Although neglected by science for a long time, the olfactory sense is now the focus of a panoply of studies that bring new insights and raises interesting questions regarding its functioning. The importance in the clarification of this process is of interest for science, but also motivated by the food and perfume industries boosted by a consumer society with increasingly demands for higher quality standards. In this review, a general overview of the state of art of science regarding the olfactory sense is presented with the main focus on the peripheral olfactory system. Special emphasis will be given to the deorphanization of the olfactory receptors (ORs), a critical issue because the specificity and functional properties of about 90% of human ORs remain unknown mainly due to the difficulties associated with the functional expression of ORs in high yields.
Amino acid depletion in the blood serum is currently being exploited and explored for therapies in tumors or viral infections that are auxotrophic for a certain amino acid or have a metabolic defect and cannot produce it. The success of these treatments is because normal cells remain unaltered since they are less demanding and/or can synthesize these compounds in sufficient amounts for their needs by other mechanisms. Areas covered: This review is focused on amino acid depriving enzymes and their formulations that have been successfully used in the treatment of several types of cancer and viral infections. Particular attention will be given to the enzymes L-asparaginase, L-arginase, L-arginine deiminase, and L-methionine-γ-lyase. Expert opinion: The immunogenicity and other toxic effects are perhaps the major limitations of these therapies, but they have been successfully decreased either through the expression of these enzymes from other organisms, recombination processes, pegylation of the selected enzymes or by specific mutations in the proteins. In 2006, FDA has already approved the use of L-asparaginase in the treatment of acute lymphoblastic leukemia. Other enzymes and in particular L-arginase, L-arginine deiminase, and L-methioninase have been showing promising results in vitro and in vivo studies.
The protein acetylation of either the α-amino groups of amino-terminal residues or of internal lysine or cysteine residues is one of the major posttranslational protein modifications that occur in the cell with repercussions at the protein as well as at the metabolome level. The lysine acetylation status is determined by the opposing activities of lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), which add and remove acetyl groups from proteins, respectively. A special group of KDACs, named sirtuins, that require NAD+ as a substrate have received particular attention in recent years. They play critical roles in metabolism, and their abnormal activity has been implicated in several diseases. Conversely, the modulation of their activity has been associated with protection from age-related cardiovascular and metabolic diseases and with increased longevity. The benefits of either activating or inhibiting these enzymes have turned sirtuins into attractive therapeutic targets, and considerable effort has been directed toward developing specific sirtuin modulators. This review summarizes the protein acylation/deacylation processes with a special focus on the current developments in the sirtuin research field.
This work describes the utility and efficiency of a metabolic profiling pipeline that relies on an unsupervised and untargeted approach applied to a HS-SPME/GC-MS data. This noninvasive and high throughput methodology enables "real time" monitoring of the metabolic changes inherent to the biochemical dynamics of a perturbed complex biological system and the extraction of molecular candidates that are latter validated on its biochemical context. To evaluate the efficiency of the pipeline five different fermentations, carried on a synthetic media and whose perturbation was the nitrogen source, were performed in 5 and 500 mL. The smaller volume fermentations were monitored online by HS-SPME/GC-MS, allowing to obtain metabolic profiles and molecular candidates time expression. Nontarget analysis was applied using MS data in two ways: (i) one dimension (1D), where the total ion chromatogram per sample was used, (ii) two dimensions (2D), where the integrity time vs m/z per sample was used. Results indicate that the 2D procedure captured the relevant information more efficiently than the 1D. It was also seen that although there were differences in the fermentation performance in different scales, the metabolic pathways responsible for production of metabolites that impact the quality of the volatile fraction was unaffected, so the proposed pipeline is suitable for the study of different fermentation systems that can undergo subsequent sensory validation on a larger scale.
Tryptophan Synthase (TSase) is an emergent therapeutic target in the treatment of tuberculosis. Interest in TSase as a drug target arose from the fact that this enzyme is not present in humans, while in bacteria, like M. tuberculosis, it catalyses the last two steps in the tryptophan biosynthetic pathway. Several inhibitors of TSase have recently been developed, with promising results. However, the exact catalytic mechanism of this enzyme has remained unexplained at the atomic level. The fact that TSase is a multifunctional enzyme, with two dimers, each one with two independent active sites, interconnected by a 25 Å tunnel, has made it a challenging enzyme, from the catalytic point of view. QM/MM calculations were used to analyze and explain the two steps catalyzed by this enzyme. The results provide an atomic‐level clarification of the full catalytic mechanism of this enzyme, offering also important clues for the development of new inhibitors against tuberculosis.
