ACTIVATION OF AMPK

 ACTIVATION OF AMPK

AMP-activated protein kinase (AMPK) can be activated through several

different pathways. Two major ways are discussed here: -

➔ Direct Activation.

➔ Indirect Activation.

Direct Activation: Direct activation of AMP-activated protein kinase (AMPK)

refers to the activation of AMPK through mechanisms that bypass the classical

energy-sensing pathway involving AMP and ADP binding to the γ-subunit.

Here are some examples of direct activation of AMPK:

Pharmacological Activators:

1. AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide): AICAR is

a synthetic compound that can be taken up by cells and converted into

its active form, ZMP (Z-nucleotide). ZMP is a natural intermediate in

the purine nucleotide synthetic pathway and is metabolized by AICAR

transformylase, which catalyzes the synthesis of the purine nucleotide

inosinate. ZMP mimics the effects of AMP, directly binding to site 3 of

the γ-subunit and activating AMPK.

2. A-769662: A-769662 (Thienopyridone) is a synthetic compound that

activates AMPK by binding to the β-subunit. It inhibits

dephosphorylation of Thr172 in the AMPK α subunit; It induces

conformational changes in the complex, leading to the activation of

AMPK independent of changes in nucleotide levels.

3. 911: 911 has been demonstrated to exhibit 5–10 times greater potency

than A-769662 in its ability to allosterically activate AMPK and prevent

dephosphorylation.

4. PT-1 and C24: PT-1 directly binds to the cleft between the KD and the

AID, thereby relieving auto inhibition. Consistently with results from a

cell-free kinase assay, PT-1 has been shown to increase the

phosphorylation of ACC at Ser79, changes AMP: ATP. PT1 is not

effective in vivo due to a poor pharmacokinetic profile, but its structural

optimization led to the discovery of the similar, but orally bioavailable

compound, C24.

Indirect Activation: Indirect activation of AMP-activated protein kinase

(AMPK) refers to the stimulation of AMPK activity through pathways that do

not directly interact with AMPK itself. AMPK is a key enzyme that plays a

central role in cellular energy homeostasis. It is activated when cellular energy

levels are low, such as during conditions of exercise or nutrient deprivation.

Indirect ways to activate AMPK, which typically involve signaling pathways

that modulate the levels of AMP and other metabolites.

Some common indirect mechanisms of AMPK activation include:

1. Activation of AMPK via Adenosine Triphosphate (ATP) depletion:

ATP is the primary energy currency of cells. When ATP levels are low,

it is converted into AMP. Elevated AMP levels lead to the allosteric

activation of AMPK, promoting its activity.

2. Liver kinase B1 (LKB1): It has been extensively documented to

phosphorylate Thr-172 of the AMPKα subunit. Notably, there are lines

of evidence showing that the LKB1-dependent AMPKα

phosphorylation at Thr172 is greatly enhanced by the binding of AMP

to the AMPK γ-subunit, and, at the same time, the AMP-binding

inhibits dephosphorylation of this activating phosphorylation by

protein phosphatases, such as PP2A and PP2C in vitro.

3. Calcium signaling: Increases in intracellular calcium levels can activate

AMPK through the calcium/calmodulin-dependent protein kinase

kinase (CaMKKβ) pathway. CaMKKβ directly phosphorylates and

activates AMPK.

4. Cellular stress and reactive oxygen species (ROS): Conditions of

cellular stress, such as oxidative stress and endoplasmic reticulum (ER)

stress, can activate AMPK. Reactive oxygen species (ROS) generated

during oxidative stress can activate AMPK indirectly by altering the

AMP/ATP ratio or activating upstream kinases.

5. Hormones and cytokines: Some hormones and cytokines, such as

adiponectin and leptin, can activate AMPK through various signaling

cascades.

6. Pharmacological agents: Certain drugs and compounds can indirectly

activate AMPK by affecting cellular energy status or signaling

pathways related to AMPK activation. Metformin, an indirect activator

of AMPK, is a type of biguanide, a synthetic derivative of guanide from

the plant Galega officinalis, and has been used as a first-line anti-diabetic

drug because of its ability to reduce hepatic glucose production and

enhance peripheral insulin sensitivity.