Methylation suppresses the proteasome-inhibitory function of green tea polyphenols
Methylation suppresses the proteasome-inhibitory function of green tea polyphenols
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DOI：
10.1002/jcp.21124
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发表时间：
2007-10-01
影响因子：
5.6
通讯作者：
Dou, Q. Ping
中科院分区：
文献类型：
--
作者：
Landis-Piwowar, Kristin R.;Wan, Sheng Biao;Dou, Q. Ping
在生理条件下，生物转化反应，如甲基化，可以修饰绿茶多酚（gtp），从而限制其在体内的抗癌活性。尽管最近的一项研究表明甲基化多酚对癌症的保护作用较弱，但其分子基础尚不清楚。我们之前报道了含有酯键的gtp，例如(-)-表儿茶素-3-没食子酸酯[(-)- egcg]或(-)-表儿茶素-3-没食子酸酯[(-)- ecg]，能有效地特异性抑制蛋白酶体凝乳胰蛋白酶样活性。在这项研究中，我们假设甲基化的gtp降低了蛋白酶体抑制能力。为了验证这一假设，我们合成了体内可发现的甲基化（-）EGCG和(-)- ecg类似物，并使用纯化的20S蛋白酶体研究了它们的结构-活性关系（SARs）。在(-)- egcg或(-)- ecg上添加单个甲基导致蛋白酶体抑制降低，并且随着甲基数量的增加，抑制效力进一步降低。我们最近发表的计算机对接分析结果支持了这些sar。之前，我们合成了一种过酸盐保护的(-)- egcg分子，Pro-EGCG(1)，以增强其细胞渗透性和稳定性，目前的HPLC分析证实，在培养的人类白血病Jurkat T细胞中，Pro-EGCG(1)转化为(-)- egcg。此外，在本研究中，在完整的Jurkat T细胞中加入过乙酸盐保护形式的甲基化gtp，以观察甲基化的细胞内效应。过酸盐保护的单甲基化(-)- egcg比过酸盐保护的三甲基化(-)- egcg诱导更大的细胞蛋白酶体抑制和凋亡，这与母体甲基化类似物对纯化20S蛋白酶体的作用一致。因此，在生理条件下，gtp的甲基化可以降低其蛋白酶体抑制活性，从而降低茶的预防癌症作用。(c) 2007 Wiley-Liss, Inc。
Under physiological conditions, biotransformation reactions, such as methylation, can modify green tea polyphenols (GTPs) and therefore limit their in vivo cancer-preventive activity. Although a recent study suggested that methylated polyphenols are less cancer-protective, the molecular basis is unknown. We previously reported that ester bond-containing GTPs, for example (-)-epigallocatech in-3-gallate [(-)-EGCG] or (-)-epicatechin-3-gallate [(-)-ECG], potently and specifically inhibit the proteasomal chymotrypsin-like activity. In this study, we hypothesize that methylated GTPs have decreased proteasome-inhibitory abilities. To test this hypothesis, methylated (-)EGCG and (-)-ECG analogs that can be found in vivo were synthesized and studied for their structure-activity relationships (SARs) using a purified 20S proteasome. The addition of a single methyl group on (-)-EGCG or (-)-ECG led to decreased proteasome inhibition and, as the number of methyl groups increased, the inhibitory potencies further decreased. These SARs were supported by our findings from in silico docking analysis published recently. Previously, we synthesized a peracetate-protected (-)-EGCG molecule, Pro-EGCG (1), to enhance its cellular permeability and stability, and current HPLC analysis confirms conversion of Pro-EGCG (1) to (-)-EGCG in cultured human leukemic Jurkat T cells. Furthermore, in this study, peracetate-protected forms of methylated GTPs were added in intact Jurkat T cells to observe the intracellular effects of methylation. Peracetate-protected, monomethylated (-)-EGCG induced greater cellular proteasome inhibition and apoptosis than did peracetate-protected, trimethylated (-)-EGCG, consistent with the potencies of the parent methylated analogs against a purified 20S proteasome. Therefore, methylation on GTPs, under physiological conditions, could decrease their proteasome-inhibitory activity, contributing to decreased cancer-preventive effects of tea consumption. (c) 2007 Wiley-Liss, Inc.