scholarly journals A systematic approach to diverse, lead-like scaffolds from α,α-disubstituted amino acids

2015 ◽  
Vol 51 (56) ◽  
pp. 11174-11177 ◽  
Author(s):  
Daniel J. Foley ◽  
Richard G. Doveston ◽  
Ian Churcher ◽  
Adam Nelson ◽  
Stephen P. Marsden
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Systematic Approach ◽  
Chemical Space ◽  
Building Blocks ◽  
Molecular Scaffolds ◽  
Disubstituted Amino Acids

A strategy for the efficient lead-oriented synthesis of novel molecular scaffolds is demonstrated. Twenty two scaffolds were prepared from four quaternary α-amino acid building blocks in only 49 synthetic operations, using six connective reactions. The ability of each scaffold to specifically target leadlike chemical space was demonstrated computationally.

scholarly journals Amino Acid Compositions of 27 Food Fishes and Their Importance in Clinical Nutrition

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Bimal Mohanty ◽  
Arabinda Mahanty ◽  
Satabdi Ganguly ◽  
T. V. Sankar ◽  
Kajal Chakraborty ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Protein Content ◽  
High Performance ◽  
Crude Protein ◽  
Cold Water ◽  
Building Blocks ◽  
Crude Protein Content ◽  
Dietary Counseling ◽  
Amino Acid Compositions

Proteins and amino acids are important biomolecules which regulate key metabolic pathways and serve as precursors for synthesis of biologically important substances; moreover, amino acids are building blocks of proteins. Fish is an important dietary source of quality animal proteins and amino acids and play important role in human nutrition. In the present investigation, crude protein content and amino acid compositions of important food fishes from different habitats have been studied. Crude protein content was determined by Kjeldahl method and amino acid composition was analyzed by high performance liquid chromatography and information on 27 food fishes was generated. The analysis showed that the cold water species are rich in lysine and aspartic acid, marine fishes in leucine, small indigenous fishes in histidine, and the carps and catfishes in glutamic acid and glycine. The enriched nutrition knowledge base would enhance the utility of fish as a source of quality animal proteins and amino acids and aid in their inclusion in dietary counseling and patient guidance for specific nutritional needs.

Amino Acid Functional Polymers: Biomimetic Polymer Design Enabling Catalysis, Chiral Materials, and Drug Delivery

2016 ◽  
Vol 69 (7) ◽  
pp. 705 ◽  
Author(s):  
Emma R. L. Brisson ◽  
Zeyun Xiao ◽  
Luke A. Connal
Keyword(s):  
Drug Delivery ◽  
Amino Acids ◽  
Amino Acid ◽  
Self Assembly ◽  
Building Blocks ◽  
Functional Polymers ◽  
Responsive Materials ◽  
Biomimetic Polymer ◽  
Tunable Optical Properties ◽  
Natural Building

Amino acids are the natural building blocks for the world around us. Highly functional, these small molecules have unique catalytic properties, chirality, and biocompatibility. Imparting these properties to surfaces and other macromolecules is highly sought after and represents a fast-growing field. Polymers functionalized with amino acids in the side chains have tunable optical properties, pH responsiveness, biocompatibility, structure and self-assembly properties. Herein, we review the synthesis of amino acid functional polymers, discuss manipulation of available strategies to achieve the desired responsive materials, and summarize some exciting applications in catalysis, chiral particles, and drug delivery.

The role of amino acid transporters in inherited and acquired diseases

2011 ◽  
Vol 436 (2) ◽  
pp. 193-211 ◽  
Author(s):  
Stefan Bröer ◽  
Manuel Palacín
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Mammalian Cells ◽  
Neuronal Excitability ◽  
Tumour Progression ◽  
Building Blocks ◽  
Amino Acid Uptake ◽  
Whole Body ◽  
Amino Acid Transporters ◽  
Acid Uptake

Amino acids are essential building blocks of all mammalian cells. In addition to their role in protein synthesis, amino acids play an important role as energy fuels, precursors for a variety of metabolites and as signalling molecules. Disorders associated with the malfunction of amino acid transporters reflect the variety of roles that they fulfil in human physiology. Mutations of brain amino acid transporters affect neuronal excitability. Mutations of renal and intestinal amino acid transporters affect whole-body homoeostasis, resulting in malabsorption and renal problems. Amino acid transporters that are integral parts of metabolic pathways reduce the function of these pathways. Finally, amino acid uptake is essential for cell growth, thereby explaining their role in tumour progression. The present review summarizes the involvement of amino acid transporters in these roles as illustrated by diseases resulting from transporter malfunction.

