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Arginine methylation: the promise of a 'silver bullet' for brain tumours?
Samuel, SF, Barry, A, Greenman, J, Beltran-Alvarez, P
Amino acids. 2021;(4):489-506
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Abstract
Despite intense research efforts, our pharmaceutical repertoire against high-grade brain tumours has not been able to increase patient survival for a decade and life expectancy remains at less than 16 months after diagnosis, on average. Inhibitors of protein arginine methyltransferases (PRMTs) have been developed and investigated over the past 15 years and have now entered oncology clinical trials, including for brain tumours. This review collates recent advances in the understanding of the role of PRMTs and arginine methylation in brain tumours. We provide an up-to-date literature review on the mechanisms for PRMT regulation. These include endogenous modulators such as alternative splicing, miRNA, post-translational modifications and PRMT-protein interactions, and synthetic inhibitors. We discuss the relevance of PRMTs in brain tumours with a particular focus on PRMT1, -2, -5 and -8. Finally, we include a future perspective where we discuss possible routes for further research on arginine methylation and on the use of PRMT inhibitors in the context of brain tumours.
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Protein arginine phosphorylation in organisms.
Huang, B, Zhao, Z, Zhao, Y, Huang, S
International journal of biological macromolecules. 2021;:414-422
Abstract
Protein arginine phosphorylation (pArg), a novel molecular switch, plays a key role in regulating cellular processes. The intrinsic acid lability, hot sensitivity, and hot-alkali instability of "high-energy" phosphoamidate (PN bond) in pArg, make the investigation highly difficult and challenging. Recently, the progress in identifying prokaryotic protein arginine kinase/phosphatase and assigning hundreds of pArg proteins and phosphosites has been made, which is arousing scientists' interest and passions. It shows that pArg is tightly connected to bacteria stress response and pathogenicity, and is probably implied in human diseases. In this review, we highlight the strategies for investigation of this mysterious modification and its momentous physiological functions, and also prospect for the potentiality of drugs development targeting pArg-relative pathways.
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3.
Arginine supplementation and cardiometabolic risk.
Mariotti, F
Current opinion in clinical nutrition and metabolic care. 2020;(1):29-34
Abstract
PURPOSE OF REVIEW Because arginine is the substrate for nitric oxide synthesis, which is pivotal to vascular homeostasis and linked to the insulin response, it has long been posited that supplemental arginine could benefit cardiometabolic health. RECENT FINDINGS Recent data have supported the view that supplemental arginine could alleviate the initiation and development of endothelial dysfunction and also shown that it may reduce the risk of type 2 diabetes. One important finding is that these effects may indeed vary as a function of the amount of arginine, its form and notably the metabolic status of the population. Some studies have shown that low doses of slow-release arginine are better used for nitric oxide synthesis and beneficial in individuals with abnormal arginine metabolism/bioavailability. Pathophysiological data in rodents have emphasized the importance of arginase activation during the development of cardiometabolic risk, which lends credence to a potential benefit for arginine supplements. Likewise, epidemiological evidence suggests that alterations to arginine bioavailability are important regarding the cardiometabolic risk. However, other metabolic mechanisms linked to the multiple pathways of arginine metabolism may also play a role. SUMMARY Further studies are needed to confirm and analyze how and when supplemental arginine is beneficial to cardiometabolic health.
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The Role of Immunonutrition in Patients Undergoing Pancreaticoduodenectomy.
