Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.2.13 (aldolase)
 3,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mammalian AMPK is known to be activated by falling cellular energy status, signaled by rising AMP/ATP and ADP/ATP ratios. We review recent information about how this occurs but also discuss new studies suggesting that AMPK is able to sense glucose availability independently of changes in adenine nucleotides. The glycolytic intermediate fructose-1,6-bisphosphate (FBP) is sensed by aldolase, which binds to the v-ATPase on the lysosomal surface. In the absence of FBP, interactions between aldolase and the v-ATPase are altered, allowing formation of an AXIN-based AMPK-activation complex containing the v-ATPase, Ragulator, AXIN, LKB1, and AMPK, causing increased Thr172 phosphorylation and AMPK activation. This nutrient-sensing mechanism activates AMPK but also primes it for further activation if cellular energy status subsequently falls. Glucose sensing at the lysosome, in which AMPK and other components of the activation complex act antagonistically with another key nutrient sensor, mTORC1, may have been one of the ancestral roles of AMPK.
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PMID:AMPK: Sensing Glucose as well as Cellular Energy Status. 2915 8

Fructose-1,6-bisphosphate (FBP) aldolase links sensing of declining glucose availability to AMPK activation via the lysosomal pathway. However, how aldolase transmits lack of occupancy by FBP to AMPK activation remains unclear. Here, we show that FBP-unoccupied aldolase interacts with and inhibits endoplasmic reticulum (ER)-localized transient receptor potential channel subfamily V, inhibiting calcium release in low glucose. The decrease of calcium at contact sites between ER and lysosome renders the inhibited TRPV accessible to bind the lysosomal v-ATPase that then recruits AXIN:LKB1 to activate AMPK independently of AMP. Genetic depletion of TRPVs blocks glucose starvation-induced AMPK activation in cells and liver of mice, and in nematodes, indicative of physical requirement of TRPVs. Pharmacological inhibition of TRPVs activates AMPK and elevates NAD+ levels in aged muscles, rejuvenating the animals' running capacity. Our study elucidates that TRPVs relay the FBP-free status of aldolase to the reconfiguration of v-ATPase, leading to AMPK activation in low glucose.
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PMID:Transient Receptor Potential V Channels Are Essential for Glucose Sensing by Aldolase and AMPK. 3120 82