-
Chemical & Pharmaceutical Bulletin 2016γ-Glutamylcyclotransferase (GGCT) is an important enzyme that cleaves γ-glutamyl-amino acid in the γ-glutamyl cycle to release 5-oxoproline and amino acid. Eighteen...
γ-Glutamylcyclotransferase (GGCT) is an important enzyme that cleaves γ-glutamyl-amino acid in the γ-glutamyl cycle to release 5-oxoproline and amino acid. Eighteen N-acyl-L-alanine analogues including eleven new compounds have been synthesized and examined for their inhibitory activity against recombinant human GGCT protein. Simple N-glutaryl-L-alanine was found to be the most potent inhibitor for GGCT. Other N-glutaryl-L-alanine analogues having methyl and dimethyl substituents at the 2-position were moderately effective, while N-(3R-aminoglutary)-L-alanine, the substrate having an (R)-amino group at the 3-position or N-(N-methyl-3-azaglutaryl)-L-alanine, the substrate having an N-methyl substituent on the 3-azaglutaryl carbon, in constract, exhibited excellent inhibition properties.
Topics: Alanine; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Molecular Structure; Structure-Activity Relationship; gamma-Glutamylcyclotransferase
PubMed: 27373633
DOI: 10.1248/cpb.c16-00167 -
Molecules (Basel, Switzerland) Aug 2010Lanthionine (Lan), the thioether analog of cystine, is a natural but nonproteogenic amino acid thought to form naturally in mammals through promiscuous reactivity of the... (Review)
Review
Lanthionine (Lan), the thioether analog of cystine, is a natural but nonproteogenic amino acid thought to form naturally in mammals through promiscuous reactivity of the transsulfuration enzyme cystathionine-beta-synthase (CbetaS). Lanthionine exists at appreciable concentrations in mammalian brain, where it undergoes aminotransferase conversion to yield an unusual cyclic thioether, lanthionine ketimine (LK; 2H-1,4-thiazine-5,6-dihydro-3,5-dicarboxylic acid). Recently, LK was discovered to possess neuroprotective, neuritigenic and anti-inflammatory activities. Moreover, both LK and the ubiquitous redox regulator glutathione (gamma-glutamyl-cysteine-glycine) bind to mammalian lanthionine synthetase-like protein-1 (LanCL1) protein which, along with its homolog LanCL2, has been associated with important physiological processes including signal transduction and insulin sensitization. These findings begin to suggest that Lan and its downstream metabolites may be physiologically important substances rather than mere metabolic waste. This review summarizes the current state of knowledge about lanthionyl metabolites with emphasis on their possible relationships to LanCL1/2 proteins and glutathione. The potential significance of lanthionines in paracrine signaling is discussed with reference to opportunities for utilizing bioavailable pro-drug derivatives of these compounds as novel pharmacophores.
Topics: Alanine; Amination; Animals; Central Nervous System; Cystathionine beta-Synthase; Humans; Neuroprotective Agents; Substrate Specificity; Sulfides
PubMed: 20714314
DOI: 10.3390/molecules15085581 -
ACS Chemical Biology Jan 2015Formylglycine (fGly) is a catalytically essential residue found almost exclusively in the active sites of type I sulfatases. Formed by post-translational oxidation of... (Review)
Review
Formylglycine (fGly) is a catalytically essential residue found almost exclusively in the active sites of type I sulfatases. Formed by post-translational oxidation of cysteine or serine side chains, this aldehyde-functionalized residue participates in a unique and highly efficient catalytic mechanism for sulfate ester hydrolysis. The enzymes that produce fGly, formylglycine-generating enzyme (FGE) and anaerobic sulfatase-maturating enzyme (anSME), are as unique and specialized as fGly itself. FGE especially is structurally and mechanistically distinct, and serves the sole function of activating type I sulfatase targets. This review summarizes the current state of knowledge regarding the mechanism by which fGly contributes to sulfate ester hydrolysis, the molecular details of fGly biogenesis by FGE and anSME, and finally, recent biotechnology applications of fGly beyond its natural catalytic function.
Topics: Alanine; Animals; Binding Sites; Biotechnology; Catalysis; Catalytic Domain; Cysteine; Glycine; Humans; Models, Molecular; Protein Processing, Post-Translational; Serine; Sulfotransferases
PubMed: 25514000
DOI: 10.1021/cb500897w -
Nuclear Medicine and Biology Oct 2012This paper reports the synthesis and labeling of (18)F alanine derivatives. We also investigate their biological characteristics as potential tumor imaging agents...
