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Angewandte Chemie (International Ed. in... Jan 2020Aspartic acid derivatives with branched N-alkyl or N-arylalkyl substituents are valuable precursors to artificial dipeptide sweeteners such as neotame and advantame. The...
Aspartic acid derivatives with branched N-alkyl or N-arylalkyl substituents are valuable precursors to artificial dipeptide sweeteners such as neotame and advantame. The development of a biocatalyst to synthesize these compounds in a single asymmetric step is an as yet unmet challenge. Reported here is an enantioselective biocatalytic synthesis of various difficult N-substituted aspartic acids, including N-(3,3-dimethylbutyl)-l-aspartic acid and N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-l-aspartic acid, precursors to neotame and advantame, respectively, using an engineered variant of ethylenediamine-N,N'-disuccinic acid (EDDS) lyase from Chelativorans sp. BNC1. This engineered C-N lyase (mutant D290M/Y320M) displayed a remarkable 1140-fold increase in activity for the selective hydroamination of fumarate compared to that of the wild-type enzyme. These results present new opportunities to develop practical multienzymatic processes for the more sustainable and step-economic synthesis of an important class of food additives.
Topics: Aspartic Acid; Dipeptides; Lyases; Stereoisomerism; Sweetening Agents
PubMed: 31625664
DOI: 10.1002/anie.201910704 -
Current Opinion in Chemical Biology Apr 2020The field of organic chemistry has recently witnessed a rapid rise in the use of chemoenzymatic strategies for the synthesis of complex molecules. Under this paradigm,... (Review)
Review
The field of organic chemistry has recently witnessed a rapid rise in the use of chemoenzymatic strategies for the synthesis of complex molecules. Under this paradigm, biocatalytic methods and contemporary synthetic methods are used synergistically in a multistep approach toward a target molecule. In light of the unparalleled regioselectivity and stereoselectivity of enzymatic transformations and the reaction diversity of contemporary organic chemistry, chemoenzymatic strategies hold enormous potential for streamlining access to important bioactive molecules. This review covers recent demonstrations of chemoenzymatic approaches in chemical synthesis, with special emphasis on the preparation of medicinally relevant natural products.
Topics: Aspartic Acid; Biocatalysis; Biological Products; Enzymes; Isoquinolines; Kainic Acid; Molecular Conformation; Podophyllotoxin; Quinolines; Quinolones; Stereoisomerism
PubMed: 32086167
DOI: 10.1016/j.cbpa.2020.01.005 -
Electrophoresis Jun 2010One of the most frequent modifications in proteins and peptides is the deamidation of asparagine, a spontaneous non-enzymatic reaction leading to a mixture of... (Review)
Review
One of the most frequent modifications in proteins and peptides is the deamidation of asparagine, a spontaneous non-enzymatic reaction leading to a mixture of L,D-succinimidyl, L,D-aspartyl, and L,D-isoaspartyl forms, with L-isoaspartyl dominating. Spontaneous isomerization of L-Asp yields the same products. In vivo, these unusual forms of aspartate are repaired by the protein L-isoaspartyl O-methyltransferase enzyme, with the balance between isomerization and repair affecting the organism physiology. Mass spectrometric analysis of this balance involves isomer separation, iso-Asp/Asp quantification, and iso-Asp site identification. This review highlights the issues associated with these steps and discusses the prospects of high-throughput iso-Asp analysis.
Topics: Amides; Animals; Asparagine; Aspartic Acid; Electrophoresis, Gel, Two-Dimensional; Humans; Isomerism; Mass Spectrometry; Mice; Proteomics
PubMed: 20446295
DOI: 10.1002/elps.201000027 -
International Journal of Molecular... Aug 2022The exact neurobiological mechanisms of bipolar disorder (BD) remain unknown. However, some neurometabolites could be implicated, including Glutamate (Glu), Glutamine... (Meta-Analysis)
Meta-Analysis Review
The exact neurobiological mechanisms of bipolar disorder (BD) remain unknown. However, some neurometabolites could be implicated, including Glutamate (Glu), Glutamine (Gln), Glx, and N-acetylaspartate (NAA). Proton Magnetic Resonance Spectroscopy (H-MRS) allows one to quantify these metabolites in the human brain. Thus, we conducted a systematic review and meta-analysis of the literature to compare their levels between BD patients and healthy controls (HC). The main inclusion criteria for inclusion were H-MRS studies comparing levels of Glu, Gln, Glx, and NAA in the prefrontal cortex (PFC), anterior cingulate cortex (ACC), and hippocampi between patients with BD in clinical remission or a major depressive episode and HC. Thirty-three studies were included. NAA levels were significantly lower in the left white matter PFC (wmPFC) of depressive and remitted BD patients compared to controls and were also significantly higher in the left dorsolateral PFC (dlPFC) of depressive BD patients compared to HC. Gln levels were significantly higher in the ACC of remitted BD patients compared to in HC. The decreased levels of NAA of BD patients may be related to the alterations in neuroplasticity and synaptic plasticity found in BD patients and may explain the deep white matter hyperintensities frequently observed via magnetic resonance imagery.
