scholarly journals Functional Amino Acids and Autophagy: Diverse Signal Transduction and Application

2021 ◽  
Vol 22 (21) ◽  
pp. 11427
Author(s):  
Chunchen Liu ◽  
Linbao Ji ◽  
Jinhua Hu ◽  
Ying Zhao ◽  
Lee J. Johnston ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Amino Acids ◽  
Amino Acid ◽  
Mammalian Target Of Rapamycin ◽  
Comprehensive Overview ◽  
Related Disease ◽  
Signal Relay ◽  
Amino Acid Levels ◽  
Amino Acid Sensing

Functional amino acids provide great potential for treating autophagy-related diseases by regulating autophagy. The purpose of the autophagy process is to remove unwanted cellular contents and to recycle nutrients, which is controlled by many factors. Disordered autophagy has been reported to be associated with various diseases, such as cancer, neurodegeneration, aging, and obesity. Autophagy cannot be directly controlled and dynamic amino acid levels are sufficient to regulate autophagy. To date, arginine, leucine, glutamine, and methionine are widely reported functional amino acids that regulate autophagy. As a signal relay station, mammalian target of rapamycin complex 1 (mTORC1) turns various amino acid signals into autophagy signaling pathways for functional amino acids. Deficiency or supplementation of functional amino acids can immediately regulate autophagy and is associated with autophagy-related disease. This review summarizes the mechanisms currently involved in autophagy and amino acid sensing, diverse signal transduction among functional amino acids and autophagy, and the therapeutic appeal of amino acids to autophagy-related diseases. We aim to provide a comprehensive overview of the mechanisms of amino acid regulation of autophagy and the role of functional amino acids in clinical autophagy-related diseases and to further convert these mechanisms into feasible therapeutic applications.

scholarly journals Amino acid sensing and mTOR regulation: inside or out?

2009 ◽  
Vol 37 (1) ◽  
pp. 248-252 ◽  
Author(s):  
Deborah C.I. Goberdhan ◽  
Margret H. Ögmundsdóttir ◽  
Shubana Kazi ◽  
Bruno Reynolds ◽  
Shivanthy M. Visvalingam ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Growth Factor ◽  
Environmental Conditions ◽  
Detection System ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Amino Acid Sensing ◽  
The Impact ◽  
Mtor Signalling

mTOR (mammalian target of rapamycin) plays a key role in determining how growth factor, nutrient and oxygen levels modulate intracellular events critical for the viability and growth of the cell. This is reflected in the impact of aberrant mTOR signalling on a number of major human diseases and has helped to drive research to understand how TOR (target of rapamycin) is itself regulated. While it is clear that amino acids can affect TOR signalling, how these molecules are sensed by TOR remains controversial, perhaps because cells use different mechanisms as environmental conditions change. Even the question of whether they have an effect inside the cell or at its surface remains unresolved. The present review summarizes current ideas and suggests ways in which some of the models proposed might be unified to produce an amino acid detection system that can adapt to environmental change.

scholarly journals The E3 ubiquitin ligase ZNRF2 is a substrate of mTORC1 and regulates its activation by amino acids

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Gerta Hoxhaj ◽  
Edward Caddye ◽  
Ayaz Najafov ◽  
Vanessa P Houde ◽  
Catherine Johnson ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Ubiquitin Ligase ◽  
Protein Phosphatase ◽  
E3 Ubiquitin Ligase ◽  
Mechanistic Target Of Rapamycin ◽  
Rag Gtpases ◽  
Intracellular Amino Acid ◽  
Amino Acid Levels ◽  
Amino Acid Sensing

