Slow-Binding and Covalent HDAC Inhibition: A New Paradigm?

The dysregulated post-translational modification of proteins is an established hallmark of human disease. Through Zn-dependent hydrolysis of acyl-lysine modifications, histone deacetylases (HDACs) are key regulators of disease-implicated signaling pathways and tractable drug targets in the clinic. Early targeting of this family of 11 enzymes (HDAC1-11) afforded a first generation of broadly acting inhibitors with medicinal applications in oncology, specifically in cutaneous and peripheral T-cell lymphomas and in multiple myeloma.

Distribution and diversity of classical deacylases in bacteria.

Classical Zn-dependent deac(et)ylases play fundamental regulatory roles in life and are well characterized in eukaryotes regarding their structures, substrates and physiological roles. In bacteria, however, classical deacylases are less well understood. We construct a Generalized Profile (GP) and identify thousands of uncharacterized classical deacylases in bacteria, which are grouped into five clusters.

Revealing chromatin-specific functions of histone deacylases.

Histone deacylases are erasers of Nε-acyl-lysine post-translational modifications and have been targeted for decades for the treatment of cancer, neurodegeneration and other disorders. Due to their relatively promiscuous activity on peptide substrates in vitro, it has been challenging to determine the individual targets and substrate identification mechanisms of each isozyme, and they have been considered redundant regulators. In recent years, biochemical and biophysical studies have incorporated the use of reconstituted nucleosomes, which has revealed a diverse and complex arsenal of recognition mechanisms by which histone deacylases may differentiate themselves in vivo.

Chiral Posttranslational Modification to Lysine ε-Amino Groups.

The sophistication of proteomic analysis has revealed that protein lysine residues are posttranslationally modified by a variety of acyl groups. Protein lysine acetylation regulates metabolism, gene expression, and microtubule formation and has been extensively studied; however, the understanding of the biological significance of other acyl posttranslational modifications (PTMs) is still in its infancy. The acylation of lysine residues is mediated either by acyltransferase "writer" enzymes or by nonenzymatic mechanisms and hydrolase enzymes, termed "erasers", that cleave various acyl PTMs to reverse the modified state.

Class I histone deacetylases (HDAC1-3) are histone lysine delactylases.

Lysine L-lactylation [K(L-la)] is a newly discovered histone mark stimulated under conditions of high glycolysis, such as the Warburg effect. K(L-la) is associated with functions that are different from the widely studied histone acetylation. While K(L-la) can be introduced by the acetyltransferase p300, histone delactylases enzymes remained unknown.

Mechanism-based inhibitors of SIRT2: structure-activity relationship, X-ray structures, target engagement, regulation of α-tubulin acetylation and inhibition of breast cancer cell migration.

Sirtuin 2 (SIRT2) is a protein deacylase enzyme that removes acetyl groups and longer chain acyl groups from post-translationally modified lysine residues. It affects diverse biological functions in the cell and has been considered a drug target in relation to both neurodegenerative diseases and cancer. Therefore, access to well-characterized and robust tool compounds is essential for the continued investigation of the complex functions of this enzyme.

Zn-Dependent Histone Deacetylases in Plants: Structure and Evolution.

Zn-dependent histone deacetylases are widely distributed in archaea, bacteria, and eukaryotes. Through deacetylation of histones and other biomolecules, these enzymes regulate mammalian gene expression, microtubule stability, and polyamine metabolism. In plants, they play essential roles in development and stress response, but little is known about their biochemistry.

Hydroxamic acid-modified peptide microarrays for profiling isozyme-selective interactions and inhibition of histone deacetylases.

Histones control gene expression by regulating chromatin structure and function. The posttranslational modifications (PTMs) on the side chains of histones form the epigenetic landscape, which is tightly controlled by epigenetic modulator enzymes and further recognized by so-called reader domains. Histone microarrays have been widely applied to investigate histone-reader interactions, but not the transient interactions of Zn-dependent histone deacetylase (HDAC) eraser enzymes.

Kinetic Tuning of HDAC Inhibitors Affords Potent Inducers of Progranulin Expression.

Histone deacetylases (HDACs) are enzymes involved in the epigenetic control of gene expression. A handful of HDAC inhibitors have been approved for the treatment of cancer, and HDAC inhibition has also been proposed as a novel therapeutic strategy for neurodegenerative disorders. These disorders include progranulin (PGRN)-deficient forms of frontotemporal dementia caused by mutations in the gene that lead to haploinsufficiency.

Histone Deacetylase 11 Is an ε-N-Myristoyllysine Hydrolase.

Histone deacetylase (HDAC) enzymes regulate 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 zinc-dependent HDACs, the most recently discovered member, HDAC11, is the only member assigned to subclass IV. It is the smallest protein and has the least well understood biological function.

D-π-A Compounds with Tunable Intramolecular Charge Transfer Achieved by Incorporation of Butenolide Nitriles as Acceptor Moieties.

Chromophores where a polyenic spacer separates a 4H-pyranylidene or benzothiazolylidene donor and three different butenolide nitriles have been synthesized and characterized. The role of 2(5H)-furanones as acceptor units on the polarization and the second-order nonlinear (NLO) properties has been studied. Thus, their incorporation gives rise to moderately polarized structures with NLO responses that compare favorably to those of related compounds featuring more efficient electron-withdrawing moieties.