Modification affects cells' energy supply

For every cell in our body, allocation of proper energy supply is very important. Lack of it could lead to fatal outcomes, such as death or cancer. Adenosine monophosphate-activated protein kinase, also known as AMPK, plays a critical role in maintaining cellular energy homeostasis.

The functional enzyme is composed of three subunits, which are conserved from yeast to humans. It is found in liver, brain and skeletal muscles.

A recent study done at Hopkins reveals that AMPK plays an important role in determining whether cells will store or use their energy reserves. It was discovered that the opposing catalytic activities of deacetylases HDAC1 and acetyltransferase p300 control the activity of AMPK.

According to the study, acetylation — addition of acetyl functional group — of many non-histone proteins involved in chromatin, metabolism or cytoskeleton regulation have previously been identified. However, the corresponding enzymes and substrate-specific functions of the modifications are still unclear.

This study took first step in identifying proteins involved in that process of acetylation and de-acetylation. In this study, authors tried to identify the functional specificity of 12 critical human deacetylases. One of those deacetylases, HDAC1 was discovered to be very important for this mechanism.

In the study, authors confirmed that deacetylation of AMPK leads to AMPK phosphorylation and activation by the upstream kinase LKB1 resulting in lipid breakdown in human liver cells. This means that deacetylation of AMPK activates it and cells use its reserved energy.

The exact opposite happens with the acetylation of AMPK by p300. With the flow of decent energy, AMPK is turned off and cell starts to store energy in the form of sugar or fat for future use.

According to the authors of this study, findings provided new insights into previously under appreciated metabolic regulatory roles of HDAC1.

The whole purpose of this study was to understand the role various deacetylases played in the regulation of cellular homeostasis. Recently, deacetylase inhibitors have been increasingly used for the treatment of cancer and neurodegenerative diseases and also the generation of induced pluripotent stem cells.

Thus, it becomes critical to understand the molecular mechanism of these enzymes. In the future, authors hope to study the enzyme–substrate relationships of other deacetylases and try to understand the mechanisms underlying deacetylase inhibitor activities.