The mechanistic Target of Rapamycin complex 1 (mTORC1) senses intracellular amino acid levels through an intricate machinery, which includes the Rag GTPases, Ragulator and vacuolar ATPase (V-ATPase). The membrane-associated E3 ubiquitin ligase ZNRF2 is released into the cytosol upon its phosphorylation by Akt. In this study, we show that ZNRF2 interacts with mTOR on membranes, promoting the amino acid-stimulated translocation of mTORC1 to lysosomes and its activation in human cells. ZNRF2 also interacts with the V-ATPase and preserves lysosomal acidity. Moreover, knockdown of ZNRF2 decreases cell size and cell proliferation. Upon growth factor and amino acid stimulation, mTORC1 phosphorylates ZNRF2 on Ser145, and this phosphosite is dephosphorylated by protein phosphatase 6. Ser145 phosphorylation stimulates vesicle-to-cytosol translocation of ZNRF2 and forms a novel negative feedback on mTORC1. Our findings uncover ZNRF2 as a component of the amino acid sensing machinery that acts upstream of Rag-GTPases and the V-ATPase to activate mTORC1.

scholarly journals Amino Acid Metabolic Vulnerabilities in Acute and Chronic Myeloid Leukemias

2021 ◽  
Vol 11 ◽  
Author(s):  
Aboli Bhingarkar ◽  
Hima V. Vangapandu ◽  
Sanjay Rathod ◽  
Keito Hoshitsuki ◽  
Christian A. Fernandez
Keyword(s):  
Amino Acid ◽  
Energy Demand ◽  
Mammalian Target Of Rapamycin ◽  
Metabolic Reprogramming ◽  
General Control ◽  
Comprehensive Overview ◽  
Pyrimidine Synthesis ◽  
Cellular Processes ◽  
Myeloid Leukemias

Amino acid (AA) metabolism plays an important role in many cellular processes including energy production, immune function, and purine and pyrimidine synthesis. Cancer cells therefore require increased AA uptake and undergo metabolic reprogramming to satisfy the energy demand associated with their rapid proliferation. Like many other cancers, myeloid leukemias are vulnerable to specific therapeutic strategies targeting metabolic dependencies. Herein, our review provides a comprehensive overview and TCGA data analysis of biosynthetic enzymes required for non-essential AA synthesis and their dysregulation in myeloid leukemias. Furthermore, we discuss the role of the general control nonderepressible 2 (GCN2) and-mammalian target of rapamycin (mTOR) pathways of AA sensing on metabolic vulnerability and drug resistance.

scholarly journals The lysosome: a crucial hub for AMPK and mTORC1 signalling

2017 ◽  
Vol 474 (9) ◽  
pp. 1453-1466 ◽  
Author(s):  
Bernadette Carroll ◽  
Elaine A. Dunlop
Keyword(s):  
Amino Acid ◽  
Mammalian Target Of Rapamycin ◽  
Signalling Pathways ◽  
Initial Discovery ◽  
Multiple Levels ◽  
Energy Sensing ◽  
Amino Acid Sensing ◽  
Amp Activated Protein Kinase ◽  
Mtorc1 Activation

Much attention has recently been focussed on the lysosome as a signalling hub. Following the initial discovery that localisation of the nutrient-sensitive kinase, mammalian target of rapamycin complex 1 (mTORC1), to the lysosome was essential for mTORC1 activation, the field has rapidly expanded to reveal the role of the lysosome as a platform permitting the co-ordination of several homeostatic signalling pathways. Much is now understood about how the lysosome contributes to amino acid sensing by mTORC1, the involvement of the energy-sensing kinase, AMP-activated protein kinase (AMPK), at the lysosome and how both AMPK and mTORC1 signalling pathways feedback to lysosomal biogenesis and regeneration following autophagy. This review will cover the classical role of the lysosome in autophagy, the dynamic signalling interactions which take place on the lysosomal surface and the multiple levels of cross-talk which exist between lysosomes, AMPK and mTORC1.

