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@ARTICLE{Lechner:276875,
author = {S. Lechner and R. R. Steimbach$^*$ and L. Wang and M. L.
Deline and Y.-C. Chang and T. Fromme and M. Klingenspor and
P. Matthias and A. K. Miller$^*$ and G. Médard and B.
Kuster$^*$},
title = {{C}hemoproteomic target deconvolution reveals {H}istone
{D}eacetylases as targets of ({R})-lipoic acid.},
journal = {Nature Communications},
volume = {14},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Nature Publishing Group UK},
reportid = {DKFZ-2023-01184},
pages = {3548},
year = {2023},
abstract = {Lipoic acid is an essential enzyme cofactor in central
metabolic pathways. Due to its claimed antioxidant
properties, racemic (R/S)-lipoic acid is used as a food
supplement but is also investigated as a pharmaceutical in
over 180 clinical trials covering a broad range of diseases.
Moreover, (R/S)-lipoic acid is an approved drug for the
treatment of diabetic neuropathy. However, its mechanism of
action remains elusive. Here, we performed
chemoproteomics-aided target deconvolution of lipoic acid
and its active close analog lipoamide. We find that histone
deacetylases HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, and HDAC10
are molecular targets of the reduced form of lipoic acid and
lipoamide. Importantly, only the naturally occurring
(R)-enantiomer inhibits HDACs at physiologically relevant
concentrations and leads to hyperacetylation of HDAC
substrates. The inhibition of HDACs by (R)-lipoic acid and
lipoamide explain why both compounds prevent stress granule
formation in cells and may also provide a molecular
rationale for many other phenotypic effects elicited by
lipoic acid.},
cin = {A390 / HD01 / MU01},
ddc = {500},
cid = {I:(DE-He78)A390-20160331 / I:(DE-He78)HD01-20160331 /
I:(DE-He78)MU01-20160331},
pnm = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
pid = {G:(DE-HGF)POF4-311},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:37322067},
doi = {10.1038/s41467-023-39151-8},
url = {https://inrepo02.dkfz.de/record/276875},
}