title: Mutagenesis studies of the 14 Å internal cavity of histone deacetylase 1: insights toward the acetate-escape hypothesis and selective inhibitor design.
abstract: Histone deacetylase (HDAC) proteins are promising targets for cancer treatment, as shown by the approval of two HDAC inhibitors for the treatment of cutaneous T-cell lymphoma. HDAC1 in particular has been linked to cell growth and cell cycle regulation and is therefore an attractive target for anticancer drugs. The HDAC1 active site contains a hydrophobic 11 Å active-site channel, with a 14 Å internal cavity at the bottom of the active site. Several computational and biochemical studies have proposed an acetate-escape hypothesis where the acetate byproduct of the deacetylation reaction escapes via the 14 Å internal cavity. Selective HDAC inhibitors that bind to the 14 Å cavity have also been created. To understand the influence of amino acids lining the HDAC1 14 Å cavity in acetate escape and inhibitor binding, we used mutagenesis coupled with acetate competition assays. The results indicate that amino acids lining the 14 Å cavity are critical for catalytic activity and acetate competition, confirming the role of the cavity in acetate escape. In addition, these mutagenesis studies will aid in HDAC1-inhibitor design that exploits the 14 Å cavity.
authors.affiliation: Department of Chemistry, Wayne State University , 5101 Cass Avenue, Detroit, Michigan 48202, United States.
authors.forename: Magdalene K
authors.initials: MK
authors.lastname: Wambua
authors.forename: Dhanusha A
authors.initials: DA
authors.lastname: Nalawansha
authors.forename: Ahmed T
authors.initials: AT
authors.lastname: Negmeldin
authors.forename: Mary Kay H
authors.initials: MK
authors.lastname: Pflum
mesh_terms: D000085:Acetates / Q000737:chemistry*; D000596:Amino Acids / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry*; D020134:Catalytic Domain; D047630:Depsipeptides / Q000737:chemistry; D015195:Drug Design; D056284:Histone Deacetylase 1 / Q000737:chemistry* / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D019169:Jurkat Cells; D062105:Molecular Docking Simulation; D009154:Mutation; D000077337:Vorinostat
chemical_list: D000085:Acetates; D000596:Amino Acids; D000970:Antineoplastic Agents; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; C087123:romidepsin; D056284:Histone Deacetylase 1