tregs in the tumor microenvironment (TME), such approaches generally result in the inhibition of the Tregs non-specifically, which may cause immunopathologies such as autoimmunity. Therefore, specifically targeting the Tregs in the TME would be vital in terms of achieving a successful and specific treatment. Recently, an association between Tregs and isoleucine, which represents one type of branched-chain amino acids (BCAAs), has been demonstrated. The presence of isoleucine seems to affect majorly Tregs, rather than conventional T cells. Considering the fact that Tregs bear several distinct metabolic features in the TME, targeting their immunometabolic pathways may be a rational approach. In this Review, we provide a general overview on the potential distinct metabolic features of T cells, especially focusing on BCAAs in Tregs as well as in their subtypes.
Topics: Amino Acids, Branched-Chain; Humans; Isoleucine; Neoplasms; T-Lymphocytes, Regulatory; Tumor Microenvironment
PubMed: 35812393
DOI: 10.3389/fimmu.2022.886822 -
Physiological Research Jul 2021The article shows that skeletal muscle plays a dominant role in the catabolism of branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) and the... (Review)
Review
The role of skeletal muscle in the pathogenesis of altered concentrations of branched-chain amino acids (valine, leucine, and isoleucine) in liver cirrhosis, diabetes, and other diseases.
The article shows that skeletal muscle plays a dominant role in the catabolism of branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) and the pathogenesis of their decreased concentrations in liver cirrhosis, increased concentrations in diabetes, and nonspecific alterations in disorders with signs of systemic inflammatory response syndrome (SIRS), such as burn injury and sepsis. The main role of skeletal muscle in BCAA catabolism is due to its mass and high activity of BCAA aminotransferase, which is absent in the liver. Decreased BCAA levels in liver cirrhosis are due to increased use of the BCAA as a donor of amino group to alpha-ketoglutarate for synthesis of glutamate, which in muscles acts as a substrate for ammonia detoxification to glutamine. Increased BCAA levels in diabetes are due to alterations in glycolysis, citric acid cycle, and fatty acid oxidation. Decreased glycolysis and citric cycle activity impair BCAA transamination to branched-chain keto acids (BCKAs) due to decreased supply of amino group acceptors (alpha-ketoglutarate, pyruvate, and oxaloacetate); increased fatty acid oxidation inhibits flux of BCKA through BCKA dehydrogenase due to increased supply of NADH and acyl-CoAs. Alterations in BCAA levels in disorders with SIRS are inconsistent due to contradictory effects of SIRS on muscles. Specifically, increased proteolysis and insulin resistance tend to increase BCAA levels, whereas activation of BCKA dehydrogenase and glutamine synthesis tend to decrease BCAA levels. The studies are needed to elucidate the role of alterations in BCAA metabolism and the effects of BCAA supplementation on the outcomes of specific diseases.
Topics: Amino Acids, Branched-Chain; Animals; Diabetes Mellitus; Humans; Isoleucine; Leucine; Liver Cirrhosis; Metabolic Diseases; Muscle, Skeletal; Valine
PubMed: 33982576
DOI: 10.33549/physiolres.934648 -
Oxidative Medicine and Cellular... 2022Leucine and isoleucine possess antioxidative and anti-inflammatory properties. However, their underlying protective mechanisms against oxidative damage remain unknown....
Leucine and isoleucine possess antioxidative and anti-inflammatory properties. However, their underlying protective mechanisms against oxidative damage remain unknown. Therefore, in this study, the protective mechanism of leucine and isoleucine against HO-induced oxidative damage in a bovine mammary epithelial cell lines (MAC-T cells) were investigated. Briefly, MAC-T cells exposed or free to HO were incubated with different combinations of leucine and isoleucine. The cellular relative proliferation rate and viability, oxidative stress indicators, and inflammatory factors were determined by specific commercial kits. The genes related to barrier functions was measured by real-time quantitative PCR. The protein expression differences were explored by 4D label-free quantitative proteomic analyses and validated by parallel reaction monitoring. The results revealed that leucine and isoleucine increased cell proliferation, total antioxidant status (TAS), and the relative mRNA expression of occludin, as well as decreased malondialdehyde (MDA), total oxidant status (TOS)/TAS, IL-6, IL-1, and TOS. When leucine and isoleucine were combined, MDA, TOS/TAS, and the relative mRNA expression levels of claudin-1, occludin, and zonula occludens-1 increased when compared to leucine or isoleucine alone. Proteomics analyses revealed that leucine significantly upregulated the propanoate metabolism; valine, leucine, and isoleucine degradation; and thermogenesis pathways, whereas isoleucine significantly upregulated the peroxisome and propanoate metabolism pathways. In conclusion, leucine protected MAC-T cells from HO-induced oxidative stress by generating more ATP to supplement energy demands, and isoleucine improved the deficit in peroxisome transport and promoted acetyl-CoA production. The findings of this study enhance our understanding of the protective mechanisms of leucine and isoleucine against oxidative damage.
