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Annual Review of Microbiology Sep 2023Amino acids are indispensable substrates for protein synthesis in all organisms and incorporated into diverse aspects of metabolic physiology and signaling. However,... (Review)
Review
Amino acids are indispensable substrates for protein synthesis in all organisms and incorporated into diverse aspects of metabolic physiology and signaling. However, animals lack the ability to synthesize several of them and must acquire these essential amino acids from their diet or perhaps their associated microbial communities. The essential amino acids therefore occupy a unique position in the health of animals and their relationships with microbes. Here we review recent work connecting microbial production and metabolism of essential amino acids to host biology, and the reciprocal impacts of host metabolism of essential amino acids on their associated microbes. We focus on the roles of the branched-chain amino acids (valine, leucine, and isoleucine) and tryptophan on host-microbe communication in the intestine of humans and other vertebrates. We then conclude by highlighting research questions surrounding the less-understood aspects of microbial essential amino acid synthesis in animal hosts.
Topics: Animals; Humans; Host Microbial Interactions; Amino Acids, Essential; Amino Acids, Branched-Chain; Leucine; Isoleucine
PubMed: 37339735
DOI: 10.1146/annurev-micro-032421-111819 -
Frontiers in Cardiovascular Medicine 2022Globally, cardiovascular diseases are the leading cause of death. Research has focused on the metabolism of carbohydrates, fatty acids, and amino acids to improve the... (Review)
Review
Globally, cardiovascular diseases are the leading cause of death. Research has focused on the metabolism of carbohydrates, fatty acids, and amino acids to improve the prognosis of cardiovascular diseases. There are three types of branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) required for protein homeostasis, energy balance, and signaling pathways. Increasing evidence has implicated BCAAs in the pathogenesis of multiple cardiovascular diseases. This review summarizes the biological origin, signal transduction pathways and function of BCAAs as well as their significance in cardiovascular diseases, including myocardial hypertrophy, heart failure, coronary artery disease, diabetic cardiomyopathy, dilated cardiomyopathy, arrhythmia and hypertension.
PubMed: 35911554
DOI: 10.3389/fcvm.2022.965899 -
International Journal of Molecular... Sep 2022Age-induced osteoporosis is a global problem. Essential amino acids (EAAs) work as an energy source and a molecular pathway modulator in bone, but their functions have... (Review)
Review
Age-induced osteoporosis is a global problem. Essential amino acids (EAAs) work as an energy source and a molecular pathway modulator in bone, but their functions have not been systematically reviewed in aging bone. This study aimed to discuss the contribution of EAAs on aging bone from in vitro, in vivo, and human investigations. In aged people with osteoporosis, serum EAAs were detected changing up and down, without a well-established conclusion. The supply of EAAs in aged people either rescued or did not affect bone mineral density (BMD) and bone volume. In most signaling studies, EAAs were proven to increase bone mass. Lysine, threonine, methionine, tryptophan, and isoleucine can increase osteoblast proliferation, activation, and differentiation, and decrease osteoclast activity. Oxidized L-tryptophan promotes bone marrow stem cells (BMSCs) differentiating into osteoblasts. However, the oxidation product of tryptophan called kynurenine increases osteoclast activity, and enhances the differentiation of adipocytes from BMSCs. Taken together, in terms of bone minerals and volume, more views consider EAAs to have a positive effect on aging bone, but the function of EAAs in bone metabolism has not been fully demonstrated and more studies are needed in this area in the future.
Topics: Aged; Amino Acids, Essential; Bone Density; Cell Differentiation; Humans; Isoleucine; Kynurenine; Lysine; Methionine; Osteoblasts; Osteoporosis; Threonine; Tryptophan
PubMed: 36232583
DOI: 10.3390/ijms231911281 -
BMC Medicine Mar 2021Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep...
Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses.
BACKGROUND
Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease.
METHODS
We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions.
