DOI: 10.1073/pnas.98.1.87. Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin

Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin

10.1073/pnas.98.1.87

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Trichostatin A (TSA) and trapoxin (TPX) are potent inhibitors of histone deacetylases (HDACs). TSA is proposed to block the catalytic reaction by chelating a zinc ion in the active-site pocket through its hydroxamic acid group. On the other hand, the epoxyketone is suggested to be the functional group of TPX capable of alkylating the enzyme. We synthesized a novel TPX analogue containing a hydroxamic acid instead of the epoxyketone. The hybrid compound cyclic hydroxamic acid-containing peptide (CHAP) 1 inhibited HDAC1 at low nanomolar concentrations. The HDAC1 inhibition by CHAP1 was reversible as it was by TSA, in contrast to the irreversible inhibition by TPX. CHAP with an aliphatic chain length of five, which corresponded to that of acetylated lysine, was stronger than those with other lengths. These results suggest that TPX is a substrate mimic and that the replacement of the epoxyketone with the hydroxamic acid converted TPX to an inhibitor chelating the zinc like TSA. Interestingly, HDAC6, but not HDAC1 or HDAC4, was resistant to TPX and CHAP1, whereas TSA inhibited these HDACs to a similar extent. HDAC6 inhibition by TPX at a high concentration was reversible, probably because HDAC6 is not alkylated by TPX. We further synthesized the counterparts of all known naturally occurring cyclic tetrapeptides containing the epoxyketone. HDAC1 was highly sensitive to all these CHAPs much more than HDAC6, indicating that the structure of the cyclic tetrapeptide framework affects the target enzyme specificity. These results suggest that CHAP is a unique lead to develop isoform-specific HDAC inhibitors.

Bibliography

Furumai, R., Komatsu, Y., Nishino, N., Khochbin, S., Yoshida, M., & Horinouchi, S. (2000). Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin. Proceedings of the National Academy of Sciences, 98(1), 87â92.

Authors 6

Ryohei Furumai (first)
Yasuhiko Komatsu (additional)
Norikazu Nishino (additional)
Saadi Khochbin (additional)
Minoru Yoshida (additional)
Sueharu Horinouchi (additional)

References 47 Referenced 306

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Dates

Type	When
Created	13 years, 1 month ago (July 30, 2012, 1:19 p.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 5:54 p.m.)
Indexed	4 weeks, 1 day ago (Aug. 3, 2025, 6:57 p.m.)
Issued	24 years, 8 months ago (Dec. 26, 2000)
Published	24 years, 8 months ago (Dec. 26, 2000)
Published Online	24 years, 8 months ago (Dec. 26, 2000)
Published Print	24 years, 7 months ago (Jan. 2, 2001)

Funders 0

None

BibTeX

@article{Furumai_2000, title={Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin}, volume={98}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.98.1.87}, DOI={10.1073/pnas.98.1.87}, number={1}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Furumai, Ryohei and Komatsu, Yasuhiko and Nishino, Norikazu and Khochbin, Saadi and Yoshida, Minoru and Horinouchi, Sueharu}, year={2000}, month=dec, pages={87–92} }

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