10 THE ROLE OF DIETARY L-SERINE IN THE REGULATION OF INTESTINAL MUCUS BARRIER DURING INFLAMMATION

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S42-S42
Author(s):  
Kohei Sugihara ◽  
Nobuhiko Kamada
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Gut Microbiota ◽  
Control Diet ◽  
Bacterial Strains ◽  
Germ Free ◽  
Intestinal Mucus ◽  
Gnotobiotic Mice ◽  
Mucus Barrier

Abstract Background Recent accumulating evidence suggests that amino acids have crucial roles in the maintenance of intestinal homeostasis. In inflammatory bowel disease (IBD), amino acid metabolism is changed in both host and the gut microbiota. Among amino acids, L-serine plays a central role in several metabolic processes that are essential for the growth and survival of both mammalian and bacterial cells. However, the role of L-serine in intestinal homeostasis and IBD remains incompletely understood. In this study, we investigated the effect of dietary L-serine on intestinal inflammation in a murine model of colitis. Methods Specific pathogen-free (SPF) mice were fed either a control diet (amino acid-based diet) or an L-serine-deficient diet (SDD). Colitis was induced by the treatment of dextran sodium sulfate (DSS). The gut microbiome was analyzed by 16S rRNA sequencing. We also evaluate the effect of dietary L-serine in germ-free mice and gnotobiotic mice that were colonized by a consortium of non-mucolytic bacterial strains or the consortium plus mucolytic bacterial strains. Results We found that the SDD exacerbated experimental colitis in SPF mice. However, the severity of colitis in SDD-fed mice was comparable to control diet-fed mice in germ-free condition, suggesting that the gut microbiota is required for exacerbation of colitis caused by the restriction of dietary L-serine. The gut microbiome analysis revealed that dietary L-serine restriction fosters the blooms of a mucus-degrading bacterium Akkermansia muciniphila and adherent-invasive Escherichia coli in the inflamed gut. Consistent with the expansion of mucolytic bacteria, SDD-fed mice showed a loss of the intestinal mucus layer. Dysfunction of the mucus barrier resulted in increased intestinal permeability, thereby leading to bacterial translocation to the intestinal mucosa, which subsequently increased the severity of colitis. The increased intestinal permeability and subsequent bacterial translocation were observed in SDD-fed gnotobiotic mice that colonized by mucolytic bacteria. In contrast, dietary L-serine restriction did not alter intestinal barrier integrity in gnotobiotic mice that colonized only by non-mucolytic bacteria. Conclusion Our results suggest that dietary L-serine regulates the integrity of the intestinal mucus barrier during inflammation by limiting the expansion of mucus degrading bacteria.

scholarly journals Biological role of D-amino acid oxidase and D-aspartate oxidase. Effects of D-amino acids.

1993 ◽  
Vol 268 (36) ◽  
pp. 26941-26949
Author(s):  
A D'Aniello ◽  
G D'Onofrio ◽  
M Pischetola ◽  
G D'Aniello ◽  
A Vetere ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Biological Role ◽  
Acid Oxidase ◽  
Amino Acid Oxidase

scholarly journals Roles of the C-Terminal Amino Acids of Non-Hexameric Helicases: Insights from Escherichia coli UvrD

2021 ◽  
Vol 22 (3) ◽  
pp. 1018
Author(s):  
Hiroaki Yokota
Keyword(s):  
Escherichia Coli ◽  
Amino Acids ◽  
Amino Acid ◽  
Single Molecule ◽  
Underlying Mechanism ◽  
Amino Acid Sequences ◽  
E Coli ◽  
X Ray Crystallography ◽  
Terminal Amino

Helicases are nucleic acid-unwinding enzymes that are involved in the maintenance of genome integrity. Several parts of the amino acid sequences of helicases are very similar, and these quite well-conserved amino acid sequences are termed “helicase motifs”. Previous studies by X-ray crystallography and single-molecule measurements have suggested a common underlying mechanism for their function. These studies indicate the role of the helicase motifs in unwinding nucleic acids. In contrast, the sequence and length of the C-terminal amino acids of helicases are highly variable. In this paper, I review past and recent studies that proposed helicase mechanisms and studies that investigated the roles of the C-terminal amino acids on helicase and dimerization activities, primarily on the non-hexermeric Escherichia coli (E. coli) UvrD helicase. Then, I center on my recent study of single-molecule direct visualization of a UvrD mutant lacking the C-terminal 40 amino acids (UvrDΔ40C) used in studies proposing the monomer helicase model. The study demonstrated that multiple UvrDΔ40C molecules jointly participated in DNA unwinding, presumably by forming an oligomer. Thus, the single-molecule observation addressed how the C-terminal amino acids affect the number of helicases bound to DNA, oligomerization, and unwinding activity, which can be applied to other helicases.

