Histone deacetylase 11 is a fatty-acid deacylase

Z Kutil, Z Novakova, M Meleshin, J Mikesova… - ACS Chemical …, 2018 - ACS Publications
Z Kutil, Z Novakova, M Meleshin, J Mikesova, M Schutkowski, C Barinka
ACS Chemical Biology, 2018ACS Publications
Histone deacetylase 11 (HDAC11) is a sole member of the class IV HDAC subfamily with
negligible intrinsic deacetylation activity. Here, we report in vitro profiling of HDAC11
deacylase activities, and our data unequivocally show that the enzyme efficiently removes
acyl moieties spanning 8–18 carbons from the side chain nitrogen of the lysine residue of a
peptidic substrate. Additionally, N-linked lipoic acid and biotin are removed by the enzyme,
although with lower efficacy. Catalytic efficiencies toward dodecanoylated and myristoylated …
Histone deacetylase 11 (HDAC11) is a sole member of the class IV HDAC subfamily with negligible intrinsic deacetylation activity. Here, we report in vitro profiling of HDAC11 deacylase activities, and our data unequivocally show that the enzyme efficiently removes acyl moieties spanning 8–18 carbons from the side chain nitrogen of the lysine residue of a peptidic substrate. Additionally, N-linked lipoic acid and biotin are removed by the enzyme, although with lower efficacy. Catalytic efficiencies toward dodecanoylated and myristoylated peptides were 77 700 and 149 000 M–1 s–1, respectively, making HDAC11 the most proficient fatty-acid deacylase of the HDAC family. Interestingly, HDAC11 is strongly inhibited by free myristic, palmitic, and stearic acids with inhibition constants of 6.5, 0.9, and 1.6 μM, respectively. At the same time, its deacylase activity is stimulated more than 2.5-fold by both palmitoyl-coenzyme A and myristoyl-coenzyme A, pointing toward metabolic control of the enzymatic activity by fatty-acid metabolites. Our data reveal novel enzymatic activity of HDAC11 that can, in turn, facilitate the uncovering of additional biological functions of the enzyme as well as the design of isoform-specific HDAC inhibitors.
ACS Publications