In this paper, computational means were used to explain and predict the interaction of several odorant molecules, including three haloanisoles, 2,4,6-trichloroanisole (TCA), 2,4,6-tribromoanisole (TBA), and 2,4,6-trichlorophenol (TCP), with three olfactory receptors (ORs): OR1A1, OR1A2, and OR3A1. As the X-ray structure of these ORs is not known, the three-dimensional structure of each OR was modeled by homology modeling. The structures of these ORs were stabilized by molecular dynamic simulations and the complexes of the odorant molecules with each ORs were generated by molecular docking. The theoretical results have shown that each OR has distinct but well-defined binding regions for each type of odorant molecules (aldehydes and alcohols). In OR3A1, the aldehydes bind in the bottom region of the binding pocket nearby Ser257 and Thr249. In the paralogues OR1A1 and OR1A2, the aldehydes tend to interact in the top region of the binding pocket and close to a positively charged lysine. On the other hand, the alcohols interact in the bottom region of the active site and close to a negatively charged aspartate. These results indicate that when aldehydes and alcohols odorants compete in these two ORs, the aldehydes can block the access of the alcohols odorants to their specific binding site. This observation goes in line with the experimental data that reveals that when the odorant is an aldehyde, a lower quantity of ligand is needed to cause 50% of the maximum response (lower EC50), when compared with the alcohols. The theoretical results have also allowed to explain the differences in the activity of (S)-(-)-citronellol in the wild-type and mutated OR1A1. The theoretical results show that Asn109 has a preponderant role in this matter, since when it is mutated, it leads to a conformational rearrangement of the binding pocket that prevents the interaction of (S)-(-)-citronellol with Asp111 that was shown to be important for the OR activation. The good agreement between the theoretical and experimental results also lead us to study the potential interaction of the haloanisoles, TCA, TBA, and TCP with these ORs. The results have shown that these compounds can compete with other known agonists/antagonists for the access to the binding regions of ORs. These results may partially explain the capability of these compounds to give a musty odor to food and beverages at very low concentrations.
Nature has tailored a wide range of metalloenzymes that play a vast array of functions in all living organisms and from which their survival and evolution depends on. These enzymes catalyze some of the most important biological processes in nature, such as photosynthesis, respiration, water oxidation, molecular oxygen reduction, and nitrogen fixation. They are also among the most proficient catalysts in terms of their activity, selectivity, and ability to operate at mild conditions of temperature, pH, and pressure. In the absence of these enzymes, these reactions would proceed very slowly, if at all, suggesting that these enzymes made the way for the emergence of life as we know today. In this review, the structure and catalytic mechanism of a selection of diverse metalloenzymes that are involved in the production of highly reactive and unstable species, such as hydroxide anions, hydrides, radical species, and superoxide molecules are analyzed. The formation of such reaction intermediates is very difficult to occur under biological conditions and only a rationalized selection of a particular metal ion, coordinated to a very specific group of ligands, and immersed in specific proteins allows these reactions to proceed. Interestingly, different metal coordination spheres can be used to produce the same reactive and unstable species, although through a different chemistry. A selection of hand-picked examples of different metalloenzymes illustrating this diversity is provided and the participation of different metal ions in similar reactions (but involving different mechanism) is discussed.
Nitrilase 2 (Nit2) is a representative member of the nitrilase superfamily that catalyzes the hydrolysis of α-ketosuccinamate into oxaloacetate. It has been associated with the metabolism of rapidly dividing cells like cancer cells. The catalytic mechanism of Nit2 employs a catalytic triad formed by Cys191, Glu81 and Lys150. The Cys191 and Glu81 play an active role during the catalytic process while the Lys150 is shown to play only a secondary role. The results demonstrate that the catalytic mechanism of Nit2 involves four steps. The nucleophilic attack of Cys191 to the α-ketosuccinamate, the formation of two tetrahedral enzyme adducts and the hydrolysis of a thioacylenzyme intermediate, from which results the formation of oxaloacetate and enzymatic turnover. The rate limiting step of the catalytic process is the formation of the first tetrahedral intermediate with a calculated activation free energy of 18.4 kcal/mol, which agrees very well with the experimental k cat (17.67 kcal/mol).
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