scholarly journals Homochirality May Not Be a Prerequisite for Protein Structure and Function: A Computational Model Investigation of Prebiotic Peptides

2020 ◽  
Author(s):  
Jianxun Shen ◽  
Pauline M. Schwartz ◽  
Carl Barratt
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Hierarchical Cluster ◽  
Building Blocks ◽  
Beta Sheets ◽  
Folding Energy ◽  
Primitive Earth ◽  
C Terminus ◽  
Significant Difference ◽  
Prebiotic Amino Acids

On the primitive Earth, both L- and D-amino acids would have been present. However, only L-amino acids are essential blocks to construct proteins in modern life. To study the relative stability of homochiral and heterochiral peptides, a variety of computational methods were employed. 10 prebiotic amino acids (Gly, Ala, Asp, Glu, Ile, Leu, Pro, Ser, Thr, and Val) were previously determined by multiple previous meteorite, spark discharge, and hydrothermal vent studies. We focused on what had been reported as primary early Earth polypeptide analogs: 1ARK, 1PPT, 1ZFI, and 2LZE. Tripeptide composed of only Asp, Ser, and Val exemplified that different positions (i.e., N-terminus, C-terminus, and middle) made a difference in minimal folding energy of peptides, while the classification of amino acid (hydrophobic, acidic, or hydroxylic) did not show significant difference. Hierarchical cluster analysis for dipeptides with all possible combinations of the proposed 10 prebiotic amino acids and their D-amino acid substituted derivatives generated five clusters. Prebiotic polypeptides were built up to test the significance of molecular fluctuations, secondary structure occupancies, and folding energy differences based on these clusters. Most interestingly, among 129 residues, mutation sensitivity profiles presented that the ratio of more stable to less stable to equally stable D-amino acids was about 1:1:1. In conclusion, some combinations of a mixture of L- and D-amino acids can act as essential building blocks of life. Peptides with α-helices, long β-sheets, and long loops are usually less sensitive to D-amino acid replacements in comparison to short β-sheets.

scholarly journals Non-ribosomal peptide synthetase docking domains : structure, function and engineering strategies

2021 ◽  
Author(s):  
◽  
Jonas Watzel
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Building Blocks ◽  
Peptide Chain ◽  
Solution Nmr ◽  
High Affinity ◽  
Single Protein ◽  
T Domain ◽  
Α Helix ◽  
Affinity Interaction

