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1.
Making Sense of "Nonsense" and More: Challenges and Opportunities in the Genetic Code Expansion, in the World of tRNA Modifications.
Lateef, OM, Akintubosun, MO, Olaoba, OT, Samson, SO, Adamczyk, M
International journal of molecular sciences. 2022;(2)
Abstract
The evolutional development of the RNA translation process that leads to protein synthesis based on naturally occurring amino acids has its continuation via synthetic biology, the so-called rational bioengineering. Genetic code expansion (GCE) explores beyond the natural translational processes to further enhance the structural properties and augment the functionality of a wide range of proteins. Prokaryotic and eukaryotic ribosomal machinery have been proven to accept engineered tRNAs from orthogonal organisms to efficiently incorporate noncanonical amino acids (ncAAs) with rationally designed side chains. These side chains can be reactive or functional groups, which can be extensively utilized in biochemical, biophysical, and cellular studies. Genetic code extension offers the contingency of introducing more than one ncAA into protein through frameshift suppression, multi-site-specific incorporation of ncAAs, thereby increasing the vast number of possible applications. However, different mediating factors reduce the yield and efficiency of ncAA incorporation into synthetic proteins. In this review, we comment on the recent advancements in genetic code expansion to signify the relevance of systems biology in improving ncAA incorporation efficiency. We discuss the emerging impact of tRNA modifications and metabolism in protein design. We also provide examples of the latest successful accomplishments in synthetic protein therapeutics and show how codon expansion has been employed in various scientific and biotechnological applications.
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2.
Amino Acid Metabolism in Cancer Drug Resistance.
Yoo, HC, Han, JM
Cells. 2022;(1)
Abstract
Despite the numerous investigations on resistance mechanisms, drug resistance in cancer therapies still limits favorable outcomes in cancer patients. The complexities of the inherent characteristics of tumors, such as tumor heterogeneity and the complicated interaction within the tumor microenvironment, still hinder efforts to overcome drug resistance in cancer cells, requiring innovative approaches. In this review, we describe recent studies offering evidence for the essential roles of amino acid metabolism in driving drug resistance in cancer cells. Amino acids support cancer cells in counteracting therapies by maintaining redox homeostasis, sustaining biosynthetic processes, regulating epigenetic modification, and providing metabolic intermediates for energy generation. In addition, amino acid metabolism impacts anticancer immune responses, creating an immunosuppressive or immunoeffective microenvironment. A comprehensive understanding of amino acid metabolism as it relates to therapeutic resistance mechanisms will improve anticancer therapeutic strategies.
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3.
Metalloprotein-Specific or Critical Amino Acid Residues: Perspectives on Plant-Precise Detoxification and Recognition Mechanisms under Cadmium Stress.
Li, D, He, T, Saleem, M, He, G
International journal of molecular sciences. 2022;(3)
Abstract
Cadmium (Cd) pollution in cultivated land is caused by irresistible geological factors and human activities; intense diffusion and migration have seriously affected the safety of food crops. Plants have evolved mechanisms to control excessive influx of Cd in the environment, such as directional transport, chelation and detoxification. This is done by some specific metalloproteins, whose key amino acid motifs have been investigated by scientists one by one. The application of powerful cell biology, crystal structure science, and molecular probe targeted labeling technology has identified a series of protein families involved in the influx, transport and detoxification of the heavy metal Cd. This review summarizes them as influx proteins (NRAMP, ZIP), chelating proteins (MT, PDF), vacuolar proteins (CAX, ABCC, MTP), long-distance transport proteins (OPT, HMA) and efflux proteins (PCR, ABCG). We selected representative proteins from each family, and compared their amino acid sequence, motif structure, subcellular location, tissue specific distribution and other characteristics of differences and common points, so as to summarize the key residues of the Cd binding target. Then, we explain its special mechanism of action from the molecular structure. In conclusion, this review is expected to provide a reference for the exploration of key amino acid targets of Cd, and lay a foundation for the intelligent design and breeding of crops with high/low Cd accumulation.
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4.
Parahydrogen-Induced Polarization of Amino Acids.
