Synthesis and conformational analysis of linear homo- and heterooligomers from novel 2-C-branched sugar amino acids (SAAs).
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ABSTRACT:
SUBMITTER: Tian GZ
PROVIDER: S-EPMC5919921 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivesThis work aimed to design, synthesize and characterize replacement natural moisturizing factor (NMF) composed of modified hygroscopic linear amino acids to pre-empt or repair skin barrier dysfunction.MethodsFollowing synthesis and characterization, thermo-gravimetric analysis and quantum mechanics molecular modelling quantified and depicted water binding to the new compounds. Deliquescence relative humidity demonstrated the water-scavenging ability of the compounds, whereas snake skin moisturizing studies showed they increased water uptake into snake skin.ResultsFrom thermal analysis, N-hydroxyglycine showed greatest water-holding capacity followed by N-hydroxyserine, l-homoserine and ?-hydroxyglycine; coupled with quantum mechanics molecular modelling, between 8 and 12 molecules of water could associate with each molecule of either N-hydroxyglycine, N-hydroxyserine or l-homoserine. All of our modified amino acids were efficacious and induced similar or greater water uptake compared with the established moisturizing compounds hyaluronic acid, glycerine and urea in snake skin. Incorporated at 10% in Oilatum, N-hydroxyserine induced >200% greater moisture uptake into dry snake skin compared to treatment with water alone, with efficacy related to the molecule structure and ability to bind to 12 water molecules. Oilatum cream spiked with all our unnatural amino acid hydrotropes increased water uptake into snake skin compared with Oilatum alone. The compound series was designed to elucidate some structure - efficacy relationships. Amino acid chirality did not affect the water-holding capacity but did affect uptake into skin. Compounds with high melting points and bond energies tended to decrease water-holding capacity. With isosteric replacement, the more electronegative atoms gave greater water-holding capacities.ConclusionsThis work demonstrates the potential of unnatural amino acid hydrotropes as skin moisturizers and has developed some predictive 'rules' for further design and refinement of chemical structures.
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Project description:UnlabelledMany if not most proteins function in oligomeric assemblies of one or more protein sequences. The Protein Data Bank provides coordinates for biological assemblies for each entry, at least 60% of which are dimers or larger assemblies. BioAssemblyModeler (BAM) is a graphical user interface to the basic steps in homology modeling of protein homooligomers and heterooligomers from the biological assemblies provided in the PDB. BAM takes as input up to six different protein sequences and begins by assigning Pfam domains to the target sequences. The program utilizes a complete assignment of Pfam domains to sequences in the PDB, PDBfam (http://dunbrack2.fccc.edu/protcid/pdbfam), to obtain templates that contain any or all of the domains assigned to the target sequence(s). The contents of the biological assemblies of potential templates are provided, and alignments of the target sequences to the templates are produced with a profile-profile alignment algorithm. BAM provides for visual examination and mouse-editing of the alignments supported by target and template secondary structure information and a 3D viewer of the template biological assembly. Side-chain coordinates for a model of the biological assembly are built with the program SCWRL4. A built-in protocol navigation system guides the user through all stages of homology modeling from input sequences to a three-dimensional model of the target complex.Availabilityhttp://dunbrack.fccc.edu/BAM.
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Project description:The uptake of branched-chain amino acids (BCAA) from plasma by lactating porcine mammary gland substantially exceeds their output in milk, whereas glutamine output is 125% greater than its uptake from plasma. In this study, we tested the hypothesis that BCAA are catabolized for glutamine synthesis in mammary tissue. Mammary tissue slices from sows on d 28 of lactation were incubated at 37 degrees C for 1 h in Krebs buffer containing 0.5 or 2 mmol/L l-[1-(14)C]- or l-[U-(14)C]-labeled leucine, isoleucine, or valine. Rates of BCAA transport and degradation in mammary tissue were high, with approximately 60% of transaminated BCAA undergoing oxidative decarboxylation and the remainder being released as branched-chain alpha-ketoacids (BCKA). Most ( approximately 70%) of the decarboxylated BCAA were oxidized to CO(2). Rates of net BCAA transamination were similar to rates of glutamate, glutamine, aspartate, asparagine, and alanine synthesis. Consistent with the metabolic data, mammary tissue expressed BCAA aminotransferase (BCAT), BCKA decarboxylase, glutamine synthetase (GS), glutamate-oxaloacetate aminotransferase, glutamate-pyruvate aminotransferase, and asparagine synthetase, but no phosphate-activated glutaminase, activity. Western blot analysis indicated relatively high levels of mitochondrial and cytosolic isoforms of BCAT, as well as BCKA dehydrogenase and GS proteins in mammary tissue. Our results demonstrate that glutamine and aspartate (abundant amino acids in milk protein) were the major nitrogenous products of BCAA catabolism in lactating porcine mammary tissue and provide a biochemical basis to explain an enrichment of glutamine and aspartate in sow milk.