RESULTS
We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (- 0.08 standard deviation (SD)[95% confidence interval (CI) - 0.12, - 0.03] in AMV and - 0.03SD [- 0.07, - 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (- 0.04SD [- 0.08, 0.00] in AMV and - 0.05SD [- 0.09, - 0.02] in MR), and lower phospholipids in very large HDL particles (- 0.04SD [- 0.08, 0.002] in AMV and - 0.05SD [- 0.08, - 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures.
CONCLUSIONS
Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.
Topics: Aged; Coronary Artery Disease; Creatinine; Cross-Sectional Studies; Genome-Wide Association Study; Humans; Isoleucine; Mendelian Randomization Analysis; Metabolic Diseases; Phenotype; Polymorphism, Single Nucleotide; Risk Factors; Sleep
PubMed: 33731105
DOI: 10.1186/s12916-021-01939-0 -
Frontiers in Cell and Developmental... 2021parasites responsible for the disease malaria reside within erythrocytes. Inside this niche host cell, parasites internalize and digest host hemoglobin to source amino... (Review)
Review
parasites responsible for the disease malaria reside within erythrocytes. Inside this niche host cell, parasites internalize and digest host hemoglobin to source amino acids required for protein production. However, hemoglobin does not contain isoleucine, an amino acid essential for growth, and the parasite cannot synthesize it . The parasite is also more metabolically active than its host cell, and the rate at which some nutrients are consumed exceeds the rate at which they can be taken up by erythrocyte transporters. To overcome these constraints, parasites increase the permeability of the erythrocyte membrane to isoleucine and other low-molecular-weight solutes it requires for growth by forming new permeation pathways (NPPs). In addition to the erythrocyte membrane, host nutrients also need to cross the encasing parasitophorous vacuole membrane (PVM) and the parasite plasma membrane to access the parasite. This review outlines recent advances that have been made in identifying the molecular constituents of the NPPs, the PVM nutrient channel, and the endocytic apparatus that transports host hemoglobin and identifies key knowledge gaps that remain. Importantly, blocking the ability of to source essential nutrients is lethal to the parasite, and thus, components of these key pathways represent potential antimalaria drug targets.
PubMed: 33842474
DOI: 10.3389/fcell.2021.649184 -
Journal of Clinical Medicine Mar 2020Girls with Turner syndrome (TS) are at increased risk of developing insulin resistance and coronary artery disease as a result of hypertension and obesity frequently...
Girls with Turner syndrome (TS) are at increased risk of developing insulin resistance and coronary artery disease as a result of hypertension and obesity frequently seen in these patients. On the other hand, it is known that obesity is associated with increased serum levels of branched-chain amino acids (BCAAs: valine; leucine and isoleucine) and aromatic amino acids. The aim of the study is to compare the metabolic fingerprint of girls with TS to the metabolic fingerprint of girls with obesity. Metabolic fingerprinting using an untargeted metabolomic approach was examined in plasma from 46 girls with TS (study group) and 22 age-matched girls with obesity (control group). The mean values of BCAAs, methionine, phenylalanine, lysine, tryptophan, histidine, tyrosine, alanine and ornithine were significantly lower in the study group than in the control ( from 0.0025 to <0.000001). Strong significant correlation between BCAAs, phenylalanine, arginine, tyrosine, glutamic acid, citrulline and alanine, and body mass index expressed as standard deviation score BMI-SDS in the patients with obesity ( from 0.049 to 0.0005) was found. In contrast; there was no correlation between these amino acids and BMI-SDS in the girls with TS. It is suggested that obesity in patients with TS is not associated with altered amino acids metabolism.
PubMed: 32131408
DOI: 10.3390/jcm9030664 -
Journal of Peptide Science : An... Jul 2022Side-chain-to-side-chain cyclization is frequently used to stabilize the α-helical conformation of short peptides. In a previous study, we incorporated a lactam bridge...
