Structure, mechanism, and inhibition of histone deacetylases and related metalloenzymes

Abstract

Metal-dependent histone deacetylases (HDACs) catalyze the hydrolysis of acetyl-L-lysine side chains in histone and non-histone proteins to yield L-lysine and acetate. This chemistry plays a critical role in the regulation of numerous biological processes. Aberrant HDAC activity is implicated in various diseases, and HDACs are validated targets for drug design. Two HDAC inhibitors are currently approved for cancer chemotherapy, and other inhibitors are in clinical trials. To date, X-ray crystal structures are available for four human HDACs (2, 4, 7, 8) and three HDAC-related deacetylases from bacteria (histone deacetylase-like protein, HDLP; histone deacetylase-like amidohydrolase, HDAH; acetylpolyamine amidohydrolase, APAH). Structural comparisons among these enzymes reveal a conserved constellation of active site residues, suggesting a common mechanism for the metal-dependent hydrolysis of acetylated substrates. Structural analyses of HDACs and HDAC-related deacetylases guide the design of tight-binding inhibitors, and future prospects for developing isozyme-specific inhibitors are quite promising.

Design, Synthesis, and Evaluation of Polyamine Deacetylase Inhibitors, and High-Resolution Crystal Structures of Their Complexes with Acetylpolyamine Amidohydrolase

“…The imidazole side chains of H158 and H159 are presumed to hydrogen bond with the nucleophilic Zn 2+ -bound water molecule; by analogy with enzymological studies of HDAC8, , H159 of APAH likely serves as a general base in a promoted water mechanism in which both H159 and Zn 2+ serve to activate the nucleophilic water molecule. Thus, the observed binding modes of trifluoromethylketone 1 as well as the substrate N 8 -acetylspermidine strongly support the mechanistic proposal for APAH recently presented by Lombardi and colleagues as summarized in Figure .…”

Design, Synthesis, and Evaluation of Polyamine Deacetylase Inhibitors, and High-Resolution Crystal Structures of Their Complexes with Acetylpolyamine Amidohydrolase

“…The imidazole side chains of H158 and H159 are presumed to hydrogen bond with the nucleophilic Zn 2+ -bound water molecule; by analogy with enzymological studies of HDAC8, , H159 of APAH likely serves as a general base in a promoted water mechanism in which both H159 and Zn 2+ serve to activate the nucleophilic water molecule. Thus, the observed binding modes of trifluoromethylketone 1 as well as the substrate N 8 -acetylspermidine strongly support the mechanistic proposal for APAH recently presented by Lombardi and colleagues as summarized in Figure .…”

Crystal Structure of a Histone Deacetylase Homologue from Pseudomonas aeruginosa

“…The electron density could be interpreted for residues 2–374 of one monomer and 2–379 of the other of a total number of 384 possible residues. The enzyme core adopts an open α/β fold that is characteristic of this class of enzymes. ,, It consists of eight central stranded parallel β-sheets surrounded by 14 helices and two smaller antiparallel β-turns (Figure ).…”

Macrocycle-Induced Modulation of Internuclear Interactions in Homobimetallic Complexes

“…It is worth highlighting that 4 [Mn] is the only 4 [M] complex reported here with antiferromagnetic coupling, despite having a M−Cl−M bond angle in the same range as the other ferromagnetically coupled n [M] complexes (Table 3). Similarly, the magnetic data for 3 [Mn] (∠Mn−Cl−Mn = 84.91(2)°) more closely resemble the antiferromagnetic coupling observed in the distorted 2 [M] complexes (∠M− Cl−M < 78°) than the more similarly structured, yet ferromagnetically coupled, 3 [Fe] [86.12(2)°] and 3 [Co] [86.12(2)°]. The magnetochemistry of octahedral d 5 metals is reported to break from the Goodenough−Kanamori rules due to a significant component of the magnetic spin residing in the pseudo-t 2g set, which lies orthogonal to the bridging interaction.…”

“…The fit for these 2 [Ni] data revealed the largest magnitude coupling constant of the series at J = −16.7 cm −1 , a value that is consistent with an S tot = 0 ground state for the complex as a whole. 2 [Co] and 2 [Fe] are also both best fit with antiferromagnetic coupling constants, but the magnitudes of J in these latter systems are an order of magnitude smaller than that in 2 [Ni] (Table 5).…”

Design, Synthesis, and Evaluation of Polyamine Deacetylase Inhibitors, and High-Resolution Crystal Structures of Their Complexes with Acetylpolyamine Amidohydrolase

