Histone Deacetylase 11 is an ε-N-Myristoyllysine Hydrolase

Abstract

SUMMARYHistone deacetylase (HDAC) enzymes are important regulators of diverse biological function, including gene expression, rendering them potential targets for intervention in a number of diseases, with a handful of compounds approved for treatment of certain hematologic cancers. Among the human zincdependent HDACs, the most recently discovered member, HDAC11, is the only member assigned to subclass IV, the smallest protein, and the least well understood with regards to biological function.Here we show that HDAC11 cleaves long chain acyl modifications on lysine side chains with remarkable efficiency compared to acetyl groups. We further show that several common types of HDAC inhibitors, including the approved drugs romidepsin and vorinostat, do not inhibit this enzymatic activity. Macrocyclic hydroxamic acid-containing peptides, on the other hand, potently inhibit HDAC11 demyristoylation activity. These findings should be taken carefully into consideration in future investigations of the biological function of HDAC11 and will serve as a foundation for the development of selective chemical probes targeting HDAC11.All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx

High-resolution snapshots of human N-myristoyltransferase in action illuminate a mechanism promoting N-terminal Lys and Gly myristoylation

“…Two possible reasons include the likely reversibility of this modification and its putative role in an N-degron pathway. A number of active acyl hydrolases targeting Lys-MYR have been described over recent years including Sirtuin6, HDAC8 and HDAC11 32,[36][37][38] , making Lys-MYR a reversible modification dependent on the activity of these specific hydrolases, in contrast to the irreversible Gly-MYR. This implies that Lys-MYR, as with other reversible modifications (i.e., phosphorylation and ε-acetylation), might be intimately related to signal transduction pathways and tightly regulated by as yet unknown biotic or abiotic signals.…”

HDAC11 Suppresses the Thermogenic Program of Adipose Tissue via BRD2

“…A recent discovery highlights the attainability of selective HDAC11 inhibitors. Unlike other HDACs, HDAC11 is a weak histone deacetylase, and instead is a highly effective lysine defattyacylase; HDAC11 defatty-acylates substrates with an efficiency that is >10,000-fold greater than its deacetylase activity (51)(52)(53). This finding suggests that HDAC11 functions, at least in part, in a manner analogous to sirtuins, which have the ability to proficiently catalyze removal of acyl groups in addition to acetyl, as opposed to other zinc-dependent HDACs, which primarily target acetyl moieties on lysine (54).…”

An NAD+-Dependent Sirtuin Depropionylase and Deacetylase (Sir2La) from the Probiotic Bacterium Lactobacillus acidophilus NCFM

“…Chemical synthesis-Fluorogenic substrates from the series 1 and substrates 2c and 2d were synthesized using protocols similar to previous reports (see the Supporting Information for full experimental details). The remaining substrates from series 2 and substrates from series 3-5 were reported earlier (44,60,61,70,104,105,106) and synthesized using a combination of solution-phase and solid-phase peptide synthesis (see the Supporting Information for references). Compound 6 has previously been reported (65) and compound 7 was synthesized from bis(1benzotriazolyl)methanethione, methyl amine, and Cbz-Lys-Trp-NHiPr•TFA using a protocol reported in the same paper (see the Supporting Information for full experimental details).…”