Fig. 4. Metabolites can influence signal transduction.

(A) The AMPK pathway is influenced by adenylate concentration. AMPKα is activated by phosphorylation on Thr¹⁷² of its activation loop by the kinases LKB1, TAK1, or CaMKKβ. LKB1 promotes enhanced AMPK phosphorylation under a high AMP:ATP ratio. One biological output of AMPK activity is the inhibition of mRNA translation under low-energy conditions through inhibition of mTORC1 activity. (B) α-KG– dependent enzymes (in yellow) are a class of enzymes regulated by TCA cycle intermediates that require molecular oxygen (O₂) and α-KG for their enzymatic activity. Oxygen, α-KG, ascorbate, and iron (green) are positive regulators of these enzymes, whereas the TCA cycle intermediates fumarate and succinate (blue) antagonize their reactions. PHDs destabilize HIF-1α protein, resulting in decreased expression of HIF-1α targets and a reduction in glycolysis. TET2 hydroxylates 5-methylcytosine residues to promote DNA demethylation, whereas JmjC promotes demethylation of trimethylated histones in chromatin.