Topics: Aspartic Acid; Bipolar Disorder; Depressive Disorder, Major; Glutamic Acid; Glutamine; Humans; Proton Magnetic Resonance Spectroscopy
PubMed: 36012234
DOI: 10.3390/ijms23168974 -
Molecular Plant Jan 2010Plants are either directly or indirectly the source of most of the essential amino acids in animal diets. Four of these essential amino acids-methionine, threonine,... (Review)
Review
Plants are either directly or indirectly the source of most of the essential amino acids in animal diets. Four of these essential amino acids-methionine, threonine, isoleucine, and lysine-are all produced from aspartate via a well studied biosynthesis pathway. Given the nutritional interest in essential amino acids, the aspartate-derived amino acid pathway has been the subject of extensive research. Additionally, several pathway enzymes serve as targets for economically important herbicides, and some of the downstream products are biosynthetic precursors for other essential plant metabolites such as ethylene and S-adenosylmethionine. Recent and ongoing research on the aspartate-derived family of amino acids has identified new enzyme activities, regulatory mechanisms, and in vivo metabolic functions. Together, these discoveries will open up new possibilities for plant metabolic engineering.
Topics: Amino Acids; Arabidopsis; Aspartic Acid; Models, Biological; Plants
PubMed: 20019093
DOI: 10.1093/mp/ssp104 -
Journal of the American Society For... Jul 2022There is an increasing emphasis on the critical evaluation of interbatch purity and physical stability of therapeutic peptides. This is due to concerns over the impact...
There is an increasing emphasis on the critical evaluation of interbatch purity and physical stability of therapeutic peptides. This is due to concerns over the impact that product- and process-related impurities may have on safety and efficacy of this class of drug. Aspartic acid isomerization to isoaspartic acid is a common isobaric impurity that can be very difficult to identify without first synthesizing isoAsp peptide standards for comparison by chromatography. As such, analytical tools that can determine if an Asp residue has isomerized, as well as the site of isomerization within the peptide sequence, are highly sought after. Ion mobility-mass spectrometry is a conformation-selective method that has developed rapidly in recent years particularly with the commercialization of traveling wave ion mobility instruments. This study employed a cyclic ion mobility (cIMS) mass spectrometry system to investigate the conformational characteristics of a therapeutic peptide and three synthetic isomeric forms, each with a single Asp residue isomerized to isoAsp. cIMS was able to not only show distinct conformational differences between each peptide but crucially, in conjunction with a simple workflow for comparing ion mobility data, it correctly located which Asp residue in each peptide had isomerized to isoAsp. This work highlights the value of cIMS as a potential screening tool in the analysis of therapeutic peptides prone to the formation of isoAsp impurities.
Topics: Aspartic Acid; Chromatography, High Pressure Liquid; Isomerism; Mass Spectrometry; Peptides
PubMed: 35609180
DOI: 10.1021/jasms.2c00053 -
Psychiatry Research Aug 2013Over the past two decades, many magnetic resonance spectroscopy (MRS) studies reported lower N-acetylaspartate (NAA) in key brain regions of patients with schizophrenia... (Meta-Analysis)
Meta-Analysis Review
Over the past two decades, many magnetic resonance spectroscopy (MRS) studies reported lower N-acetylaspartate (NAA) in key brain regions of patients with schizophrenia (SZ) compared to healthy subjects. A smaller number of studies report no difference in NAA. Many sources of variance may contribute to these discordant results including heterogeneity of the SZ subject populations and methodological differences such as MRS acquisition parameters, and post-acquisition analytic methods. The current study reviewed proton MRS literature reporting measurements of NAA in SZ with a focus on methodology. Studies which reported lower NAA were significantly more likely to have used longer echo times (TEs), while studies with shorter TEs reported no concentration difference. This suggests that NAA quantitation using MRS was affected by the choice of TE, and that published MRS literature reporting NAA in SZ using a long TE is confounded by apparent differential T2 relaxation effects between SZ and healthy control groups. Future MRS studies should measure T2 relaxation times. This would allow for spectral concentration measurements to be appropriately corrected for these relaxation effects. In addition, as metabolite concentration and T2 relaxation times are completely independent variables, this could offer distinct information about the metabolite of interest.
Topics: Aspartic Acid; Brain; Humans; Magnetic Resonance Spectroscopy; Reproducibility of Results; Schizophrenia
PubMed: 23769421
DOI: 10.1016/j.pscychresns.2013.03.005 -
The Journal of Biological Chemistry Nov 2023Hybrid insulin peptides (HIPs) form in beta-cells when insulin fragments link to other peptides through a peptide bond. HIPs contain nongenomic amino acid sequences and...
