-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
-
Cosmetic Ingredient
- Water Treatment Chemical
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
Editor-in-charge | Xi
The metabolism of sugar, lipid and protein is the basis of all life activities, but at the same time, it inevitably produces substances
that are harmful to life.
Sugar and lipid metabolism produces energy while forming harmful free radicals, while protein catabolism releases the chronic cytotoxic molecule ammonia (NH3).
The cells of various tissues and organs have a powerful antioxidant (scavenging free radical) function, which has been widely studied, but the clearance of ammonia is rarely studied
except for the known conversion of NH3 into urea detoxification by liver cells.
On December 5, 2022, Professor Huang Bo of the School of Basic Medicine of Huazhong University of Science and Technology and Peking Union Medical College of the Chinese Academy of Medical Sciences published an article on NatureImmunology Ammonia detoxification promotes CD8+T cell memory development by UREA and Citrulline Cycles, this study reveals the importance of urea cycle metabolism for maintaining the development and long-term survival of memory T cells, and explains the fundamental immunological problem
of T cell memory formation from a new metabolic pathway.
Memory T (Tm) cells belong to a typical class of long-lived cells, which can survive in the body for months to years or even life, memory T cell formation and maintenance is a vaccine protection, tumor immunotherapy, The basis of
the body's antiviral infection.
How to analyze the root cause of memory T cells to maintain long lifespan is still a major problem
for immunologists.
In 2018, the research group found that the long-term survival of memory T cells is related to the unique metabolic mode of gluconeogenesis-glycogen metabolism, Tm promotes glycogen synthesis through the key rate-limiting enzyme phosphoenolpyruvate carboxykinase PCK1 that highly expresses the gluconeogenesis pathway, and produces reduced NADPH through the pentose phosphate pathway, maintaining high levels of reducing glutathione, and timely scavenging oxygen free radicals in the cell.
This maintains the long-term viability
of memory T cells.
Tm is derived from effector T cells, why is the expression of PCK1 different? The research group continued to conduct in-depth research and found that ketone metabolism exists in memory T cells, and unlike the conventional belief that ketone body energy supply, ketone body metabolism in Tm mediates the high expression of PCK1 through β-hydroxybutyric acid to promote epigenetic modification of histones, which plays an important role in the maintenance of function and long-term survival of memory T cells, and the relevant research results were published in NCB (Nat Cell Biol.
2018) in 2018 and 2020; 20:21-27；Nat Cell Biol.
2020; 22:18-25）
。
As we all know, cells need to use the energy molecule ATP to maintain life activities
.
Glucose and fatty acid oxidation are the main sources of
ATP production.
In addition, amino acids can also be oxidized after deamination to provide or regulate energy production
.
However, reactive oxygen species (ROS) and ammonia (NH3) are also unavoidably produced as by-products of ATP production in cells, both of which are cytotoxic and impair cell lifespan
.
Therefore, long-lived cells must utilize efficient mechanisms to remove ROS and ammonia to prolong survival
.
In previous studies, the team has revealed how memory T cells clear ROS, but whether CD8+ T cells can remove toxic ammonia through metabolism remains an unsolved mystery
.
The deamination of amino acids is the main source of intracellular ammonia through two steps: the first step is transamination-mediated production of glutamate or glutamine, and the second step is the deamination of glutamate or glutamine
.
It is generally believed that ammonia is processed in the liver through the urea cycle, which is absorbed by hepatocytes from the peripheral cycle and catalyzed ammonia and bicarbonate (HCO3-) using carbamoyl phosphate synthetase-1 (CPS1) to form carbamoyl phosphate (CP) in mitochondria
。 CP then reacts with ornithine to produce citrulline by ornithine carbamoyl phosphotransferase (OTC).
Citrulline then enters the cytoplasm and binds to aspartate to produce arginine by arginine succinate synthase 1 (ASS1), which is then metabolized by arginine lyase (ASL) to arginine and fumarate and finally arginase 1 (ARG1).
Arginine is hydrolyzed to ornithine and urea, and finally ornithine enters the mitochondrial formation cycle
.
The traditional concept is that urea cycle only occurs in the liver, but the research group proved for the first time that urea cycle exists in memory T cells and plays an important function by constructing in vivo adoptive models of specific antigen memory T cells, isotope tracing technology and ultra-high-resolution liquid mass spectrometry, and verified that urea cycle is necessary for Tm cell memory maintenance through a series of animal models and in vitro mechanism analysis.
In a follow-up study, the authors further found that unlike the traditional urea cycle that produces urea through arginase 1, CD8+Tm cells use arginase 2 localized in mitochondria to catalyze arginine production of urea, and further studied the entry and exit of arginine and urea through SLC25A29 and SLC14A1, respectively, through two solute protein transporters, SLC25A29 and SLC14A1.
In-depth mechanism studies also found that in addition to the urea cycle, CD8+ Tm cells also use the citrulline cycle for ammonia lysis, which works in combination with the urea cycle; In addition, the authors used a variety of animal models to verify that gene expression of Cps1, a key enzyme in the urea cycle, is essential for ammonia processing and memory maintenance in Tm cells, and used epigenetic means to find that β-hydroxybutyrylation in the Cps1 transcription promoter region is the key
to inducing Cps1 expression.
Finally, in the in vivo tumor treatment model, Tm cells with high expression of Cps1 also showed more efficient anti-tumor function, which provided a new metabolic regulation idea for T cell infusion immunotherapy, which has clear clinical transformation significance
.
The discovery of this study will enable us to elucidate the mechanism of long-term survival of Tm cells from a new metabolic perspective, and will provide a new anti-tumor thinking and transformation method for T cells
.
Associate Professor Tang Ke, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Huazhong University of Science and Technology, is the first author of the paper, and Associate Professor Zhang Huafeng, Department of Pathology, and Dr.
Deng Jinghui, Class of 2020, Department of Biochemistry, are the co-first authors
of the paper.
Professor Huang Bo is the corresponding author
of the paper.
Original link:
https://doi.
org/10.
1038/s41590-022-01365-1
Platemaker: Eleven
Reprint instructions
【Non-original article】The copyright of this article belongs to the author of the article, welcome to forward and share, reprinting is prohibited without the permission of the author, the author has all legal rights, violators will be investigated
.