scholarly journals BIOSYNTHESIS IN ISOLATED ACETABULARIA CHLOROPLASTS

1972 ◽  
Vol 54 (2) ◽  
pp. 279-294 ◽  
Author(s):  
David C. Shephard ◽  
Wendy B. Levin
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Technical Problems ◽  
Hydrolyzed Protein ◽  
Protein Amino Acids ◽  
Amino Acid Labeling ◽  
Labeling Pattern

The ability of chloroplasts isolated from Acetabulana mediterranea to synthesize the protein amino acids has been investigated. When this chloroplast isolate was presented with 14CO2 for periods of 6–8 hr, tracer was found in essentially all amino acid species of their hydrolyzed protein Phenylalanine labeling was not detected, probably due to technical problems, and hydroxyproline labeling was not tested for The incorporation of 14CO2 into the amino acids is driven by light and, as indicated by the amount of radioactivity lost during ninhydrin decarboxylation on the chromatograms, the amino acids appear to be uniformly labeled. The amino acid labeling pattern of the isolate is similar to that found in plastids labeled with 14CO2 in vivo. The chloroplast isolate did not utilize detectable amounts of externally supplied amino acids in light or, with added adenosine triphosphate (ATP), in darkness. It is concluded that these chloroplasts are a tight cytoplasmic compartment that is independent in supplying the amino acids used for its own protein synthesis. These results are discussed in terms of the role of contaminants in the observed synthesis, the "normalcy" of Acetabularia chloroplasts, the synthetic pathways for amino acids in plastids, and the implications of these observations for cell compartmentation and chloroplast autonomy.

Interrelationship between hepatic ureagenesis and gluconeogenesis in early sepsis

1991 ◽  
Vol 260 (3) ◽  
pp. E453-E458 ◽  
Author(s):  
Y. Ohtake ◽  
M. G. Clemens
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Substrate Preference ◽  
Hormone Sensitivity ◽  
Urea Production ◽  
Urea Release ◽  
Amino Acid Levels ◽  
Early Sepsis ◽  
Septic Group

This study was performed to investigate the interrelationship between gluconeogenesis and ureagenesis during sepsis. In isolated perfused livers, gluconeogenesis was assessed using either lactate or a combination of lactate, glutamine, and alanine as substrate. Ureagenesis was assessed using either NH4Cl or glutamine plus alanine as substrate. NH4Cl stimulated urea production in livers from both septic and sham-operated control rats. Urea release was approximately 1.2 and 2.0 mg urea nitrogen.g-1.h-1 for 1 and 5 mM NH4Cl, respectively, and was equal for both groups. With amino acids as substrate, urea production was significantly greater in livers from septic animals compared with controls. Phenylephrine stimulated urea production in the sham-operated group by about twofold, whereas in the septic group urea release was slightly inhibited. Gluconeogenesis from lactate was inhibited by NH4Cl (1 and 5 mM) in both groups, with no difference between groups. In contrast to enhanced ureagenesis from amino acids in septic rats, gluconeogenesis was decreased by approximately 24% (P less than 0.5). Similarly, phenylephrine (1 microM) stimulated gluconeogenesis by 13 +/- 1 mumol.g-1.h-1 in sham-operated rats but only by 9 +/- 1 mumol.g-1.h-1 in septic rats (P less than 0.02). These results suggest that hepatic gluconeogenic and ureagenic pathways are intact in sepsis but that altered substrate preference and hormone sensitivity may result in decreased gluconeogenesis in the presence of elevated amino acid levels.

Sign in / Sign up

Export Citation Format

Share Document