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Journal of the American Chemical Society Mar 2022Via the design of a new, soluble poly(-alkyl-l-cysteine) precursor, a route was developed for the successful preparation of long-chain poly(dehydroalanine), , as well as...
Via the design of a new, soluble poly(-alkyl-l-cysteine) precursor, a route was developed for the successful preparation of long-chain poly(dehydroalanine), , as well as the incorporation of dehydroalanine residues and segments into copolypeptides. Based on experimental and computational data, was found to adopt a previously unobserved "hybrid coil" structure, which combines the elements of 2-helical and 3-helical conformations. Analysis of the spectroscopic properties of revealed that it possesses a strong inherent blue fluorescence, which may be amenable for use in imaging applications. also contains reactive electrophilic groups that allowed its efficient modification to functionalized polypeptides after reactions under mild conditions with thiol and amine nucleophiles. The combined structural, spectroscopic, and reactivity properties of make it a unique reactive and fluorescent polypeptide component for utilization in self-assembled biomaterials.
Topics: Alanine; Cysteine; Peptides; Sulfhydryl Compounds
PubMed: 35224969
DOI: 10.1021/jacs.2c00383 -
Pharmacotherapy Jul 2020The global pandemic of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created an urgent need for... (Review)
Review
The global pandemic of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created an urgent need for effective antivirals. Remdesivir (formerly GS-5734) is a nucleoside analogue pro-drug currently being evaluated in COVID-19 clinical trials. Its unique structural features allow high concentrations of the active triphosphate metabolite to be delivered intracellularly and it evades proofreading to successfully inhibit viral RNA synthesis. In pre-clinical models, remdesivir has demonstrated potent antiviral activity against diverse human and zoonotic β-coronaviruses, including SARS-CoV-2. In this article, we critically review available data on remdesivir with an emphasis on biochemistry, pharmacology, pharmacokinetics, and in vitro activity against coronaviruses as well as clinical experience and current progress in COVID-19 clinical trials.
Topics: Adenosine Monophosphate; Alanine; Animals; Antiviral Agents; Betacoronavirus; COVID-19; Coronavirus Infections; Humans; Pandemics; Pneumonia, Viral; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 32446287
DOI: 10.1002/phar.2429 -
International Journal of Molecular... Jun 2023d-amino acids have recently been found to be present in the extracellular milieu at millimolar levels and are therefore assumed to play a physiological function....
d-amino acids have recently been found to be present in the extracellular milieu at millimolar levels and are therefore assumed to play a physiological function. However, the pathway (or potential pathways) by which these d-amino acids are secreted remains unknown. Recently, has been found to possess one or more energy-dependent d-alanine export systems. To gain insight into these systems, we developed a novel screening system in which cells expressing a putative d-alanine exporter could support the growth of d-alanine auxotrophs in the presence of l-alanyl-l-alanine. In the initial screening, five d-alanine exporter candidates, AlaE, YmcD, YciC, YraM, and YidH, were identified. Transport assays of radiolabeled d-alanine in cells expressing these candidates indicated that YciC and AlaE resulted in lower intracellular levels of d-alanine. Further detailed transport assays of AlaE in intact cells showed that it exports d-alanine in an expression-dependent manner. In addition, the growth constraints on cells in the presence of 90 mM d-alanine were mitigated by the overexpression of AlaE, implying that AlaE could export free d-alanine in addition to l-alanine under conditions in which intracellular d/l-alanine levels are raised. This study also shows, for the first time, that YciC could function as a d-alanine exporter in intact cells.
Topics: Escherichia coli; Alanine; Escherichia coli Proteins; Amino Acids; Biological Transport; Amino Acid Transport Systems, Neutral
PubMed: 37373388
DOI: 10.3390/ijms241210242 -
Angewandte Chemie (International Ed. in... Dec 2022Design of pyroelectric crystals decoupled from piezoelectricity is not only a topic of scientific curiosity but also demonstrates effects in principle that have the...
