AMPK

1. AMPK

The AMP-activated protein kinase (AMPK) is a crucial enzyme in cellular energy homeostasis. It is a serine/threonine kinase that is activated in response to low cellular energy levels, specifically when the ratio of AMP to ATP is high. AMPK plays a significant role in regulating metabolic pathways to restore energy balance by promoting catabolic processes that generate ATP and inhibiting anabolic processes that consume ATP.

Structure

AMPK is a heterotrimeric complex composed of three subunits: α (alpha), β (beta), and γ (gamma). The α subunit contains the catalytic domain, while the β and γ subunits are regulatory. The γ subunit binds AMP, ADP, and ATP, which are crucial for the enzyme's activation and regulation.

Activation

AMPK is activated by an increase in the AMP/ATP ratio, which occurs during cellular stress such as exercise, hypoxia, or glucose deprivation. Binding of AMP to the γ subunit induces a conformational change that promotes phosphorylation of the α subunit at a specific threonine residue (Thr172) by upstream kinases such as LKB1, CaMKKβ, or TAK1. This phosphorylation is essential for AMPK activation.

Function

Once activated, AMPK initiates a series of cellular responses to restore energy balance:

• **Inhibition of anabolic pathways:** AMPK inhibits processes such as fatty acid synthesis, cholesterol synthesis, and protein synthesis by phosphorylating and inactivating key enzymes like acetyl-CoA carboxylase (ACC) and HMG-CoA reductase.

• **Stimulation of catabolic pathways:** AMPK enhances glucose uptake and fatty acid oxidation to generate ATP. It also promotes autophagy, a process that recycles cellular components to provide energy.

• **Regulation of gene expression:** AMPK influences the expression of genes involved in metabolism by modulating transcription factors and coactivators such as PGC-1α and FOXO.

Clinical Significance

AMPK is a target for therapeutic interventions in metabolic disorders such as type 2 diabetes, obesity, and cardiovascular diseases. Drugs like metformin, commonly used to treat diabetes, activate AMPK and improve insulin sensitivity. Research is ongoing to develop new AMPK activators for various metabolic conditions.

Research Directions

Current research on AMPK focuses on understanding its role in aging, cancer, and neurodegenerative diseases. The enzyme's ability to regulate autophagy and mitochondrial biogenesis makes it a potential target for interventions in these areas.

Also see

• Metabolism
• Enzyme regulation
• Cellular respiration
• Signal transduction
• LKB1