Searching for unknown enzyme targets

Enzymes issue orders to other proteins by appending and removing chemical groups at specific amino acids. These changes can dramatically alter their stability or function. For example, the lysine acetyltransferases (KATs) and deacetylases (KDACs) modulate diverse cellular pathways by respectively adding or removing acetyl groups from lysine residues on selected targets.

A powerful assay developed recently by Yu-Yi Lin of National Taiwan University and Jef Boeke at Johns Hopkins University School of Medicine, USA, offers a powerful tool for characterizing the function of these enzymes¹. Their screen allowed them to ‘query’ individual KDACs and identify proteins that either facilitate KDAC function and amplify their deacetylating activity or provide a counterbalance by inhibiting their effects. This strategy revealed numerous cellular pathways under KDAC control. It also provided insights into the functional interactions between KDACs and KATs.

The researchers also teased apart functional differences between two highly similar KDACs, HDAC1 and HDAC2. In particular, they identified a prominent role for HDAC1 in the regulation of AMPK, a multi-protein complex that coordinates energy production and consumption in cells, and learned that HDAC1 promotes AMPK activation by removing multiple acetylations from its catalytic subunit. Lin and colleagues conclude that data from their assay may yield equally valuable insights about related proteins in the future.