Design of pyroelectric crystals decoupled from piezoelectricity is not only a topic of scientific curiosity but also demonstrates effects in principle that have the potential to be technologically advantageous. Here we report a new method for the design of such materials. Thus, the co-doping of centrosymmetric crystals with tailor-made guest molecules, as illustrated by the doping of α-glycine with different amino acids (Threonine, Alanine and Serine). The polarization of those crystals displays two distinct contributions, one arising from the difference in dipole moments between guest and host and the other from the displacement of host molecules from their symmetry-related positions. These contributions exhibit different temperature dependences and response to mechanical deformation. Thus, providing a proof of concept for the ability to design pyroelectric materials with reduced piezoelectric coefficient (d ) to a minimal value, below the resolution limit of the method (<0.005 pm/V).
Topics: Glycine; Crystallization; Amino Acids; Alanine
PubMed: 36200991
DOI: 10.1002/anie.202213955 -
JAMA Jul 2020
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Betacoronavirus; COVID-19; Clinical Trials, Phase III as Topic; Coronavirus Infections; Drug Approval; Drug Costs; Drugs, Investigational; Hemorrhagic Fever, Ebola; Humans; Length of Stay; National Institute of Allergy and Infectious Diseases (U.S.); Pandemics; Pneumonia, Viral; Registries; SARS-CoV-2; Treatment Outcome; United States; COVID-19 Drug Treatment
PubMed: 32579163
DOI: 10.1001/jama.2020.11932 -
Molecules (Basel, Switzerland) Feb 2023A comparative investigation of amino acids (proline, cysteine, and alanine) as dosimetric materials using electron paramagnetic resonance (EPR) spectroscopy in the...
A comparative investigation of amino acids (proline, cysteine, and alanine) as dosimetric materials using electron paramagnetic resonance (EPR) spectroscopy in the absorbed dosage range of 1-25 kGy is presented. There were no signals in the EPR spectra of the samples before irradiation. After irradiation, the complex spectra were recorded. These results showed that the investigated amino acids were sensitive to radiation. In the EPR spectrum of cysteine after irradiation, RS• radicals dominated. The effects of the microwave power on the saturation of the EPR signals showed the presence of at least three different types of free radicals in proline. It was also found out that the DL-proline and cysteine had stable free radicals after irradiation and represented a linear dosage response up to 10 kGy. On the other hand, the amino acid alanine has been accepted by the International Atomic Energy Agency as a transfer standard dosimetry system. In view of this, the obtained results of the proline and cysteine studies have been compared with those of the alanine studies. The results showed that the amino acids proline and cysteine could be used as alternative dosimetric materials in lieu of alanine in a dosage range of 1-10 kGy of an absorbed dose of γ-rays using EPR spectroscopy. Regarding the radiation sensitivity, the following order of decreased dosage responses was determined: alanine > DL-proline > cysteine > L-proline.
Topics: Amino Acids; Electron Spin Resonance Spectroscopy; Cysteine; Alanine; Proline; Free Radicals
PubMed: 36838733
DOI: 10.3390/molecules28041745 -
Bioinformatics (Oxford, England) Oct 2022Poly-alanine (polyA) regions are protein stretches mostly composed of alanines. Despite their abundance in eukaryotic proteomes and their association to nine inherited...
MOTIVATION
Poly-alanine (polyA) regions are protein stretches mostly composed of alanines. Despite their abundance in eukaryotic proteomes and their association to nine inherited human diseases, the structural and functional roles exerted by polyA stretches remain poorly understood. In this work we study how the amino acid context in which polyA regions are settled in proteins influences their structure and function.
RESULTS
We identified glycine and proline as the most abundant amino acids within polyA and in the flanking regions of polyA tracts, in human proteins as well as in 17 additional eukaryotic species. Our analyses indicate that the non-structuring nature of these two amino acids influences the α-helical conformations predicted for polyA, suggesting a relevant role in reducing the inherent aggregation propensity of long polyA. Then, we show how polyA position in protein N-termini relates with their function as transit peptides. PolyA placed just after the initial methionine is often predicted as part of mitochondrial transit peptides, whereas when placed in downstream positions, polyA are part of signal peptides. A few examples from known structures suggest that short polyA can emerge by alanine substitutions in α-helices; but evolution by insertion is observed for longer polyA. Our results showcase the importance of studying the sequence context of homorepeats as a mechanism to shape their structure-function relationships.
