Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.27 (AMPK)
 6,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyaluronan (HA) is a critical component of cancer microenvironment that is known to increase tumor progression and aggressiveness. The synthesis of HA starts from the cytosolic precursors UDP-N-acetylglucosamine and UDP-glucuronic acid. These two sugar nucleotides have several functions in addition to glycoconjugate synthesis and glucuronidation reactions, each of which can have a critical role in cancer. HA is synthesized by a family of three HA synthase (HAS) enzymes and, in this review, we described the main posttranslational modifications that are known to regulate HA metabolism. In particular, as the main HAS in adult tissues is HAS2, we focused on the role of AMPK-mediated phosphorylation and glycosylation by O-linked N-acetylglucosamine (O-GlcNAcylation) of HAS2 which mediate HAS2 inactivation and activation, respectively. HA catabolism, furnishing glucuronic acid and N-acetylglucosamine, can represent for a cancer cell a valid source of substrates to sustain complex tumor metabolism, and we highlight a presumable metabolic fate of such sugars in tumor cells.
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PMID:Hyaluronan synthases posttranslational regulation in cancer. 2508 27

The mechanistic target of rapamycin (mTOR) controls metabolic pathways in response to nutrients. Recently, we have shown that mTOR complex 2 (mTORC2) modulates the hexosamine biosynthetic pathway (HBP) by promoting the expression of the key enzyme of the HBP, glutamine:fructose-6-phosphate aminotransferase 1 (GFAT1). Here, we found that GFAT1 Ser-243 phosphorylation is also modulated in an mTORC2-dependent manner. In response to glutamine limitation, active mTORC2 prolongs the duration of Ser-243 phosphorylation, albeit at lower amplitude. Blocking glycolysis using 2-deoxyglucose robustly enhances Ser-243 phosphorylation, correlating with heightened mTORC2 activation, increased AMPK activity, and O-GlcNAcylation. However, when 2-deoxyglucose is combined with glutamine deprivation, GFAT1 Ser-243 phosphorylation and mTORC2 activation remain elevated, whereas AMPK activation and O-GlcNAcylation diminish. Phosphorylation at Ser-243 promotes GFAT1 expression and production of GFAT1-generated metabolites including ample production of the HBP end-product, UDP-GlcNAc, despite nutrient starvation. Hence, we propose that the mTORC2-mediated increase in GFAT1 Ser-243 phosphorylation promotes flux through the HBP to maintain production of UDP-GlcNAc when nutrients are limiting. Our findings provide insights on how the HBP is reprogrammed via mTORC2 in nutrient-addicted cancer cells.
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PMID:mTORC2 modulates the amplitude and duration of GFAT1 Ser-243 phosphorylation to maintain flux through the hexosamine pathway during starvation. 3020 9