“…The imidazole side chains of H158 and H159 are presumed to hydrogen bond with the nucleophilic Zn 2+ -bound water molecule; by analogy with enzymological studies of HDAC8, , H159 of APAH likely serves as a general base in a promoted water mechanism in which both H159 and Zn 2+ serve to activate the nucleophilic water molecule. Thus, the observed binding modes of trifluoromethylketone 1 as well as the substrate N 8 -acetylspermidine strongly support the mechanistic proposal for APAH recently presented by Lombardi and colleagues as summarized in Figure .…”

Crystal Structure of a Histone Deacetylase Homologue from Pseudomonas aeruginosa

“…The electron density could be interpreted for residues 2–374 of one monomer and 2–379 of the other of a total number of 384 possible residues. The enzyme core adopts an open α/β fold that is characteristic of this class of enzymes. ,, It consists of eight central stranded parallel β-sheets surrounded by 14 helices and two smaller antiparallel β-turns (Figure ).…”

Macrocycle-Induced Modulation of Internuclear Interactions in Homobimetallic Complexes

“…It is worth highlighting that 4 [Mn] is the only 4 [M] complex reported here with antiferromagnetic coupling, despite having a M−Cl−M bond angle in the same range as the other ferromagnetically coupled n [M] complexes (Table 3). Similarly, the magnetic data for 3 [Mn] (∠Mn−Cl−Mn = 84.91(2)°) more closely resemble the antiferromagnetic coupling observed in the distorted 2 [M] complexes (∠M− Cl−M < 78°) than the more similarly structured, yet ferromagnetically coupled, 3 [Fe] [86.12(2)°] and 3 [Co] [86.12(2)°]. The magnetochemistry of octahedral d 5 metals is reported to break from the Goodenough−Kanamori rules due to a significant component of the magnetic spin residing in the pseudo-t 2g set, which lies orthogonal to the bridging interaction.…”

“…The fit for these 2 [Ni] data revealed the largest magnitude coupling constant of the series at J = −16.7 cm −1 , a value that is consistent with an S tot = 0 ground state for the complex as a whole. 2 [Co] and 2 [Fe] are also both best fit with antiferromagnetic coupling constants, but the magnitudes of J in these latter systems are an order of magnitude smaller than that in 2 [Ni] (Table 5).…”

Design, Synthesis, and Evaluation of Polyamine Deacetylase Inhibitors, and High-Resolution Crystal Structures of Their Complexes with Acetylpolyamine Amidohydrolase

“…The imidazole side chains of H158 and H159 are presumed to hydrogen bond with the nucleophilic Zn 2+ -bound water molecule; by analogy with enzymological studies of HDAC8, , H159 of APAH likely serves as a general base in a promoted water mechanism in which both H159 and Zn 2+ serve to activate the nucleophilic water molecule. Thus, the observed binding modes of trifluoromethylketone 1 as well as the substrate N 8 -acetylspermidine strongly support the mechanistic proposal for APAH recently presented by Lombardi and colleagues as summarized in Figure .…”

Crystal Structure of a Histone Deacetylase Homologue from Pseudomonas aeruginosa

“…The electron density could be interpreted for residues 2–374 of one monomer and 2–379 of the other of a total number of 384 possible residues. The enzyme core adopts an open α/β fold that is characteristic of this class of enzymes. ,, It consists of eight central stranded parallel β-sheets surrounded by 14 helices and two smaller antiparallel β-turns (Figure ).…”

Macrocycle-Induced Modulation of Internuclear Interactions in Homobimetallic Complexes

“…It is worth highlighting that 4 [Mn] is the only 4 [M] complex reported here with antiferromagnetic coupling, despite having a M−Cl−M bond angle in the same range as the other ferromagnetically coupled n [M] complexes (Table 3). Similarly, the magnetic data for 3 [Mn] (∠Mn−Cl−Mn = 84.91(2)°) more closely resemble the antiferromagnetic coupling observed in the distorted 2 [M] complexes (∠M− Cl−M < 78°) than the more similarly structured, yet ferromagnetically coupled, 3 [Fe] [86.12(2)°] and 3 [Co] [86.12(2)°]. The magnetochemistry of octahedral d 5 metals is reported to break from the Goodenough−Kanamori rules due to a significant component of the magnetic spin residing in the pseudo-t 2g set, which lies orthogonal to the bridging interaction.…”

“…The fit for these 2 [Ni] data revealed the largest magnitude coupling constant of the series at J = −16.7 cm −1 , a value that is consistent with an S tot = 0 ground state for the complex as a whole. 2 [Co] and 2 [Fe] are also both best fit with antiferromagnetic coupling constants, but the magnitudes of J in these latter systems are an order of magnitude smaller than that in 2 [Ni] (Table 5).…”