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Structural basis of the nonribosomal codes for nonproteinogenic amino acid selective adenylation enzymes in the biosynthesis of natural products.
Kudo, F, Miyanaga, A, Eguchi, T
Journal of industrial microbiology & biotechnology. 2019;(3-4):515-536
Abstract
Nonproteinogenic amino acids are the unique building blocks of nonribosomal peptides (NRPs) and hybrid nonribosomal peptide-polyketides (NRP-PKs) and contribute to their diversity of chemical structures and biological activities. In the biosynthesis of NRPs and NRP-PKs, adenylation enzymes select and activate an amino acid substrate as an aminoacyl adenylate, which reacts with the thiol of the holo form of the carrier protein to afford an aminoacyl thioester as the electrophile for the condensation reaction. Therefore, the substrate specificity of adenylation enzymes is a key determinant of the structure of NRPs and NRP-PKs. Here, we focus on nonproteinogenic amino acid selective adenylation enzymes, because understanding their unique selection mechanisms will lead to accurate functional predictions and protein engineering toward the rational biosynthesis of designed molecules containing amino acids. Based on recent progress in the structural analysis of adenylation enzymes, we discuss the nonribosomal codes of nonproteinogenic amino acid selective adenylation enzymes.
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2.
Proteomic analysis and prediction of amino acid variations that influence protein posttranslational modifications.
Shi, S, Wang, L, Cao, M, Chen, G, Yu, J
Briefings in bioinformatics. 2019;(5):1597-1606
Abstract
Accumulative studies have indicated that amino acid variations through changing the type of residues of the target sites or key flanking residues could directly or indirectly influence protein posttranslational modifications (PTMs) and bring about a detrimental effect on protein function. Computational mutation analysis can greatly narrow down the efforts on experimental work. To increase the utilization of current computational resources, we first provide an overview of computational prediction of amino acid variations that influence protein PTMs and their functional analysis. We also discuss the challenges that are faced while developing novel in silico approaches in the future. The development of better methods for mutation analysis-related protein PTMs will help to facilitate the development of personalized precision medicine.
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3.
Amino and organic acid analysis: Essential tools in the diagnosis of inborn errors of metabolism.
Phipps, WS, Jones, PM, Patel, K
Advances in clinical chemistry. 2019;:59-103
Abstract
Inborn errors of metabolism (IEMs) are a large class of genetic disorders that result from defects in enzymes involved in energy production and metabolism of nutrients. For every metabolic pathway, there are defects that can occur and potentially result in an IEM. While some defects can go undetected in one's lifetime, some have moderate to severe clinical consequences. In the latter case, the biochemical defect leads to accumulation of metabolites and byproducts that are toxic or interfere with normal biological function. Disorders of amino acid metabolism, organic acid metabolism and the urea cycle comprise a large portion of IEMs. Two essential tools required for the diagnosis of these categories of disorders are amino acid and organic acid profiling. Most all clinical laboratories offering metabolic testing perform amino acid analysis, while organic acid profiling is restricted to more specialized pediatric hospitals and reference laboratories. In this chapter, we will provide an overview of various methodologies employed for amino acid and organic acid profiling as well as specific examples to demonstrate how these techniques are applied in clinical laboratories for the diagnosis of IEMs.
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4.
Enzymes in Metabolic Anticancer Therapy.
Maggi, M, Scotti, C
Advances in experimental medicine and biology. 2019;:173-199
Abstract
Cancer treatment has greatly improved over the last 50 years, but it remains challenging in several cases. Useful therapeutic targets are normally unique peculiarities of cancer cells that distinguish them from normal cells and that can be tackled with appropriate drugs. It is now known that cell metabolism is rewired during tumorigenesis and metastasis as a consequence of oncogene activation and oncosuppressors inactivation, leading to a new cellular homeostasis typically directed towards anabolism. Because of these modifications, cells can become strongly or absolutely dependent on specific substrates, like sugars, lipids or amino acids. Cancer addictions are a relevant target for therapy, as removal of an essential substrate can lead to their selective cell-cycle arrest or even to cell death, leaving normal cells untouched. Enzymes can act as powerful agents in this respect, as demonstrated by asparaginase, which has been included in the treatment of Acute Lymphoblastic Leukemia for half a century. In this review, a short outline of cancer addictions will be provided, focusing on the main cancer amino acid dependencies described so far. Therapeutic enzymes which have been already experimented at the clinical level will be discussed, along with novel potential candidates that we propose as new promising molecules. The intrinsic limitations of their present molecular forms, along with molecular engineering solutions to explore, will also be presented.
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Unexplained case of hypophosphataemic rickets.
Godden, B, Hilditch, C, Agrawal, R
Journal of paediatrics and child health. 2019;(7):851-853
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Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) for Quantitative Proteomics.