Side-chain-to-side-chain cyclization is frequently used to stabilize the α-helical conformation of short peptides. In a previous study, we incorporated a lactam bridge between the side chains of Lys-i and Asp-i+4 in the nonapeptide 1Y, cyclo-(2,6)-(Ac-VKRLQDLQY-NH ), an artificial ligand of the inhibitor of DNA binding and cell differentiation (ID) protein with antiproliferative activity on cancer cells. Herein, we show that only the cyclized five-residue segment adopts a helical turn whereas the C-terminal residues remain flexible. Moreover, we present nine 1Y analogs arising from different combinations of hydrophobic residues (leucine, isoleucine, norleucine, valine, and tyrosine) at positions 1, 4, 7, and 9. All cyclopeptides except one build a lactam-bridged helical turn; however, residue-4 reveals less helix character than the neighboring Arg-3 and Gln-5, especially with residue-4 being isoleucine, valine, and tyrosine. Surprisingly, only two cyclopeptides exhibit helix propagation until the C-terminus, whereas the others share a remarkable outward tilting of the backbone carbonyl of the lactam-bridged Asp-6 (>40° deviation from the orientation parallel to the helix axis), which prevents the formation of the H-bond between Arg-3 CO and residue-7 NH: As a result, the propagation of the helix beyond the lactam-bridged sequence becomes unfavorable. We conclude that, depending on the amino-acid sequence, the lactam bridge between Lys-i and Asp-i+4 can stabilize a helical turn but deviations from the ideal helix geometry are possible: Indeed, besides the outward tilting of the backbone carbonyls, the residues per turn increased from 3.6 (typical of a regular α-helix) to 4.2, suggesting a partial helix unwinding.
Topics: Circular Dichroism; Isoleucine; Lactams; Peptides; Peptides, Cyclic; Protein Conformation; Protein Structure, Secondary; Tyrosine; Valine
PubMed: 34984761
DOI: 10.1002/psc.3400 -
Frontiers in Immunology 2021Inflammatory bowel disease (namely, colitis) severely impairs human health. Isoleucine is reported to regulate immune function (such as the production of immunoreactive...
Inflammatory bowel disease (namely, colitis) severely impairs human health. Isoleucine is reported to regulate immune function (such as the production of immunoreactive substances). The aim of this study was to investigate whether l-isoleucine administration might alleviate dextran sulfate sodium (DSS)-induced colitis in rats. In the trial, IEC-18 cells were treated by 4 mmol/L l-isoleucine for 12 h, which relieved the decrease of cell viability that was induced by TNF-α (10 ng/ml) challenge for 24 h (0.05). Then, in the experiment, a total of 44 Wistar rats were allotted into 2 groups that were fed l-isoleucine-supplemented diet and control diet for 35 d. From 15 to 35 d, half of the rats in the 2 groups drank the 4% DSS-adding water. Average daily gain, average daily feed intake and feed conversion of rats were impaired by DSS challenge (0.05). Drinking the DSS-supplementing water also increased disease activity index (DAI) and serum urea nitrogen level (0.05), shortened colonic length (0.05), impaired colonic enterocyte apoptosis, cell cycle, and the mRNA expression (0.05), increased the ratio of CD11c-, CD64-, and CD169-positive cells in colon (0.05), and induced extensive ulcer, infiltration of inflammatory cells, and collagenous fiber hyperplasia in colon. However, dietary l-isoleucine supplementation attenuated the negative effect of DSS challenge on growth performance (0.05), DAI (0.05), colonic length and enterocyte apoptosis (0.05), and dysfunction of colonic histology, and downregulated the ratio of CD11c-, CD64-, and CD169-positive cells, pro-inflammation cytokines and the mRNA expression of , , and in the colon of rats (0.05). These results suggest that supplementing l-isoleucine in diet improved the DSS-induced growth stunting and colonic damage in rats, which could be associated with the downregulation of inflammation regulating TLR4/MyD88/NF-κB pathway in colon.
Topics: Animals; Apoptosis; Biomarkers; Cell Cycle; Colitis; Cytokines; Dextran Sulfate; Disease Susceptibility; Gene Expression Regulation; Isoleucine; Myeloid Differentiation Factor 88; NF-kappa B; Rats; Signal Transduction; Toll-Like Receptor 4
PubMed: 35087537
DOI: 10.3389/fimmu.2021.817583 -
BMC Medicine Dec 2022Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are essential amino acids that are associated with an increased risk of cardiometabolic diseases...
