Figure 2.

Metabolic Rules of Engagement of Natural Products with Cells. Some of the earliest cellular responses to natural product exposure include the alteration of mitochondrial function which increases the AMP:ATP ratio, leading to activation of AMPK by phosphorylation (1); Natural products like salicylate can also directly bind to and activate AMPK (2); AMPK activation suppresses Rheb, an upstream activator of mTOR signaling. Thus, AMPK activation by natural products can lead to mTOR inhibition. Natural products like rapamycin can also directly bind to and inhibit mTOR signaling (3); The alteration of mitochondrial energetics may be involved in natural product induction of DDIT4, a novel upstream inhibitor of mTOR (4); Finally, activation of AMPK and inhibition of mTOR by natural products may be directly involved in the suppression of pro-inflammatory signaling such as that mediated by NF-κB (5). For mTOR, there is evidence that IKK interacts with mTORC1 to mediate the connection of mTORC1 to NF-κB, while for AMPK, the route to NF-κB is not presently clear. Citations of studies supporting these interactions are provided in text. Note that the tri-molecular complexes of IKK (IKKα, IKKβ, and IKKγ), and the bimolecular complex of NF-κB are simplified as single proteins. Moreover, only the mTORC1 and canonical NF-κB pathways are shown.