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iNature
Amino acid metabolism is essential for cell survival, while ammonia, a byproduct, is toxic and can impair cell lifespan
.
On December 5, 2022, the Huang Bo research group of Huazhong University of Science and Technology was in Nature
Immunology published a title entitled "Ammonia detoxification.
"
promotes CD8+ T cell memory development by urea and citrulline cycles", which demonstrated that CD8+ Memory T (TM) cells mobilize carbamoyl phosphate The carbamoyl phosphate (CP) pathway detoxifies ammonia to maintain its long-term survival, suggesting that CD8+ T cells use urea and citrulline cycles to clear ammonia and promote memory development
.
This ammonia clearance mechanism may be used to improve T-cell-based cancer immunotherapy
.
.
Glucose and fatty acids have evolved over billions of years to be selected as molecules
that can be used as a source of ATP through oxidation.
In addition, amino acids, after deamination, can be oxidized to provide energy or regulate energy production
.
Therefore, in the ATP production process, reactive oxygen species (ROS) and ammonia (ammonia, NH3) by-products, both of which can be cytotoxic and limit cell lifespan
.
Therefore, long-lived cells need to develop mechanisms
to clear reactive oxygen species and ammonia.
Memory T (Memory T, TM) Cells are a typical long-lived cell type
.
Previously, CD8+ TM cells were shown to utilize ketogenesis and gluconeogenesis to flow carbon to glycogen and from glycogen into the pentose phosphate pathway, leading to efficient production of NADPH and subsequent clearance
of ROS.
Despite this ROS clearance, the way CD8+ TM cells detoxify ammonia is unclear
.
The deamine of amino acids is the main source of intracellular ammonia and goes through two steps: the first step is the transfer of amino groups from other amino acids to glutamate or glutamine; The second is the deamine reaction of glutamine or glutamate to produce ammonia
.
Ammonia is excreted
in the liver through the urea cycle.
Hepatocytes take up ammonium (NH4+, the ionized form of NH3) from the circulation and use CP synthetase-1 (CPS1) Condensed ammonia and bicarbonate (HCO3−) form CP
in mitochondria.
CP and ornithine transport aminoacylase (ornithine) via ornithine transcarbamoylase, OTC)16 reacts to form citrulline
.
After output to the cytoplasm, citrulline is synthesized by arginine succinate synthase 1 (argininosuccinate synthetase 1, ASS1) It binds to aspartic acid to produce arginine succinic acid, which is then catalyzed by argininosuccinate lyase (ASL) to produce arginine and fumaric acid
.
Cytosolic arginase 1 (arginase 1, ARG1) hydrolyzes arginine to ornithine and urea as the final step
in the urea cycle.
Although conventional wisdom holds that the urea cycle only occurs in the liver, the study showed that CD8+ memory T (TM) cells mobilized the carbamoyl phosphate (CP) metabolic pathway to remove ammonia.
Thus promoting memory development
.
CD8+ TM cells upregulate CP synthetase 1 by β-hydroxybutylation, triggering the CP metabolic cascade to form arginine
in cell fluid.
Cytoplasmic arginine is then transported to the mitochondria, where it is split by arginase 2 into urea and ornithine
.
Cytosolic arginine is also converted to nitric oxide and citrulline
by nitric oxide synthase.
The urea cycle is active in CD8+ TM cells (Image from Nature Immunology) In summary, the study showed CD8+ TM By expressing enzymes in the urea cycle and citrulline cycle, cells can efficiently remove ammonia, thereby maintaining lifespan
by avoiding ammonia-mediated cytotoxicity.
The findings suggest that this mechanism may also be present in other types of cells, particularly long-lived cells
.
Original link: —END—the content is [ iNature】