INTRODUCTION
This paper reports the synthesis and labeling of (18)F alanine derivatives. We also investigate their biological characteristics as potential tumor imaging agents mediated by alanine-serine-cysteine preferring (ASC) transporter system.
METHODS
Three new (18)F alanine derivatives were prepared from corresponding tosylate-precursors through a two-step labeling reaction. In vitro uptake studies to evaluate and to compare these three analogs were carried out in 9L glioma and PC-3 prostate cancer cell lines. Potential transport mechanisms, protein incorporation and stability of 3-(1-[(18)F]fluoromethyl)-L-alanine (L-[(18)F]FMA) were investigated in 9L glioma cells. Its biodistribution was determined in a rat-bearing 9L tumor model. PET imaging studies were performed on rat bearing 9L glioma tumors and transgenic mouse carrying spontaneous generated M/tomND tumor (mammary gland adenocarcinoma).
RESULTS
New (18)F alanine derivatives were prepared with 7%-34% uncorrected radiochemical yields, excellent enantiomeric purity (>99%) and good radiochemical purity (>99%). In vitro uptake of the L-[(18)F]FMA in 9L glioma and PC-3 prostate cancer cells was higher than that observed for the other two alanine derivatives and [(18)F]FDG in the first 1h. Inhibition of cell uptake studies suggested that L-[(18)F]FMA uptake in 9L glioma was predominantly via transport system ASC. After entering into cells, L-[(18)F]FMA remained stable and was not incorporated into protein within 2h. In vivo biodistribution studies demonstrated that L-[(18)F]FMA had relatively high uptake in liver and kidney. Tumor uptake was fast, reaching a maximum within 30 min. The tumor-to-muscle, tumor-to-blood and tumor-to-brain ratios at 60 min post injection were 2.2, 1.9 and 3.0, respectively. In PET imaging studies, tumors were visualized with L-[(18)F]FMA in both 9L rat and transgenic mouse.
CONCLUSION
L-[(18)F]FMA showed promising properties as a PET imaging agent for up-regulated ASC transporter associated with tumor proliferation.
Topics: Alanine; Animals; Biological Transport; Cell Line, Tumor; Chemistry Techniques, Synthetic; Female; Fluorine Radioisotopes; Humans; Isotope Labeling; Male; Mammary Neoplasms, Experimental; Mice; Positron-Emission Tomography; Rats; Stereoisomerism
PubMed: 22542392
DOI: 10.1016/j.nucmedbio.2012.03.007 -
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 -
Biochimica Et Biophysica Acta.... Nov 2017Solid-state NMR spectra of whole cells and isolated cell walls of Enterococcus faecalis grown in media containing combinations of C and N specific labels in d- and...
Solid-state NMR spectra of whole cells and isolated cell walls of Enterococcus faecalis grown in media containing combinations of C and N specific labels in d- and l-alanine and l-lysine (in the presence of an alanine racemase inhibitor alaphosphin) have been used to determine the composition and architecture of the cell-wall peptidoglycan. The compositional variables include the concentrations of (i) peptidoglycan stems without bridges, (ii) d-alanylated wall teichoic acid, (iii) cross-links, and (iv) uncross-linked tripeptide and tetra/pentapeptide stems. Connectivities of l-alanyl carbonyl‑carbon bridge labels to d-[3-C]alanyl and l-[ε-N]lysyl stem labels prove that the peptidoglycan of E. faecalis has the same hybrid short-bridge architecture (with a mix of parallel and perpendicular stems) as the FemA mutant of Staphylococcus aureus, in which the cross-linked stems are perpendicular to one another and the cross-linking is close to the ideal 50% value. This is the first determination of the cell-wall chemical and geometrical architecture of whole cells of E. faecalis, a major source of nosocomial infections worldwide.
Topics: Alanine; Amino Acid Sequence; Carbohydrate Sequence; Cell Wall; Enterococcus faecalis; Lysine; Magnetic Resonance Spectroscopy; Peptidoglycan; Protein Structure, Tertiary; Sequence Analysis, Protein; Teichoic Acids
PubMed: 28784459
DOI: 10.1016/j.bbamem.2017.08.003 -
Acta Crystallographica. Section C,... Apr 2014The title peptide, N-benzyloxycarbonyl-α-aminoisobutyryl-α-aminoisobutyryl-α-aminoisobutyryl-L-alanine tert-butyl ester or Z-Aib-Aib-Aib-L-Ala-OtBu (Aib is...
