Alanine and inter-organ relationships in branched-chain amino and 2-oxo acid metabolism

1985 ◽  
Vol 5 (12) ◽  
pp. 1015-1033 ◽  
Author(s):  
T. Norman Palmer ◽  
Margaret A. Caldecourt ◽  
Keith Snell ◽  
Mary C. Sugden
Keyword(s):  
Amino Acid ◽  
Acid Metabolism ◽  
Relevant Literature ◽  
Carbon Skeleton ◽  
Acid Oxidation ◽  
Branched Chain Amino Acid ◽  
Branched Chain ◽  
Pep Carboxykinase

Branched-chain amino acid metabolism in skeletal muscte promotes the production of alanine, an important precursor in hepatic gluconeogenesis. There is controversy concerning the origin of the carbon skeleton of alanine produced in muscle, specifically whether it is derived from carbohydrate via glycolysis (the glucose-alanine cycle) or from amino acid precursors (viz. glutamate, valine, isoleucine, methionine, aspartate, asparagine) via a pathway involving phosphoenolpyruvate (PEP) carboxykinase and pyruvate kinase, or NADP-malate dehydrogenase (malic enzyme). The relevant literature is reviewed and it is concluded that neogenic flux from amino acids is unlikely to be of major quantitative importance for provision of the carbon skeleton of alanine either in vitro or in vivo. Evidence is presented that branched-chain amino acid oxidation in muscle is incomplete and that the branched-chain 2-oxo acids and the products of their partial oxidation (including glutamine) are released. The role of these metabolites is discussed in the context of fuel homeostasis in starvation.

scholarly journals Branched-chain amino acid aminotransferase 2 regulates ferroptotic cell death in cancer cells

2020 ◽  
Author(s):  
Kang Wang ◽  
Zhengyang Zhang ◽  
Hsiang-i Tsai ◽  
Yanfang Liu ◽  
Jie Gao ◽  
...  
Keyword(s):  
Cell Death ◽  
Amino Acid ◽  
Cancer Cells ◽  
Ectopic Expression ◽  
Branched Chain Amino Acid ◽  
Pancreatic Cancer Cells ◽  
Key Enzyme ◽  
Branched Chain

Abstract Ferroptosis, a form of iron-dependent cell death driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated as a tumor-suppressor function for cancer therapy. Recent advance revealed that the sensitivity to ferroptosis is tightly linked to numerous biological processes, including metabolism of amino acid and the biosynthesis of glutathione. Here, by using a high-throughput CRISPR/Cas9-based genetic screen in HepG2 hepatocellular carcinoma cells to search for metabolic proteins inhibiting ferroptosis, we identified a branched-chain amino acid aminotransferase 2 (BCAT2) as a novel suppressor of ferroptosis. Mechanistically, ferroptosis inducers (erastin, sorafenib, and sulfasalazine) activated AMPK/SREBP1 signaling pathway through iron-dependent ferritinophagy, which in turn inhibited BCAT2 transcription. We further confirmed that BCAT2 as the key enzyme mediating the metabolism of sulfur amino acid, regulated intracellular glutamate level, whose activation by ectopic expression specifically antagonize system Xc– inhibition and protected liver and pancreatic cancer cells from ferroptosis in vitro and in vivo. On the contrary, direct inhibition of BCAT2 by RNA interference, or indirect inhibition by blocking system Xc– activity, triggers ferroptosis. Finally, our results demonstrate the synergistic effect of sorafenib and sulfasalazine in downregulating BCAT2 expression and dictating ferroptotic death, where BCAT2 can also be used to predict the responsiveness of cancer cells to ferroptosis-inducing therapies. Collectively, these findings identify a novel role of BCAT2 in ferroptosis, suggesting a potential therapeutic strategy for overcoming sorafenib resistance.

scholarly journals Branched-chain amino acid metabolism and alanine formation in rat diaphragm muscle in vitro. Effects of dichloroacetate