Jabłońska, B, Mrowiec, S
Nutrients. 2020;(9)
Abstract
Pancreaticoduodenectomy (PD) is one of the most difficult and complex surgical procedures in abdominal surgery. Malnutrition and immune dysfunction in patients with pancreatic cancer (PC) may lead to a higher risk of postoperative infectious complications. Although immunonutrition (IN) is recommended for enhanced recovery after surgery (ERAS) in patients undergoing PD for 5-7 days perioperatively, its role in patients undergoing pancreatectomy is still unclear and controversial. It is known that the proper surgical technique is very important in order to reduce a risk of postoperative complications, such as a pancreatic fistula, and to improve disease-free survival in patients following PD. However, it has been proven that IN decreases the risk of infectious complications, and shortens hospital stays in patients undergoing PD. This is a result of the impact on altered inflammatory responses in patients with cancer. Both enteral and parenteral, as well as preoperative and postoperative IN, using various nutrients, such as glutamine, arginine, omega-3 fatty acids and nucleotides, is administered. The most frequently used preoperative oral supplementation is recommended. The aim of this paper is to present the indications and benefits of IN in patients undergoing PD.
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5.
Effects of l-arginine supplementation on glycemic profile: Evidence from a systematic review and meta-analysis of clinical trials.
Yousefi Rad, E, Nazarian, B, Saboori, S, Falahi, E, Hekmatdoost, A
Journal of integrative medicine. 2020;(4):284-291
Abstract
BACKGROUND The effects of l-arginine supplementation on indices of glycemic control and the role of many factors influencing this intervention have been controversial in clinical trials. OBJECTIVE This meta-analysis was performed to assess the effects of l-arginine supplementation on indices of glycemic control, including fasting blood glucose (FBG), hemoglobin A1c (HbA1c), serum insulin and homeostatic model assessment of insulin resistance (HOMA-IR) levels in randomized controlled trials (RCTs). SEARCH STRATEGY This study conducted a systematic review of RCTs published in PubMed, Scopus, Web of Science, Cochrane Library and Embase, up to 5 May, 2018. INCLUSION CRITERIA Studies were included in this meta-analysis if they were RCTs with parallel design and reported sufficient data on participants before and after intervention, and outcomes of glycemic profile parameters in both the arginine supplementation and control groups. DATA EXTRACTION AND ANALYSIS The screening of titles and abstracts was performed independently by two reviewers. Selected articles were considered if they met the study's inclusion criteria. The quality of included studies was assessed by using the Cochrane Collaboration modified tool. From 710 articles retrieved in the initial search, only 10 trials were suitable for pooling the effects of arginine supplementation on serum glucose, insulin, HOMA-IR and HbA1c levels, with effect sizes of nine, eight, five and five, respectively. RESULTS Pooled random-effect analysis revealed that l-arginine supplementation could significantly decrease FBG level (weighted mean difference [WMD]: 3.35 mg/dL; 95% confidence interval [CI] = [-6.55, -0.16]; P = 0.04) and serum insulin level (WMD: -2.19 μIU/mL; 95% CI = [-3.70, -0.67]; P = 0.005). However, the effects of l-arginine supplementation on HOMA-IR and HbA1c were not significant. Results of subgroup analysis showed that supplementation with l-arginine could significantly decrease serum insulin levels when the dosage of l-arginine is > 6.5 g/d (WMD: -3.49 μIU/mL; 95% CI = [-5.59, -1.38]; P = 0.001), when the duration of supplementation is ≤ 12.8 weeks (WMD: -3.76; 95% CI = [-6.50, -0.98]; P = 0.008), when the participants are not diabetic patients (WMD: -2.54 μIU/mL; 95% CI = [-4.50, -0.50]; P = 0.01) and when the baseline serum level of insulin was > 20 μIU/mL (WMD: -3.98; 95% CI = [-6.31, -1.65]; P = 0.001). CONCLUSION Although the results of this study confirmed that supplementation with l-arginine could have significant effects on some glycemic profile indices of participants in clinical trials, the clinical importance of this reduction may not be meaningful.
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6.
Exploiting binding-site arginines in drug design: Recent examples.
Lin, H, Luengo, JI
Bioorganic & medicinal chemistry letters. 2020;(19):127442
Abstract
Active or allosteric site arginines can form diverse interactions with ligands including different types of cation-π interactions, H-bond interactions and non-bond, non-canonical interactions. This provides many opportunities for creative structure-based drug design to improve potency, introduce novelty, and modulate MoA (mode of action), and even to achieve selectivity. This digest will use some recent drug targets of interest as examples to illustrate different types of interactions and how these interactions impact on potency, MoA, and selectivity.