AVAILABILITY AND IMPLEMENTATION
The datasets used and/or analyzed during the current study are available from the corresponding author onreasonable request.
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Humans; Alanine; Poly A; Amino Acid Sequence; Proteome; Peptides
PubMed: 36106994
DOI: 10.1093/bioinformatics/btac610 -
Bioprocess and Biosystems Engineering May 2022High-yielding chemical and chemo-enzymatic methods of D-pantothenic acid (DPA) synthesis are limited by using poisonous chemicals and DL-pantolactone racemic mixture...
High-yielding chemical and chemo-enzymatic methods of D-pantothenic acid (DPA) synthesis are limited by using poisonous chemicals and DL-pantolactone racemic mixture formation. Alternatively, the safe microbial fermentative route of DPA production was found promising but suffered from low productivity and precursor supplementation. In this study, Bacillus megaterium was metabolically engineered to produce DPA without precursor supplementation. In order to provide a higher supply of precursor D-pantoic acid, key genes involved in its synthesis are overexpressed, resulting strain was produced 0.53 ± 0.08 g/L DPA was attained in shake flasks. Cofactor CH2-THF was found to be vital for DPA biosynthesis and was regenerated through the serine-glycine degradation pathway. Enhanced supply of another precursor, β-alanine was achieved by codon optimization and dosing of the limiting L-asparate-1-decarboxylase (ADC). Co-expression of Pantoate-β-alanine ligase, ADC, phosphoenolpyruvate carboxylase, aspartate aminotransferase and aspartate ammonia-lyase enhanced DPA concentration to 2.56 ± 0.05 g/L at shake flasks level. Fed-batch fermentation in a bioreactor with and without the supplementation of β-alanine increased DPA concentration to 19.52 ± 0.26 and 4.78 ± 0.53 g/L, respectively. This present study successfully demonstrated a rational approach combining precursor supply engineering with cofactor regeneration for the enhancement of DPA titer in recombinant B. megaterium.
Topics: Bacillus megaterium; Fermentation; Metabolic Engineering; Pantothenic Acid; beta-Alanine
PubMed: 35175424
DOI: 10.1007/s00449-022-02701-3 -
Journal of Drugs in Dermatology : JDD May 2021
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; COVID-19; Diagnosis, Differential; Drug Eruptions; Humans
PubMed: 33938699
DOI: 10.36849/JDD.5777 -
Biophysical Journal Mar 2021This work builds upon the record-breaking speed and generous immediate release of new experimental three-dimensional structures of the severe acute respiratory syndrome...
This work builds upon the record-breaking speed and generous immediate release of new experimental three-dimensional structures of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins and complexes, which are crucial to downstream vaccine and drug development. We have surveyed those structures to catch the occasional errors that could be significant for those important uses and for which we were able to provide demonstrably higher-accuracy corrections. This process relied on new validation and correction methods such as CaBLAM and ISOLDE, which are not yet in routine use. We found such important and correctable problems in seven early SARS-CoV-2 structures. Two of the structures were soon superseded by new higher-resolution data, confirming our proposed changes. For the other five, we emailed the depositors a documented and illustrated report and encouraged them to make the model corrections themselves and use the new option at the worldwide Protein Data Bank for depositors to re-version their coordinates without changing the Protein Data Bank code. This quickly and easily makes the better-accuracy coordinates available to anyone who examines or downloads their structure, even before formal publication. The changes have involved sequence misalignments, incorrect RNA conformations near a bound inhibitor, incorrect metal ligands, and cis-trans or peptide flips that prevent good contact at interaction sites. These improvements have propagated into nearly all related structures done afterward. This process constitutes a new form of highly rigorous peer review, which is actually faster and more strict than standard publication review because it has access to coordinates and maps; journal peer review would also be strengthened by such access.
Topics: Adenosine Monophosphate; Alanine; Antibodies, Viral; Catalytic Domain; DNA-Directed RNA Polymerases; Humans; Models, Molecular; Nucleocapsid; Peer Review; Phosphoproteins; RNA-Binding Proteins; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Zinc
PubMed: 33460600
DOI: 10.1016/j.bpj.2020.12.029