1984 ◽  
Vol 223 (3) ◽  
pp. 831-835 ◽  
Author(s):  
K Snell ◽  
D A Duff
Keyword(s):  
Amino Acid ◽  
Pyruvate Dehydrogenase ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Diaphragm Muscle ◽  
Rat Diaphragm ◽  
Branched Chain Amino Acid ◽  
In Vitro Effects ◽  
Branched Chain

Dichloroacetate (which activates pyruvate dehydrogenase) decreases the release of alanine, pyruvate and lactate in hemidiaphragm incubations with valine. Dichloroacetate interferes with alanine formation by diverting pyruvate into oxidative pathways, which not only limits pyruvate availability for direct transamination to form alanine but also indirectly affects branched-chain amino acid transamination by limiting 2-oxoglutarate regeneration from glutamate.

scholarly journals Branched chain amino acid aminotransferase 2 Regulates Ferroptotic Cell Death in Cancer Cells

2020 ◽  
Author(s):  
Kang Wang ◽  
Zhengyang Zhang ◽  
Tsai Hsiang-i ◽  
Yanfang Liu ◽  
Ming Wang ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cancer Cells ◽  
Therapeutic Strategy ◽  
Ectopic Expression ◽  
Branched Chain Amino Acid ◽  
Pancreatic Cancer Cells ◽  
Branched Chain

AbstractFerroptosis has been implicated as a tumor-suppressor function for cancer therapy. Recently the sensitivity to ferroptosis was tightly linked to numerous biological processes, including metabolism of amino acid. Here, using a high-throughput CRISPR/Cas9 based genetic screen in HepG2 cells to search for metabolic proteins inhibiting ferroptosis, we identified branched chain amino acid aminotransferase 2 (BCAT2) as a novel suppressor of ferroptosis. Mechanistically, ferroptosis inducers (erastin, sorafenib and sulfasalazine) activated AMPK/SREBP1 signaling pathway through ferritinophagy, which in turn inhibited BCAT2 transcription. We further confirmed that BCAT2 mediating the metabolism of sulfur amino acid, regulated intracellular glutamate level, whose activation by ectopic expression specifically antagonize system Xc– inhibition and protected liver and pancreatic cancer cells from ferroptosis in vitro and in vivo. Finally, our results demonstrate the synergistic effect of sorafenib and sulfasalazine in downregulating BCAT2 expression and dictating ferroptotic death, where BCAT2 can also be used to predict the responsiveness of cancer cells to ferroptosis-inducing therapies. Collectively, these findings identify a novel role of BCAT2 in ferroptosis, suggesting a potential therapeutic strategy for overcoming sorafenib resistance.

alpha-Ketoisocaproate stimulates branched-chain amino acid transaminase in kidney and muscle.

1979 ◽  
Vol 236 (5) ◽  
pp. E514
Author(s):  
W E Mitch ◽  
W Chan
Keyword(s):  
Amino Acid ◽  
Rat Kidney ◽  
In Vitro Perfusion ◽  
Branched Chain Amino Acid ◽  
Branched Chain ◽  
Increased Activity ◽  
In Vivo Degradation ◽  
Sequential Measurements

We have reported that branched-chain amino acid transaminase (BATase) activity of isolated rat kidney is stimulated by perfusion with alpha-ketoisocaproate (KL). This study examines the mechanism of this effect in kidney and documents that stimulation occurs in intact skeletal muscle. Increased activity was not attributable to synthesis of enzyme because it occurred in the presence of cycloheximide. The in vivo degradation rate of BATase estimated from sequential measurements of activity following intravenous cycloheximide was longer than 90 min, whereas during in vitro perfusion stimulation could be detected within 5 min. Incubation of supernatant from kidney homogenate with KL stimulated BATase; incubation with alpha-keto-beta-methylvalerate (KI), alpha-ketoisovalerate (KV), leucine (leu), or isovaleryl CoA did not. Perfusion of rat hindquarter with KL increased muscle BATase activity; perfusion with acetoacetate, KI, KV, or leu did not. Again, cycloheximide studies indicated a direct effect of KL on muscle BATase. These findings suggest that alpha-ketoisocaproate can increase BATase activity and thus may be involved in regulation of its activity.

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