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Project description:β-Branched noncanonical amino acids are valuable molecules in modern drug development efforts. However, they are still challenging to prepare due to the need to set multiple stereocenters in a stereoselective fashion, and contemporary methods for the synthesis of such compounds often rely on the use of rare-transition-metal catalysts with designer ligands. Herein, we report a highly diastereo- and enantioselective biocatalytic transamination method to prepare a broad range of aromatic β-branched α-amino acids. Mechanistic studies show that the transformation proceeds through dynamic kinetic resolution that is unique to the optimal enzyme. To highlight its utility and practicality, the biocatalytic reaction was applied to the synthesis of several sp3 -rich cyclic fragments and the first total synthesis of jomthonic acid A.
| S-EPMC8319157 | biostudies-literature
Project description: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.
| S-EPMC9259854 | biostudies-literature
Project description:BACKGROUND:Elevated fasting levels of branched chain amino acids (BCAAs: valine, isoleucine, leucine) in venous blood are associated with a variety of metabolic impairments, including increased risk of type 2 diabetes (T2D). Fasting BCAA levels are influenced by non-dietary factors. However, it is unknown whether fasting BCAAs can be altered through manipulation of dietary intake alone. OBJECTIVE:To test whether a specific dietary intervention, using differences in BCAA intake, alters fasting BCAA levels independent of other factors. DESIGN:Five healthy male volunteers underwent 4 days of a low and 4 days of a high BCAA content dietary intervention (ClinicalTrials.gov [NCT02110602]). All food and supplements were provided. Fasting BCAAs were measured from venous blood samples by mass spectrometry at baseline and after each intervention. RESULTS:Diets were isocaloric; contained equal percentages of calories from carbohydrate, fats, and protein; and differed from each other in BCAA content (1.5±0.1 vs. 14.0±0.6 g for valine; 4.5±0.9 g vs. 13.8±0.5 g for isoleucine; 2.1±0.2 g vs. 27.1±1.0 g for leucine; p<0.0001 for all). Fasting valine was significantly lower (p=0.02) and fasting isoleucine and leucine were numerically lower following the low BCAA content vs. the high BCAA content diet levels. The inter-individual response to the dietary interventions was variable and not explained by adherence. CONCLUSION:Short-term dietary manipulation of BCAA intake led to modest changes in fasting levels of BCAAs. The approach from our pilot study can be expanded to test the metabolic implications of dietary BCAA manipulation.
| S-EPMC4717153 | biostudies-literature
Project description:Elevated branched chain amino acids (BCAAs) are associated with obesity and insulin resistance. How long-term dietary BCAAs impact late-life health and lifespan is unknown. Here, we show that when dietary BCAAs are varied against a fixed, isocaloric macronutrient background, long-term exposure to high BCAA diets led to hyperphagia, obesity and reduced lifespan. These effects were not due to elevated BCAA per se or hepatic mTOR activation, but rather the shift in balance between dietary BCAAs and other AAs, notably tryptophan and threonine. Increasing the ratio of BCAAs to these AAs resulted in hyperphagia and was linked to central serotonin depletion. Preventing hyperphagia by calorie restriction or pair-feeding averted the health costs of a high BCAA diet. Our data highlight a role for amino acid quality in energy balance and show that health costs of chronic high BCAA intakes were not due to intrinsic toxicity; rather, to hyperphagia driven by AA imbalance.
2019-03-11 | GSE114855 | GEO
Project description:Cyclic peptides (CPs) are a promising class of molecules for drug development, particularly as inhibitors of protein-protein interactions. Predicting low-energy structures and global structural ensembles of individual CPs is critical for the design of bioactive molecules, but these are challenging to predict and difficult to verify experimentally. In our previous work, we used explicit-solvent molecular dynamics simulations with enhanced sampling methods to predict the global structural ensembles of cyclic hexapeptides containing different permutations of glycine, alanine, and valine. One peptide, cyclo-(VVGGVG) or P7, was predicted to be unusually well structured. In this work, we synthesized P7, along with a less well-structured control peptide, cyclo-(VVGVGG) or P6, and characterized their global structural ensembles in water using NMR spectroscopy. The NMR data revealed a structural ensemble similar to the prediction for P7 and showed that P6 was indeed much less well-structured than P7. We then simulated and experimentally characterized the global structural ensembles of several P7 analogs and discovered that ?-branching at one critical position within P7 is important for overall structural stability. The simulations allowed deconvolution of thermodynamic factors that underlie this structural stabilization. Overall, the excellent correlation between simulation and experimental data indicates that our simulation platform will be a promising approach for designing well-structured CPs and also for understanding the complex interactions that control the conformations of constrained peptides and other macrocycles.
| S-EPMC6369414 | biostudies-literature
Project description:BackgroundCirculating branched-chain amino acid (BCAA) levels reflect metabolic health and dietary intake. However, associations with breast cancer are unclear.MethodsWe evaluated circulating BCAA levels and breast cancer risk within the Nurses' Health Study (NHS) and NHSII (1997 cases and 1997 controls). A total of 592 NHS women donated 2 blood samples 10 years apart. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer risk in multivariable logistic regression models. We conducted an external validation in 1765 cases in the Women's Health Study (WHS). All statistical tests were 2-sided.ResultsAmong NHSII participants (predominantly premenopausal at blood collection), elevated circulating BCAA levels were associated with lower breast cancer risk (eg, isoleucine highest vs lowest quartile, multivariable OR = 0.86, 95% CI = 0.65 to 1.13, P trend = .20), with statistically significant linear trends among fasting samples (eg, isoleucine OR = 0.74, 95% CI = 0.53 to 1.05, P trend = .05). In contrast, among postmenopausal women, proximate measures (<10 years from blood draw) were associated with increased breast cancer risk (eg, isoleucine OR = 1.63, 95% CI = 1.12 to 2.39, P trend = .01), with stronger associations among fasting samples (OR = 1.73, 95% CI = 1.15 to 2.61, P trend = .01). Distant measures (10-20 years since blood draw) were not associated with risk. In the WHS, a positive association was observed for distant measures of leucine among postmenopausal women (OR = 1.23, 95% CI = 0.96 to 1.58, P trend = .04).ConclusionsNo statistically significant associations between BCAA levels and breast cancer risk were consistent across NHS and WHS or NHSII and WHS. Elevated circulating BCAA levels were associated with lower breast cancer risk among predominantly premenopausal NHSII women and higher risk among postmenopausal women in NHS but not in the WHS. Additional studies are needed to understand this complex relationship.
| S-EPMC8460878 | biostudies-literature