Pravdivtsev, AN, Buntkowsky, G, Duckett, SB, Koptyug, IV, Hövener, JB
Angewandte Chemie (International ed. in English). 2021;(44):23496-23507
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Abstract
Nuclear magnetic resonance (NMR) has become a universal method for biochemical and biomedical studies, including metabolomics, proteomics, and magnetic resonance imaging (MRI). By increasing the signal of selected molecules, the hyperpolarization of nuclear spin has expanded the reach of NMR and MRI even further (e.g. hyperpolarized solid-state NMR and metabolic imaging in vivo). Parahydrogen (pH2 ) offers a fast and cost-efficient way to achieve hyperpolarization, and the last decade has seen extensive advances, including the synthesis of new tracers, catalysts, and transfer methods. The portfolio of hyperpolarized molecules now includes amino acids, which are of great interest for many applications. Here, we provide an overview of the current literature and developments in the hyperpolarization of amino acids and peptides.
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5.
Effects of Micronutrients or Conditional Amino Acids on COVID-19-Related Outcomes: An Evidence Analysis Center Scoping Review.
Rozga, M, Cheng, FW, Moloney, L, Handu, D
Journal of the Academy of Nutrition and Dietetics. 2021;(7):1354-1363
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Abstract
Recent narrative reviews have described the potential efficacy of providing individuals infected with coronavirus disease 2019 (COVID-19) with additional micronutrients to reduce disease severity. Although there are compelling reasons why providing additional micronutrients or conditional amino acids may affect COVID-19-related outcomes, evidence is lacking. The objective of this scoping review is to explore and describe the literature examining the effect of providing additional micronutrients or conditional amino acids (glutamine, arginine) in adults with conditions or infections similar to COVID-19 infection on COVID-19-related health outcomes. A literature search of the MEDLINE database and hand search of Cochrane Database of systematic reviews retrieved 1,423 unique studies, and 8 studies were included in this scoping review. Four studies examined a target population with ventilator-related pneumonia and acute respiratory distress syndrome, and the other 4 studies included patients who were at risk for ventilator-associated pneumonia. Interventions included intravenous ascorbic acid, intramuscular cholecalciferol, enteral and intramuscular vitamin E, enteral zinc sulfate, and oral and parenteral glutamine. In 6 of the 8 included studies, baseline status of the nutrient of interest was not reported and, thus, it is uncertain how outcomes may vary in the context of nutrient deficiency or insufficiency compared with sufficiency. In the absence of direct evidence examining efficacy of providing additional micronutrients or conditional amino acids to standard care, registered dietitian nutritionists must rely on clinical expertise and indirect evidence to guide medical nutrition therapy for patients infected with COVID-19.
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Amino Acid-Induced Impairment of Insulin Signaling and Involvement of G-Protein Coupling Receptor.
Zakaria, NF, Hamid, M, Khayat, ME
Nutrients. 2021;(7)
Abstract
Amino acids are needed for general bodily function and well-being. Despite their importance, augmentation in their serum concentration is closely related to metabolic disorder, insulin resistance (IR), or worse, diabetes mellitus. Essential amino acids such as the branched-chain amino acids (BCAAs) have been heavily studied as a plausible biomarker or even a cause of IR. Although there is a long list of benefits, in subjects with abnormal amino acids profiles, some amino acids are correlated with a higher risk of IR. Metabolic dysfunction, upregulation of the mammalian target of the rapamycin (mTOR) pathway, the gut microbiome, 3-hydroxyisobutyrate, inflammation, and the collusion of G-protein coupled receptors (GPCRs) are among the indicators and causes of metabolic disorders generating from amino acids that contribute to IR and the onset of type 2 diabetes mellitus (T2DM). This review summarizes the current understanding of the true involvement of amino acids with IR. Additionally, the involvement of GPCRs in IR will be further discussed in this review.
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Gluconeogenesis in Plants: A Key Interface between Organic Acid/Amino Acid/Lipid and Sugar Metabolism.