Non-ribosomal peptide synthetases (NRPSs) are known for their capability to produce a wide range of natural compounds and some of them possess interesting bioactivities relevant for clinical application like antibiotics, anticancer, and immunosuppressive drugs. The diverse bioactivity of non-ribosomal peptides (NRPs) originates from their structural diversity, which results not only from the incorporation of non-proteinogenic amino acids into the growing peptide chain, but also the formation of heterocycles or further peptide modifications like methylation, hydroxylation and acetylation. The biosynthesis of NRPs is achieved via the orchestrated interplay of distinct catalytic domains, which are grouped to modules that are located on one or more polypeptide chains. Each cycle starts with the selection and activation of a specific amino acid by the adenylation (A) domain, which catalyzes the aminoacyl adenylate formation under ATP consumption. This activated amino acid is then bound via a thioester bond to the 4’-phosphopantetheine cofactor (PPant-arm) of the following thiolation (T) domain. Before substrate loading, the PPant-arm is post-translationally added to the T domain by a phosphopantetheinyl transferase (PPTase), which converts the inactive apo-T domain in its active holo-form. In the last step of the catalytic cycle, two T domain bound peptide building blocks are connected by the condensation (C) domain, resulting in peptide bond formation and transfer of the nascent peptide chain to the following module. Each catalytic cycle is performed by a C-A-T elongation module until the termination module with a C-terminal thioesterase (TE) domain is reached. Here, the peptide product is released by hydrolysis or intramolecular cyclisation. In comparison to single-protein NRPSs, where all modules are encoded on a single polypeptide chain, multi-protein NRPS systems must also maintain a specific module order during the peptide biosynthesis. Therefore, small C-terminal and N-terminal communication-mediating (COM) domains/docking domains (DD) were identified in the C- and N-terminal regions of multi-protein NRPSs. It was shown that these domains mediate specific and selective non-covalent protein-protein interaction, even though DD interactions are generally characterized by low affinities. The first publication of this work focuses on the Peptide-Antimicrobial-Xenorhabdus peptide-producing NRPS called PaxS, which consists of the three proteins PaxA, PaxB and PaxC. Here, in particular the trans DD interface between the C-terminal attached DD of PaxB and N-terminal attached DD of PaxC was structurally investigated and thermodynamically characterized by isothermal titration calorimetry (ITC), yielding a dissociation constant (KD) of ~25 µM, which is a DD typical affinity known from further characterized DD pairs. The artificial linking of the PaxB/C C/NDD pair via a glycine-serine (GS) linker facilitated the structure determination of the DD complex by solution nuclear magnetic resonance (NMR) spectroscopy. In comparison to known docking domain structures, this DD complex assembles in a completely new fold which is characterized by a central α-helix of PaxC NDD wrapped in two V-shaped α-helices of PaxB CDD. The first manuscript of this work focuses on the application of synthetic zippers (SZ) to mimic natural docking domains, enabling the easy assembly of NRPS building blocks encoded on different plasmids in a functional way. Here, the high-affinity interaction of SZs unambiguously defines the order of the synthetases derived from single-protein NRPSs in the engineered NRPS system and allows the recombination in a plug-and-play manner. Notably, the SZ engineering strategy even facilitates the functional assembly of NRPSs derived from Gram-positive and Gram-negative bacteria. Furthermore, the functional incorporation of SZs into NRPS modules is not limited to a specific linker region, so we could introduce them within all native NRPS linker regions (A-T, T-C, C-A). The second publication and the second manuscript of this thesis again focus on the multi-protein PaxS, in particular on the trans interface between the proteins PaxA and PaxB on a molecular level by solution NMR. Therefore, the PaxA CDD adjacent T domain was included into the structural investigation besides the native interaction partner PaxB NDD. Before a three-dimensional structure could be obtained from NMR data, the NH groups located in the peptide bonds had to be assigned to the respective amino acids of the proteins (backbone assignment). Based on these backbone assignments, the secondary structure of PaxA T1-CDD and PaxB NDD in the absence and presence of the respective interaction partner were predicted. The structural and functional characterization of the PaxA T1-CDD:PaxB NDD complex is summarized in manuscript two. The thermodynamic analysis of this complex by ITC determined a KD value of ~250 nM, whereas the discrete DDs did not interact at all. The high-affinity interaction allowed to determine the solution NMR structure of the PaxA T1-CDD:PaxB NDD complex without the covalent linkage of the interaction partners and an extended docking domain interface could be determined. This interface comprises on the one hand α-helix 4 of the PaxA T1 domain together with the α-helical CDD, and on the other hand the PaxB NDD, which is composed of two α-helices separated by a sharp bend. ...

scholarly journals Harnessing the value of rumen protected amino acids to enhance animal performance

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Mitra Mazinani ◽  
Erdogan Memili ◽  
Brian J. Rude
Keyword(s):  
Amino Acids ◽  
Small Intestine ◽  
Amino Acid ◽  
Current Trend ◽  
Building Blocks ◽  
Microbial Protein ◽  
Daily Production ◽  
Main Site ◽  
Rumen Degradation ◽  
Amino Acid Requirements

