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.
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DOI：
10.1073/pnas.98.1.87
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发表时间：
2001-01
影响因子：
11.1
通讯作者：
R. Furumai;Y. Komatsu;N. Nishino;S. Khochbin;M. Yoshida;S. Horinouchi
中科院分区：
文献类型：
--
作者：
R. Furumai;Y. Komatsu;N. Nishino;S. Khochbin;M. Yoshida;S. Horinouchi
曲古霉素A （TSA）和曲毒素（TPX）是组蛋白去乙酰化酶（hdac）的有效抑制剂。提出TSA通过其羟基肟酸基团螯合活性位点口袋中的锌离子来阻断催化反应。另一方面，环氧酮被认为是TPX能够烷基化酶的官能团。我们合成了一种新的含羟肟酸代替环氧酮的TPX类似物。杂化化合物环羟肟酸-含肽（CHAP） 1在低纳摩尔浓度下抑制HDAC1。与TPX的不可逆抑制作用相反，CHAP1对HDAC1的抑制作用与TSA一样具有可逆性。与乙酰化赖氨酸对应的脂肪链长度为5的CHAP比其他长度的CHAP更强。这些结果表明，TPX是一种底物模拟物，羟肟酸取代环氧酮使TPX转变为一种像TSA一样螯合锌的抑制剂。有趣的是，HDAC6，而不是HDAC1或HDAC4，对TPX和CHAP1有抗性，而TSA对这些hdac的抑制程度相似。高浓度TPX对HDAC6的抑制作用是可逆的，可能是因为HDAC6没有被TPX烷基化。我们进一步合成了所有已知的天然存在的含环氧酮的环四肽的对应物。HDAC1对所有这些CHAPs高度敏感，远高于HDAC6，这表明环四肽框架的结构影响了靶酶的特异性。这些结果表明，CHAP是开发亚型特异性HDAC抑制剂的独特先导。
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.