Walker, RP, Chen, ZH, Famiani, F
Molecules (Basel, Switzerland). 2021;(17)
Abstract
Gluconeogenesis is a key interface between organic acid/amino acid/lipid and sugar metabolism. The aims of this article are four-fold. First, to provide a concise overview of plant gluconeogenesis. Second, to emphasise the widespread occurrence of gluconeogenesis and its utilisation in diverse processes. Third, to stress the importance of the vacuolar storage and release of Krebs cycle acids/nitrogenous compounds, and of the role of gluconeogenesis and malic enzyme in this process. Fourth, to outline the contribution of fine control of enzyme activity to the coordinate-regulation of gluconeogenesis and malate metabolism, and the importance of cytosolic pH in this.
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Dietary protein and protein substitute requirements in adults with phenylketonuria: A review of the clinical guidelines.
Firman, S, Witard, OC, O'Keeffe, M, Ramachandran, R
Clinical nutrition (Edinburgh, Scotland). 2021;(3):702-709
Abstract
Lifelong dietary treatment is recommended in the management of phenylketonuria (PKU). Accordingly, an increasing adult population require age-specific PKU guidelines on protein requirements to support changing metabolic demands across the lifespan. Given that protein intake for dietary management of PKU is primarily (52-80%) derived from protein substitutes, the prescribing practice of protein substitutes must be underpinned by robust evidence. Whilst dietary guidelines for PKU management is evolving to incorporate adult specific protein recommendations, the scientific evidence underpinning these guidelines is currently limited. Instead, the determination of protein requirements for people with PKU have previously been extrapolated from estimates derived from the general healthy population, based on arguably outdated nitrogen balance methodology. Furthermore, a compensatory factor of 20-40% has been incorporated to account for the reduced uptake and utilisation of the elemental amino acids contained in protein substitutes. However, research informing this compensatory factor has been conducted in younger adults, with the majority of studies in non-PKU individuals. Given extensive evidence that the muscle anabolic response to ingested protein is impaired in older vs. young adults, the validity of current dietary protein recommendations for adults and older adults with PKU has been challenged. This narrative review aims to critically evaluate the existing scientific evidence underpinning current guidelines on protein requirements for adults with PKU, highlighting existing gaps in knowledge and directions for future research. We argue that current guidelines on protein requirements need updating to optimise long-term physical and functional outcomes in older adults with PKU.
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Targeting the Supply Lines of Cancer - A Possible Strategy for Combating the Disease?
Abrahamsen, O, Balslev, E, Høgdall, E
Anticancer research. 2021;(6):2737-2744
Abstract
Cancer cells alter and up-regulate their metabolic activity in order to facilitate the increased demands of malignancy. This leads to an increased need for metabolic "building materials", for example glucose and amino acids. The blood circulation represents the principal supply lines delivering these materials. It, therefore, becomes relevant to investigate if these supply lines - in terms of the concentrations of building materials in the blood - may exhibit a therapeutic window and could be intervened, as they deliver the most basal components required to exert malignant functioning. A key aspect in this strategy is that it targets - in theory - the thermodynamic foundation enabling the activities that, essentially, "make a cancer a cancer". As an initial step, this review examines if the metabolic supply lines carry clinical implications; specifically, if they impact survival and the development of metastases in patients with cancer. Furthermore, it presents and discusses perspectives on potentially targeting these supply lines.
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10.
Fueling T-cell Antitumor Immunity: Amino Acid Metabolism Revisited.
Han, C, Ge, M, Ho, PC, Zhang, L
Cancer immunology research. 2021;(12):1373-1382
Abstract
T cells are the key players in eliminating malignant tumors. Adoptive transfer of tumor antigen-specific T cells and immune checkpoint blockade has yielded durable antitumor responses in the clinic, but not all patients respond initially and some that do respond eventually have tumor progression. Thus, new approaches to enhance the utility of immunotherapy are needed. T-cell activation and differentiation status are tightly controlled at the transcriptional, epigenetic, and metabolic levels. Amino acids are involved in multiple steps of T-cell antitumor immunity, including T-cell activation, proliferation, effector function, memory formation as well as functional exhaustion. In this review, we briefly discuss how amino acid metabolism is linked to T-cell fate decisions and summarize how amino acid deprivation or accumulation of certain amino acid metabolites within the tumor microenvironment diminishes T-cell functionality. Furthermore, we discuss potential strategies for immunotherapy via modulating amino acid metabolism either in T cells intrinsically or extrinsically to achieve therapeutic efficacy.