Abstract In general, higher mammals need nine amino acids in their diets as building blocks to synthesize proteins while ruminants can produce some of them through the synthesis of microbial proteins. Diet is utilized by ruminal microorganisms to synthesize microbial protein (MCP) which is digested in the small intestine (SI). Although protein and amino acid requirements in ruminants are subject to microbial protein synthesis, it is not enough for optimal daily production. Therefore, there is a current trend towards supplementing amino acids in ruminant diets. In the rumen, free amino acids can be degraded by rumen bacteria, therefore, the AAs need to be supplemented in a protected form to be stable in the rumen and absorbable post-ruminal for metabolic purposes. The main site of amino acid absorption is the small intestine (SI), and there is a need to keep AA from ruminal degradation and direct them to absorption sites. Several approaches have been suggested by feed scientists to decrease this problem such as defaunation and debacterization of the rumen against amino acid-fermenting fungi and bacteria, inhibitors or antagonists of vitamin B6 enzymes, diet composition and also protecting AA from rumen degradation. A number of studies have evaluated the roles of amino acids concerning their effects on milk yield, growth, digestibility, feed intake and efficiency of nitrogen utilization of ruminants. The focus of this review was on experimental and research studies about AAs in feedstuff, metabolism, supplementing amino acids for ruminants and the current trends of using rumen protected amino acids.

scholarly journals Novel alanine serine cysteine transporter 2 (ASCT2) inhibitors based on sulfonamide and sulfonic acid ester scaffolds

2019 ◽  
Vol 151 (3) ◽  
pp. 357-368 ◽  
Author(s):  
Elias Ndaru ◽  
Rachel-Ann A. Garibsingh ◽  
YueYue Shi ◽  
Evan Wallace ◽  
Paul Zakrepine ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Binding Site ◽  
Acid Ester ◽  
Sulfonic Acid ◽  
Chemical Space ◽  
Glutamate Transporter ◽  
Homology Model ◽  
Side Chain ◽  
Large Variability

The neutral amino acid transporter alanine serine cysteine transporter 2 (ASCT2) belongs to the solute carrier 1 (SLC1) family of transport proteins and transports neutral amino acids, such as alanine and glutamine, into the cell in exchange with intracellular amino acids. This amino acid transport is sodium dependent, but not driven by the transmembrane Na+ concentration gradient. Glutamine transport by ASCT2 is proposed to be important for glutamine homoeostasis in rapidly growing cancer cells to fulfill the energy and nitrogen demands of these cells. Thus, ASCT2 is thought to be a potential anticancer drug target. However, the pharmacology of the amino acid binding site is not well established. Here, we report on the synthesis and characterization of a novel class of ASCT2 inhibitors based on an amino acid scaffold with a sulfonamide/sulfonic acid ester linker to a hydrophobic group. The compounds were designed based on an improved ASCT2 homology model using the human glutamate transporter hEAAT1 crystal structure as a modeling template. The compounds were shown to inhibit with a competitive mechanism and a potency that scales with the hydrophobicity of the side chain. The most potent compound binds with an apparent affinity, Ki, of 8 ± 4 µM and can block the alanine response with a Ki of 40 ± 23 µM at 200 µM alanine concentration. Computational analysis predicts inhibitor interactions with the binding site through molecular docking. In conclusion, the sulfonamide/sulfonic acid ester scaffold provides facile synthetic access to ASCT2 inhibitors with a potentially large variability in chemical space of the hydrophobic side chain. These inhibitors will be useful chemical tools to further characterize the role of ASCT2 in disease as well as improve our understanding of inhibition mechanisms of this transporter.

Transformation of the Carboxyl Group of an Amino Acid to Variously Substituted Imidazoles through a Davidson-Type Heterocyclization

Synthesis ◽  
2019 ◽  
Vol 51 (09) ◽  
pp. 1961-1968 ◽  
Author(s):  
Jim Küppers ◽  
Michaela Hympánová ◽  
Tim Keuler ◽  
Andreas Schneider ◽  
Gregor Schnakenburg ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Amino Acids ◽  
Amino Acid ◽  
Carboxylic Acid ◽  
Building Blocks ◽  
Carboxyl Group ◽  
Amino Group ◽  
Combinatorial Approach ◽  
X Ray ◽  
Imidazole Derivatives

The modification of amino acids leads to valuable building blocks for the synthesis of bioactive compounds. By keeping the amino group protected, the carboxylic acid functionality can be converted in two steps into an imidazole moiety via a Davidson-like heterocyclization. This reaction allows for a combinatorial approach, in which two positions at the heterocycle can be modified. Herein, we report the synthesis of such imidazole derivatives by employing N-protected cyclohexylalanine as the starting material. Different α-halo ketones were used and two points of diversity, positions 4 and 5, were examined. The structure of the final imidazole derivatives was confirmed by three X-ray crystal structure analyses and their protease inhibiting activities were evaluated.