The title peptide, N-benzyloxycarbonyl-α-aminoisobutyryl-α-aminoisobutyryl-α-aminoisobutyryl-L-alanine tert-butyl ester or Z-Aib-Aib-Aib-L-Ala-OtBu (Aib is α-aminoisobutyric acid, Z is benzyloxycarbonyl and OtBu indicates the tert-butyl ester), C27H42N4O7, is a left-handed helix with a right-handed conformation in the fourth residue, which is the only chiral residue. There are two 4→1 intramolecular hydrogen bonds in the structure. In the lattice, molecules are hydrogen bonded to form columns along the c axis.
Topics: Alanine; Amino Acid Sequence; Aminoisobutyric Acids; Crystallography, X-Ray; Hydrogen Bonding; Oligopeptides; Peptides
PubMed: 24705058
DOI: 10.1107/S2053229614005567 -
The Journal of Physical Chemistry. B Apr 2009We introduce the Gaussian-mixture umbrella sampling method (GAMUS) , a biased molecular dynamics technique based on adaptive umbrella sampling that efficiently escapes...
We introduce the Gaussian-mixture umbrella sampling method (GAMUS) , a biased molecular dynamics technique based on adaptive umbrella sampling that efficiently escapes free energy minima in multidimensional problems. The prior simulation data are reweighted with a maximum likelihood formulation, and the new approximate probability density is fit to a Gaussian-mixture model, augmented by information about the unsampled areas. The method can be used to identify free energy minima in multidimensional reaction coordinates. To illustrate GAMUS , we apply it to the alanine dipeptide (2D reaction coordinate) and tripeptide (4D reaction coordinate).
Topics: Alanine; Computer Simulation; Models, Chemical; Oligopeptides
PubMed: 19284746
DOI: 10.1021/jp808381s -
Journal of Molecular Biology Sep 2022While being a thoroughly studied model of dynamic allostery in a small protein, the pathway of signal transduction in the PDZ3 domain has not been fully determined....
While being a thoroughly studied model of dynamic allostery in a small protein, the pathway of signal transduction in the PDZ3 domain has not been fully determined. Here, we investigate peptide binding to the PDZ3 domain by conventional and fully data-driven analyses of molecular dynamics simulations. First, we identify isoleucine 37 as a key residue by widely used computational procedures such as cross-correlation and community network analysis. Simulations of the Ile37Ala mutant show disruption of the coordinated movements of spatially close regular elements of secondary structure. Then, we employ a recently developed unsupervised, data-driven procedure to determine an optimized reaction coordinate (slowest-relaxation eigenvector) of peptide binding. We use this reaction coordinate to improve sampling by restarting additional simulations from the transition state region. Significant differences in the distributions of some of the pairwise residue distances in the bound and unbound states emerge from the projection onto the optimized reaction coordinate. The unsupervised analysis shows that allosteric signaling is transduced from the β2 strand, which forms part of the peptide binding site, to the spatially adjacent β3 and β4 strands, and from there to the α3 helix. The domino-like transmission of a (peptide binding) signal along β strands and α helices that are close in three-dimensional space is likely to be a general mechanism of allostery in single-domain proteins.
Topics: Alanine; Allosteric Regulation; Allosteric Site; Isoleucine; Molecular Dynamics Simulation; Peptides; Protein Binding; Protein Structure, Secondary; Signal Transduction
PubMed: 35640719
DOI: 10.1016/j.jmb.2022.167661 -
Pharmacology 2021The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiology of COVID-19 pandemic, resulted in significant harm to the affected countries in every... (Review)
Review
BACKGROUND
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiology of COVID-19 pandemic, resulted in significant harm to the affected countries in every aspect of life. The virus infected over 139 million patients and resulted in over 2.9 million deaths until April 16, 2021. New variants of this virus were identified that spread rapidly worldwide.
SUMMARY
Remdesivir, a prodrug of adenosine nucleotide analog, is an antiviral with a broad spectrum of activity that was tested on SARS and Middle East respiratory syndrome infections. In vitro studies conducted on SARS-CoV-2 revealed that remdesivir inhibited viral replication with high selectivity index in cell cultures. In vivo studies showed that remdesivir reduced viral load in bronchoalveolar lavage fluid and attenuated pulmonary infiltrates in infected animals. Further, remdesivir showed promising results in terms of clinical improvement, shortening the recovery time, mortality rate, and the duration of oxygen need, despite that some clinical trials did not reveal significant effect on remdesivir use. Several studies showed positive results of remdesivir against the new variants. Key Messages: Remdesivir showed a promising beneficial effect against new variants of SARS-CoV-2, but more clinical evidence is needed to confirm this effect.
Topics: Adenosine Monophosphate; Alanine; Animals; Antiviral Agents; COVID-19; Humans; Pandemics; Randomized Controlled Trials as Topic; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34515227
DOI: 10.1159/000518440