Systematic analysis of relationships between plasma branched-chain amino acid concentrations and cardiometabolic parameters: an association and Mendelian randomization study.
BACKGROUND
Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are essential amino acids that are associated with an increased risk of cardiometabolic diseases (CMD). However, there are still only limited insights into potential direct associations between BCAAs and a wide range of CMD parameters, especially those remaining after correcting for covariates and underlying causal relationships.
METHODS
To shed light on these relationships, we systematically characterized the associations between plasma BCAA concentrations and a large panel of 537 CMD parameters (including atherosclerosis-related parameters, fat distribution, plasma cytokine concentrations and cell counts, circulating concentrations of cardiovascular-related proteins and plasma metabolites) in 1400 individuals from the Dutch population cohort LifeLines DEEP and 294 overweight individuals from the 300OB cohort. After correcting for age, sex, and BMI, we assessed associations between individual BCAAs and CMD parameters. We further assessed the underlying causality using Mendelian randomization.
RESULTS
A total of 838 significant associations were detected for 409 CMD parameters. BCAAs showed both common and specific associations, with the most specific associations being detected for isoleucine. Further, we found that obesity status substantially affected the strength and direction of associations for valine, which cannot be corrected for using BMI as a covariate. Subsequent univariable Mendelian randomization (UVMR), after removing BMI-associated SNPs, identified seven significant causal relationships from four CMD traits to BCAA levels, mostly for diabetes-related parameters. However, no causal effects of BCAAs on CMD parameters were supported.
CONCLUSIONS
Our cross-sectional association study reports a large number of associations between BCAAs and CMD parameters. Our results highlight some specific associations for isoleucine, as well as obesity-specific effects for valine. MR-based causality analysis suggests that altered BCAA levels can be a consequence of diabetes and alteration in lipid metabolism. We found no MR evidence to support a causal role for BCAAs in CMD. These findings provide evidence to (re)evaluate the clinical importance of individual BCAAs in CMD diagnosis, prevention, and treatment.
Topics: Humans; Isoleucine; Mendelian Randomization Analysis; Cross-Sectional Studies; Amino Acids, Branched-Chain; Diabetes Mellitus; Obesity; Valine; Atherosclerosis
PubMed: 36522747
DOI: 10.1186/s12916-022-02688-4 -
Nutrients Oct 2020Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are increased in starvation and diabetes mellitus. However, the pathogenesis has not been explained.... (Review)
Review
Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are increased in starvation and diabetes mellitus. However, the pathogenesis has not been explained. It has been shown that BCAA catabolism occurs mostly in muscles due to high activity of BCAA aminotransferase, which converts BCAA and α-ketoglutarate (α-KG) to branched-chain keto acids (BCKAs) and glutamate. The loss of α-KG from the citric cycle (cataplerosis) is attenuated by glutamate conversion to α-KG in alanine aminotransferase and aspartate aminotransferase reactions, in which glycolysis is the main source of amino group acceptors, pyruvate and oxaloacetate. Irreversible oxidation of BCKA by BCKA dehydrogenase is sensitive to BCKA supply, and ratios of NADH to NAD and acyl-CoA to CoA-SH. It is hypothesized that decreased glycolysis and increased fatty acid oxidation, characteristic features of starvation and diabetes, cause in muscles alterations resulting in increased BCAA levels. The main alterations include (i) impaired BCAA transamination due to decreased supply of amino groups acceptors (α-KG, pyruvate, and oxaloacetate) and (ii) inhibitory influence of NADH and acyl-CoAs produced in fatty acid oxidation on citric cycle and BCKA dehydrogenase. The studies supporting the hypothesis and pros and cons of elevated BCAA concentrations are discussed in the article.
Topics: Alanine; Amino Acids, Branched-Chain; Diabetes Mellitus; Fatty Acids; Female; Glycolysis; Humans; Insulin; Insulin Resistance; Ketoglutaric Acids; Male; Muscles; Obesity; Oxidation-Reduction; Pyruvates; Starvation; Transaminases
PubMed: 33050579
DOI: 10.3390/nu12103087