CPS-1 activity is regulated by liver enriched transcription factors as well as Sirtuin-mediated de-acylation.
Glutaminase breaks down glutamine into glutamate and ammonia. Glutamate also yields additional NH4+ via the enzyme glutamate dehydrogenase. From here, ammonia is initially incorporated into hepatocyte mitochondria and ultimately results in the formation of urea. Urea subsequently leaves the hepatocyte cytoplasm and is ultimately excreted in urine.
Glutaminase-1 (GLS1) is a mitochondrial enzyme found in endothelial cells (ECs) that metabolizes glutamine to glutamate and ammonia and glutaminolysis modulates the function of human umbilical vein endothelia.Glutamine deprivation or GLS1 inhibition also stimulated the production of reactive oxygen species and this was associated with a marked decline in heme oxygenase-1 (HO-1) expression. GLS1 inhibition also sensitized umbilical endothelia to the cytotoxic effect of hydrogen peroxide; a process that is blocked by the overexpression of Heme oxygenase 1. In summary, GLS1 promotes human endothelial proliferation, migration, and survival.
SIRT4 might prevent CNS excitotoxicity and subsequent apoptosis by reducing glutamine synthesis while and upregulating glutamate transport into astrocytes where increased glutamate dehydrogenase activity removes the ultimate source of this neural degeneration mechanism.
In the small intestine, SIRT5 causes deglutarylation and functional activation of glutamate dehydrogenase 1 leading to poor prognosis in colorectal cancer.
Combined, this experimental evidence suggests that the modulation of mitochondrial Sirtuin activity to pharmacologically circumvent CNS pathophysiology may not be appropriate for cancers in the digestive system and that Sirtuin isoform expression and activity is highly nuanced.
J Cell Mol Med. 2017 Sep; 21(9): 2036–2045
Hum Exp Toxicol. 2020 Jul;39(7):938-947