Fig 2: Dynamic simulations of 33d bound with IDO1 or HDAC1. RMSD analysis of IDO1 (A) and HDAC1 (C) in apo or bounding form. RMSF analysis of IDO1 (B) and HDAC1 (D) in apo or bounding form.

Fig 3: Obtained docking poses of 48 b in different HDAC isoforms: a) 48 b (yellow sticks) in drHDAC10 (PDB ID 6UHU), b) 48 b (teal sticks) in HDAC6 (PDB ID 5EDU), c) 48 b (orange sticks) in HDAC8 (PDB ID 2V5X), d) 48 b (magenta sticks) in HDAC1 (PDB ID 5ICN); the surface of HDAC1 binding site is colored according to lipophilicity; green for hydrophobic and magenta for hydrophilic. Binding site residues are shown as white sticks and the catalytic zinc ions as orange spheres. Hydrogen bonds interactions are depicted as blue-dashed lines, salt bridge interactions as magenta-dashed lines, cation-p interactions as teal-dashed lines, and coordination of the zinc ion by the ligand as yellow-dashed lines.

Fig 4: Histone H3 tail acetylation and HDAC complexes.(A) Different acetylation sites on H3 N-terminal tail studied in this manuscript; (B) Components of four well- established HDAC1 complexes CoREST (LSD1, HDAC1, CoREST1), NuRD (MTA1, HDAC1, RBBP4), Sin3B (Sin3, HDAC1, RBBP4), MiDAC (MIDEAS, HDAC1, DNTTP1), and one HDAC3 complex SMRT (GPS2-NCoR2 chimera, HDAC3, and TBL1 ).

Fig 5: Delactylase activities of HDAC1–3 at different histone sites.(A) Synthesized histone peptide sequences, with X = Kac (a), K(l-la) (b), or K(d-la) (c). (B) Sample deacetylation and delactylation HPLC assay traces (60-min reaction of 50 nM HDAC3/NCoR2 with 50 µM peptide 6a or 6b). (C) Relative conversion of Kac-, K(l-la)–, or K(d-la)–containing histone peptides. Data represent means ± SD (n = 2). (D) Relative conversion of Kac-, K(l-la)–, or K(D-la)–containing H3K18 peptide by SIRT1–3. Data represent means ± SD (n = 2). (E) Michaelis-Menten plots for HDAC1–3 against substrates 6a, 6b, and 6c. Data represent means ± SEM (n = 2) (see fig. S5 for HDAC2 data). (F) Catalytic efficiencies of HDAC1–3 against substrates 6a–c and 10a–c. Data represent means ± SEM (n = 2) (see fig. S5 for Michaelis-Menten plots of substrates 10a–c and numerical data). *HDAC3 incubated with the DAD of NCoR2.