Hoedt, E, Zhang, G, Neubert, TA
Advances in experimental medicine and biology. 2019;:531-539
Abstract
Stable isotope labeling by amino acids in cell culture (SILAC) is a powerful approach for high-throughput quantitative proteomics. SILAC allows highly accurate protein quantitation through metabolic encoding of whole cell proteomes using stable isotope labeled amino acids. Since its introduction in 2002, SILAC has become increasingly popular. In this chapter we review the methodology and application of SILAC, with an emphasis on three research areas: dynamics of posttranslational modifications, protein-protein interactions, and protein turnover.
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7.
Future prospects for noncanonical amino acids in biological therapeutics.
Rezhdo, A, Islam, M, Huang, M, Van Deventer, JA
Current opinion in biotechnology. 2019;:168-178
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Abstract
There is growing evidence that noncanonical amino acids (ncAAs) can be utilized in the creation of biological therapeutics ranging from protein conjugates to cell-based therapies. However, when does genetically encoding ncAAs yield biologics with unique properties compared to other approaches? In this review, we attempt to answer this question in the broader context of therapeutic development, emphasizing advances within the past two years. In several areas, ncAAs add valuable routes to therapeutically relevant entities, but application-specific needs ultimately determine whether ncAA-mediated or alternative solutions are preferred. Looking forward, using ncAAs to perform 'protein medicinal chemistry,' in which atomic-level changes to proteins dramatically enhance therapeutic properties, is a promising emerging area. Further upgrades to the performance of ncAA incorporation technologies will be essential to realizing the full potential of ncAAs in biological therapeutics.
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8.
Whi2: a new player in amino acid sensing.
Teng, X, Hardwick, JM
Current genetics. 2019;(3):701-709
Abstract
A critical function of human, yeast, and bacterial cells is the ability to sense and respond to available nutrients such as glucose and amino acids. Cells must also detect declining nutrient levels to adequately prepare for starvation conditions by inhibiting cell growth and activating autophagy. The evolutionarily conserved protein complex TORC1 regulates these cellular responses to nutrients, and in particular to amino acid availability. Recently, we found that yeast Whi2 (Saccharomyces cerevisiae) and a human counterpart, KCTD11, that shares a conserved BTB structural domain, are required to suppress TORC1 activity under low amino acid conditions. Using yeast, the mechanisms were more readily dissected. Unexpectedly, Whi2 suppresses TORC1 activity independently of the well-known SEACIT-GTR pathway, analogous to the GATOR1-RAG pathway in mammals. Instead, Whi2 requires the plasma membrane-associated phosphatases Psr1 and Psr2, which were known to bind Whi2, although their role was unknown. Yeast WHI2 was previously reported to be involved in regulating several fundamental cellular processes including cell cycle arrest, general stress responses, the Ras-cAMP-PKA pathway, autophagy, and mitophagy, and to be frequently mutated in the yeast knockout collections and in genome evolution studies. Most of these observations are likely explained by the ability of Whi2 to inhibit TORC1. Thus, understanding the function of yeast Whi2 will provide deeper insights into the disease-related KCTD family proteins and the pathogenesis of plant and human fungal infections.
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Selection, Addiction and Catalysis: Emerging Trends for the Incorporation of Noncanonical Amino Acids into Peptides and Proteins in Vivo.
Mayer, C
Chembiochem : a European journal of chemical biology. 2019;(11):1357-1364
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Abstract
Expanding the genetic code of organisms by incorporating noncanonical amino acids (ncAAs) into target proteins through the suppression of stop codons in vivo has profoundly impacted how we perform protein modification or detect proteins and their interaction partners in their native environment. Yet, with genetic code expansion strategies maturing over the past 15 years, new applications that make use-or indeed repurpose-these techniques are beginning to emerge. This Concept article highlights three of these developments: 1) The incorporation of ncAAs for the biosynthesis and selection of bioactive macrocyclic peptides with novel ring architectures, 2) synthetic biocontainment strategies based on the addiction of microorganisms to ncAAs, and 3) enzyme design strategies, in which ncAAs with unique functionalities enable the catalysis of new-to-nature reactions. Key advances in all three areas are presented and potential future applications discussed.
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10.
Recent Progress in Chemical Modification of Proteins.
Sakamoto, S, Hamachi, I
Analytical sciences : the international journal of the Japan Society for Analytical Chemistry. 2019;(1):5-27
Abstract
Chemical modification of proteins is important for creating a myriad of engineered proteins and for elucidating the function and dynamics of proteins in live cells. A wide variety of chemical protein modification methods have been developed and can be categorized into three classes: (i) modification of proteins using the reactivity of naturally occurring amino acids; (ii) modification by bioorthogonal reactions using unnatural amino acids, most of which can be site-selectively incorporated into proteins-of-interest using genetic codon expansion techniques; and (iii) recognition driven chemical modification, which is the only approach that allows modification of endogenous proteins without any genetic manipulation even under heavily crowded and multi-molecular conditions, as in live cells and organisms. All of these approaches have merits and limitations. In this review, we summarize these approaches and discuss their characteristics with respect to specificity, reaction rate and versatility.