Zinc-dependent histone deacetylases (HDACs) consist of the class I enzymes, HDACs 1, 2, 3, and 8; the class IIa enzymes, HDACs 4, 5, 7, and 9; the class IIb enzymes, HDACs 6 and 10; and a single class IV enzyme, HDAC11. Some of these enzymes catalyze the hydrolysis of acetyllysine in histone and non-histone proteins, but others exhibit unanticipated catalytic diversity. Consider the class IIb enzymes: HDAC6 is a tubulin deacetylase and catalyzes the hydrolysis of acetyllysine in alpha-tubulin to modulate microtubule dynamics, but HDAC10 is a polyamine deacetylase with optimal substrate specificity for N<sup>8</sup>-acetylspermidine. Inhibition of HDAC6 suppresses microtubule dynamics, leading to cell cycle arrest and apoptosis, and inhibition of HDAC10 suppresses autophagy in cancer cells, so both enzymes are targets for the design of isozyme-selective inhibitors with potential pharmaceutical applications. Our X-ray crystallographic studies of HDAC6 and HDAC10 set the stage for understanding the structural basis of substrate specificity and catalysis. Furthermore, our structural studies have illuminated key features in the design of isozyme-selective inhibitors.

Structure, mechanism, and inhibition of class IIb histone deacetylases

ACS Fall 2021

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