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Exceptionally versatile - arginine in bacterial post-translational protein modifications.
Lassak, J, Koller, F, Krafczyk, R, Volkwein, W
Biological chemistry. 2019;(11):1397-1427
Abstract
Post-translational modifications (PTM) are the evolutionary solution to challenge and extend the boundaries of genetically predetermined proteomic diversity. As PTMs are highly dynamic, they also hold an enormous regulatory potential. It is therefore not surprising that out of the 20 proteinogenic amino acids, 15 can be post-translationally modified. Even the relatively inert guanidino group of arginine is subject to a multitude of mostly enzyme mediated chemical changes. The resulting alterations can have a major influence on protein function. In this review, we will discuss how bacteria control their cellular processes and develop pathogenicity based on post-translational protein-arginine modifications.
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Evaluation of kinetic data: What the numbers tell us about PRMTs.
Frankel, A, Brown, JI
Biochimica et biophysica acta. Proteins and proteomics. 2019;(3):306-316
Abstract
Protein arginine N-methyltransferase (PRMT) kinetic parameters have been catalogued over the past fifteen years for eight of the nine mammalian enzyme family members. Like the majority of methyltransferases, these enzymes employ the highly ubiquitous cofactor S-adenosyl-l-methionine as a co-substrate to methylate arginine residues in peptidic substrates with an approximately 4-μM median KM. The median values for PRMT turnover number (kcat) and catalytic efficiency (kcat/KM) are 0.0051 s-1 and 708 M-1 s-1, respectively. When comparing PRMT metrics to entries found in the BRENDA database, we find that while PRMTs exhibit high substrate affinity relative to other enzyme-substrate pairs, PRMTs display largely lower kcat and kcat/KM values. We observe that kinetic parameters for PRMTs and arginine demethylase activity from dual-functioning lysine demethylases are statistically similar, paralleling what the broader enzyme families in which they belong reveal, and adding to the evidence in support of arginine methylation reversibility.
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9.
Protein Solvent Interaction: Transition of Protein-solvent Interaction Concept from Basic Research into Solvent Manipulation of Chromatography.
Arakawa, T, Kita, Y
Current protein & peptide science. 2019;(1):34-39
Abstract
Previously, we have reviewed in this journal (Arakawa, T., Kita, Y., Curr. Protein Pept. Sci., 15, 608-620, 2014) the interaction of arginine with proteins and various applications of this solvent additive in the area of protein formulations and downstream processes. In this special issue, we expand the concept of protein-solvent interaction into the analysis of the effects of solvent additives on various column chromatography, including mixed-mode chromatography. Earlier in our research, we have studied the interactions of such a variety of solvent additives as sugars, salts, amino acids, polymers and organic solvents with a variety of proteins, which resulted in mechanistic understanding on their protein stabilization and precipitation effects, the latter known as Hofmeister series. While such a study was then a pure academic research, rapid development of genetic engineering technologies and resultant biotechnologies made it a valuable knowledge in fully utilizing solvent additives in manipulation of protein solution, including column chromatography.
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10.
[Enzymatic production of arginine derivatives: a review].
Sun, A, Song, W, Liu, J, Luo, Q, Chen, X, Liu, L
Sheng wu gong cheng xue bao = Chinese journal of biotechnology. 2018;(2):165-176
Abstract
L-arginine (L-Arg) is an alkaline amino acid that possesses various function groups and acts as an important precursor for useful chemical synthesis. L-Arg derivatives are widely applied in pharmaceutical, food and cosmetic industries. Environment friendly and cost-effective production of L-Arg derivatives by enzymatic catalysis provides significant advantages over chemical synthesis and microbial fermentation. In this article, several typical L-Arg derivatives and their enzymatic production processes are highlighted. Furthermore, prospect is also addressed about enzymatic production of L-Arg derivatives.