Topics: Animals; Cattle; Epithelial Cells; Hydrogen Peroxide; Isoleucine; Leucine; Oxidative Stress; Proteomics
PubMed: 35360198
DOI: 10.1155/2022/4013575 -
The Plant Journal : For Cell and... May 2022Jasmonoyl-isoleucine (JA-Ile) is a key signaling molecule that activates jasmonate-regulated flower development and the wound stress response. For years, JASMONATE...
Jasmonoyl-isoleucine (JA-Ile) is a key signaling molecule that activates jasmonate-regulated flower development and the wound stress response. For years, JASMONATE RESISTANT1 (JAR1) has been the sole jasmonoyl-amino acid synthetase known to conjugate jasmonic acid (JA) to isoleucine, and the source of persisting JA-Ile in jar1 knockout mutants has remained elusive until now. Here we demonstrate through recombinant enzyme assays and loss-of-function mutant analyses that AtGH3.10 functions as a JA-amido synthetase. Recombinant AtGH3.10 could conjugate JA to isoleucine, alanine, leucine, methionine, and valine. The JA-Ile accumulation in the gh3.10-2 jar1-11 double mutant was nearly eliminated in the leaves and flower buds while its catabolism derivative 12OH-JA-Ile was undetected in the flower buds and unwounded leaves. Residual levels of JA-Ile, JA-Ala, and JA-Val were nonetheless detected in gh3.10-2 jar1-11, suggesting the activities of similar promiscuous enzymes. Upon wounding, the accumulation of JA-Ile and 12OH-JA-Ile and the expression of JA-responsive genes OXOPHYTODIENOIC ACID REDUCTASE3 and JASMONATE ZIM-DOMAIN1 observed in WT, gh3.10-1, and jar1-11 leaves were effectively abolished in gh3.10-2 jar1-11. Additionally, an increased proportion of undeveloped siliques associated with retarded stamen development was observed in gh3.10-2 jar1-11. These findings conclusively show that AtGH3.10 contributes to JA-amino acid biosynthesis and functions partially redundantly with AtJAR1 in sustaining flower development and the wound stress response in Arabidopsis.
Topics: Amino Acids; Arabidopsis; Arabidopsis Proteins; Cyclopentanes; Isoleucine; Ligases; Oxylipins
PubMed: 35247019
DOI: 10.1111/tpj.15724 -
PloS One 2022In a previous study with LSL-LITE layers (-23 to 30-week-old), isoleucine at 0.72% and 0.84% produced values for FCR at 1.45 and 1.44, respectively and shared...
In a previous study with LSL-LITE layers (-23 to 30-week-old), isoleucine at 0.72% and 0.84% produced values for FCR at 1.45 and 1.44, respectively and shared significance with 0.78% isoleucine (1.49). Considering that FCR is an important standard in the poultry industry due to the cost for adding feed ingredients such as synthetic amino acids and the low FCR of 1.45, 0.72% isoleucine was chosen for further study with LSL-LITE layers (n = 490 at 33- to 40-week-old) to determine effects on production and egg quality. The study included 7 diets (2730 Kcal kg metabolizable energy and constant isoleucine at 0.72%) containing varying quantities of valine [0.72 (Control), 0.75, 0.78, 0.81, 0.84, 0.87 or 0.90%] x 7 replicates x 10 hens/replicate. Significance at P ≤ 0.05 and P < 0.10 was determined. Level and week were significant for feed intake, egg production, and FCR; the interaction of level x week (L*W) was significant for feed intake and FCR. An isoleucine:valine of 1.233 corresponding to 0.72% isoleucine and 0.87% valine produced the lowest FCR of 1.30 (a 2.26% decrease compared to the Control at 1.33 ± 0.04). All measurements for external egg quality, except shape index and eggshell thickness, were significant for level. Week was significant for all parameters except shell thickness; L*W was significant for external quality measurements except shape index and shell thickness. Level, week, and L*W were significant for internal egg quality measurements. Serum protein and H1 titer were significant for level. Various production, egg quality, and biochemical measurements were significantly different from the control (0.72% isoleucine and 0.72% valine) at 0.81 to 0.87% valine. Findings of this study will aid researchers and commercial producers in narrowing the range of isoleucine, valine, and leucine needed for effects on particular parameters. Knowledge gained from this and others studies will eventually lead to an understanding of synergistic and antagonistic effects of branched chain amino acids in feed for various genetic types of layers throughout their productive lifetime.
Topics: Animal Feed; Animals; Chickens; Diet; Female; Isoleucine; Valine
PubMed: 35417448
DOI: 10.1371/journal.pone.0258250