Hybrid insulin peptides (HIPs) form in beta-cells when insulin fragments link to other peptides through a peptide bond. HIPs contain nongenomic amino acid sequences and have been identified as targets for autoreactive T cells in type 1 diabetes. A subgroup of HIPs, in which N-terminal amine groups of various peptides are linked to aspartic acid residues of insulin C-peptide, was detected through mass spectrometry in pancreatic islets. Here, we investigate a novel mechanism that leads to the formation of these HIPs in human and murine islets. Our research herein shows that these HIPs form spontaneously in beta-cells through a mechanism involving an aspartic anhydride intermediate. This mechanism leads to the formation of a regular HIP containing a standard peptide bond as well as a HIP-isomer containing an isopeptide bond by linkage to the carboxylic acid side chain of the aspartic acid residue. We used mass spectrometric analyses to confirm the presence of both HIP isomers in islets, thereby validating the occurrence of this novel reaction mechanism in beta-cells. The spontaneous formation of new peptide bonds within cells may lead to the development of neoepitopes that contribute to the pathogenesis of type 1 diabetes as well as other autoimmune diseases.
Topics: Animals; Humans; Mice; Aspartic Acid; Diabetes Mellitus, Type 1; Insulin; Insulin-Secreting Cells; Peptides; In Vitro Techniques; Mass Spectrometry
PubMed: 37734557
DOI: 10.1016/j.jbc.2023.105264 -
Pediatric Rheumatology Online Journal Feb 2022In comparison with the general population, adolescents with juvenile idiopathic arthritis (JIA) are at higher risk for morbidity and mortality. However, limited evidence... (Comparative Study)
Comparative Study
BACKGROUND
In comparison with the general population, adolescents with juvenile idiopathic arthritis (JIA) are at higher risk for morbidity and mortality. However, limited evidence is available about this condition's underlying metabolic profile in adolescents with JIA relative to healthy controls. In this untargeted, cross-sectional metabolomics study, we explore the plasma metabolites in this population.
METHODS
A sample of 20 adolescents with JIA and 20 controls aged 13-17 years were recruited to complete surveys, provide medical histories and biospecimens, and undergo assessments. Fasting morning plasma samples were processed with liquid chromatography-mass spectrometry. Data were centered, scaled, and analyzed using generalized linear models accounting for age, sex, and medications (p-values adjusted for multiple comparisons using the Holm method). Spearman's correlations were used to evaluate relationships among metabolites, time since diagnosis, and disease severity.
RESULTS
Of 72 metabolites identified in the samples, 55 were common to both groups. After adjustments, 6 metabolites remained significantly different between groups. Alpha-glucose, alpha-ketoglutarate, serine, and N-acetylaspartate were significantly lower in the JIA group than in controls; glycine and cystine were higher. Seven additional metabolites were detected only in the JIA group; 10 additional metabolites were detected only in the control group. Metabolites were unrelated to disease severity or time since diagnosis.
CONCLUSIONS
The metabolic signature of adolescents with JIA relative to controls reflects a disruption in oxidative stress; neurological health; and amino acid, caffeine, and energy metabolism pathways. Serine and N-acetylaspartate were promising potential biomarkers, and their metabolic pathways are linked to both JIA and cardiovascular disease risk. The pathways may be a source of new diagnostic, treatment, or prevention options. This study's findings contribute new knowledge for systems biology and precision health approaches to JIA research. Further research is warranted to confirm these findings in a larger sample.
Topics: Adolescent; Arthritis, Juvenile; Aspartic Acid; Cross-Sectional Studies; Female; Humans; Male; Metabolomics; Serine
PubMed: 35144633
DOI: 10.1186/s12969-022-00672-z -
Scientific Reports Oct 2021Recent research has revealed that shrimp sensory quality may be affected by ocean acidification but we do not exactly know why. Here we conducted controlled pH exposure...
Recent research has revealed that shrimp sensory quality may be affected by ocean acidification but we do not exactly know why. Here we conducted controlled pH exposure experiments on adult tiger shrimp, which were kept in 1000-L tanks continuously supplied with coastal seawater. We compared survival rate, carapace properties and flesh sensory properties and amino acid composition of shrimp exposed to pH 7.5 and pH 8.0 treatments for 28 days. Shrimp reared at pH 7.5 had a lower amino acid content (17.6% w/w) than those reared at pH 8.0 (19.5% w/w). Interestingly, the amino acids responsible for the umami taste, i.e. glutamate and aspartic acid, were present at significantly lower levels in the pH 7.5 than the pH 8.0 shrimp, and the pH 7.5 shrimp were also rated as less desirable in a blind quality test by 40 volunteer assessors. These results indicate that tiger shrimp may become less palatable in the future due to a lower production of some amino acids. Finally, tiger shrimp also had a lower survival rate over 28 days at pH 7.5 than at pH 8.0 (73% vs. 81%) suggesting that ocean acidification may affect both the quality and quantity of future shrimp resources.
Topics: Animals; Aspartic Acid; Climate Change; Crassostrea; Glutamic Acid; Hydrogen-Ion Concentration; Seafood; Seawater
PubMed: 34707152
DOI: 10.1038/s41598-021-00612-z