Browsing by Subject "Alanine"

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Open Access
Application of the Ugi reaction with multiple amino acid-derived components: Synthesis and conformational evaluation of piperazine-based minimalist peptidomimetics
(Royal Society of Chemistry, 2015) Stucchi, M.; Cairati, S.; Cetin-Atalay, R.; Christodoulou, M.S.; Grazioso G.; Pescitelli G.; Silvani, A.; Yildirim, D.C.; Lesma G.
The concurrent employment of α-amino acid-derived chiral components such as aldehydes and α-isocyanoacetates, in a sequential Ugi reaction/cyclization two-step strategy, opens the door to the synthesis of three structurally distinct piperazine-based scaffolds, characterized by the presence of l-Ala and/or l-Phe-derived side chains and bearing appropriate functionalities to be easily applied in peptide chemistry. By means of computational studies, these scaffolds have been demonstrated to act as minimalist peptidomimetics, able to mimic a well defined range of peptide secondary structures and therefore potentially useful for the synthesis of small-molecule PPI modulators. Preliminary biological evaluation of two different resistant hepatocellular carcinoma cellular lines, for which differentiation versus resistance ability seem to be strongly correlated with well defined types of PPIs, has revealed a promising antiproliferative activity for selected compounds. © The Royal Society of Chemistry 2015.
Open Access
High-resolution magic anglespinning ¹H nuclear magnetic resonance spectroscopy metabolomics of hyperfunctioning parathyroid glands
(Mosby, Inc., 2016) Battini, S.; Imperiale, A.; Taïeb, D.; Elbayed, K.; Cicek, A. E.; Sebag, F.; Brunaud, L.; Namer, Izzie-Jacques
Background Primary hyperparathyroidism (PHPT) may be related to a single gland disease or multiglandular disease, which requires specific treatments. At present, an operation is the only curative treatment for PHPT. Currently, there are no biomarkers available to identify these 2 entities (single vs. multiple gland disease). The aims of the present study were to compare (1) the tissue metabolomics profiles between PHPT and renal hyperparathyroidism (secondary and tertiary) and (2) single gland disease with multiglandular disease in PHPT using metabolomics analysis. Methods The method used was 1H high-resolution magic angle spinning nuclear magnetic resonance spectroscopy. Forty-three samples from 32 patients suffering from hyperparathyroidism were included in this study. Results Significant differences in the metabolomics profile were assessed according to PHPT and renal hyperparathyroidism. A bicomponent orthogonal partial least square-discriminant analysis showed a clear distinction between PHPT and renal hyperparathyroidism (R2Y = 0.85, Q2 = 0.63). Interestingly, the model also distinguished single gland disease from multiglandular disease (R2Y = 0.96, Q2 = 0.55). A network analysis was also performed using the Algorithm to Determine Expected Metabolite Level Alterations Using Mutual Information (ADEMA). Single gland disease was accurately predicted by ADEMA and was associated with higher levels of phosphorylcholine, choline, glycerophosphocholine, fumarate, succinate, lactate, glucose, glutamine, and ascorbate compared with multiglandular disease. Conclusion This study shows for the first time that 1H high-resolution magic angle spinning nuclear magnetic resonance spectroscopy is a reliable and fast technique to distinguish single gland disease from multiglandular disease in patients with PHPT. The potential use of this method as an intraoperative tool requires specific further studies.
Open Access
Structures and free energy landscapes of the wild-type and A30P mutant-type α-synuclein proteins with dynamics
(2013) Wise-Scira O.; Aloglu, A.K.; Dunn, A.; Sakallioglu I.T.; Coskuner O.
The genetic missense A30P mutation of the wild-type α-synuclein protein results in the replacement of the 30th amino acid residue from alanine (Ala) to proline (Pro) and was initially found in the members of a German family who developed Parkinson's disease. Even though the structures of these proteins have been measured before, detailed understanding about the structures and their relationships with free energy landscapes is lacking, which is of interest to provide insights into the pathogenic mechanism of Parkinson's disease. We report the secondary and tertiary structures and conformational free energy landscapes of the wild-type and A30P mutant-type α-synuclein proteins in an aqueous solution environment via extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations. In addition, we present the residual secondary structure component transition stabilities at the atomic level with dynamics in terms of free energy change calculations using a new strategy that we reported most recently. Our studies yield new interesting results; for instance, we find that the A30P mutation has local as well as long-range effects on the structural properties of the wild-type α-synuclein protein. The helical content at Ala18-Gly31 is less prominent in comparison to the wild-type α-synuclein protein. The β-sheet structure abundance decreases in the N-terminal region upon A30P mutation of the wild-type α-synuclein, whereas the NAC and C-terminal regions possess larger tendencies for β-sheet structure formation. Long-range intramolecular protein interactions are less abundant upon A30P mutation, especially between the NAC and C-terminal regions, which is linked to the less compact and less stable structures of the A30P mutant-type rather than the wild-type α-synuclein protein. Results including the usage of our new strategy for secondary structure transition stabilities show that the A30P mutant-type α-synuclein tendency toward aggregation is higher than the wild-type α-synuclein but we also find that the C-terminal and NAC regions of the A30P mutant-type α-synuclein are reactive toward fibrillzation and aggregation based on atomic level studies with dynamics in an aqueous solution environment. Therefore, we propose that small molecules or drugs blocking the specific residues, which we report herein, located in the NAC- and C-terminal regions of the A30P mutant-type α-synuclein protein might help to reduce the toxicity of the A30P mutant-type α-synuclein protein. © 2013 American Chemical Society.