How to fragment a polypeptide? An ab initio computational study of pair interactions between amino acids and ligand-amino acids in proteins

2011 ◽  
Vol 76 (5) ◽  
pp. 605-618
Author(s):  
Vojtěch Klusák ◽  
Petr Dobeš ◽  
Jiří Černý ◽  
Jiří Vondrášek
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Ab Initio ◽  
Building Blocks ◽  
Basis Set ◽  
Single Amino Acid ◽  
Amino Acid Side Chain ◽  
Protein Chain ◽  
The Stability ◽  
Dispersion Term

To determine reasonably which amino acid side chain contributes significantly to the stability of a protein or to the stability of a protein–ligand complex is not a straightforward task. We suggest a partial but systematic solution of the problem by a specific fragmentation of a protein chain into blocks of single amino acid side chains with their corresponding backbone part. For such systems of building blocks, we have calculated the stabilisation/interaction energies by means of correlated ab initio calculations. We have shown that a reasonable way to treat an amino-acid residue composing the protein is to break the homonuclear C–C bond between the Cα atom and the C(O) carboxyl carbon. The reference data obtained by the RI-MP2 method with the cc-pVDZ basis set were compared with RIDFT, RIDFT augmented by the dispersion term, SCC-DFTB-D and Hartree–Fock calculations. The results clearly show the failure of those methods lacking an appropriate treatment of the correlation energy. The DFT methods augmented by the empirical dispersion term on the other hand describe the interaction in good agreement with the reference method.

scholarly journals Unusual metabolism and hypervariation in the genome of a Gracilibacteria (BD1-5) from an oil degrading community

2019 ◽  
Author(s):  
Christian M.K. Sieber ◽  
Blair G. Paul ◽  
Cindy J. Castelle ◽  
Ping Hu ◽  
Susannah G. Tringe ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Surface Protein ◽  
Local Variation ◽  
Building Blocks ◽  
Pentose Phosphate ◽  
Stabilizing Selection ◽  
Repeat Region ◽  
Colwellia Psychrerythraea ◽  
Pentose Sugars

AbstractThe Candidate Phyla Radiation (CPR) comprises a large monophyletic group of bacterial lineages known almost exclusively based on genomes obtained using cultivation-independent methods. Within the CPR, Gracilibacteria (BD1-5) are particularly poorly understood due to undersampling and the inherent fragmented nature of available genomes. Here, we report the first closed, curated genome of a Gracilibacteria from an enrichment experiment inoculated from the Gulf of Mexico and designed to investigate hydrocarbon degradation. The gracilibacterium rose in abundance after the community switched to dominance byColwellia. Notably, we predict that this gracilibacterium completely lacks glycolysis, the pentose phosphate and Entner-Doudoroff pathways. It appears to acquire pyruvate, acetyl-CoA and oxaloacetate via degradation of externally derived citrate, malate and amino acids and may use compound interconversion and oxidoreductases to generate and recycle reductive power. The initial genome assembly was fragmented in an unusual gene that is hypervariable within a repeat region. Such extreme local variation is rare, but characteristic of genes that confer traits under pressure to diversify within a population. Notably, the four major repeated 9-mer nucleotide sequences all generate a proline-threonine-aspartic acid (PTD) repeat. The genome of an abundantColwellia psychrerythraeapopulation has a large extracellular protein that also contains the repeated PTD motif. Although we do not know the host for the BD1-5 cell, the high relative abundance of theC. psychrerythraeapopulation and the shared surface protein repeat may indicate an association between these bacteria.ImportanceCPR bacteria are generally predicted to be symbionts due to their extensive biosynthetic deficits. Although monophyletic, they are not monolithic in terms of their lifestyles. The organism described here appears to have evolved an unusual metabolic platform not reliant on glucose or pentose sugars. Its biology appears to be centered around bacterial host-derived compounds and/or cell detritus. Amino acids likely provide building blocks for nucleic acids, peptidoglycan and protein synthesis. We resolved an unusual repeat region that would be invisible without genome curation. The nucleotide sequence is apparently under strong diversifying selection but the amino acid sequence is under stabilizing selection. The amino acid repeat also occurs in a surface protein of a coexisting bacterium, suggesting co-location and possibly interdependence.

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