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bioRxiv · 10.1101/2023.08.08.552419

Crystal Structure of Histone Deacetylase 6 Complexed with (R)-Lipoic Acid, an Essential Cofactor in Central Carbon Metabolism

Watson, P. R.·Stollmaier, J. G.·Christianson, D. W.
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Abstract

The enzyme cofactor (R)-lipoic acid plays a critical role in central carbon metabolism due to its catalytic function in the generation of acetyl-CoA, which links glycolysis with the tricarboxylic acid cycle. This cofactor is also essential for the generation of succinyl CoA within the tricarboxylic acid cycle. However, the biological functions of (R)-lipoic acid extend beyond metabolism owing to its facile redox chemistry. Most recently, the reduced form of (R)-lipoic acid, (R)-dihydrolipoic acid, has been shown to inhibit histone deacetylases (HDACs) with selectivity for the inhibition of HDAC6. Here, we report the 2.4 [A]-resolution X-ray crystal structure of the HDAC6-(R)-dihydrolipoic acid complex, and we report a dissociation constant (KD) of 350 nM for this complex as determined by isothermal titration calorimetry. The crystal structure illuminates key affinity determinants in the enzyme active site, including thiolate-Zn2+ coordination and S-{pi} interactions in the F583-F643 aromatic crevice. This study provides the first visualization of the connection between HDAC function and the biological response to oxidative stress: the dithiol moiety of (R)-dihydrolipoic acid can serve as a redox-regulated pharmacophore capable of simultaneously targeting the catalytic Zn2+ ion and the aromatic crevice in the active site of HDAC6.

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Watson, P. R., Stollmaier, J. G., Christianson, D. W.. 2023-08-09. Crystal Structure of Histone Deacetylase 6 Complexed with (R)-Lipoic Acid, an Essential Cofactor in Central Carbon Metabolism. https://doi.org/10.1101/2023.08.08.552419

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