l-Ascorbic Acid 6-Hexadecanoate, a Potent Hyaluronidase Inhibitor
l-Ascorbic Acid 6-Hexadecanoate, a Potent Hyaluronidase Inhibitor
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L-抗坏血酸 6-十六酸酯，一种有效的透明质酸酶抑制剂
DOI：
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发表时间：
2004
影响因子：
4.8
通讯作者：
A. Buschauer
中科院分区：
文献类型：
--
作者：
Alexander Botzki;D. Rigden;S. Braun;M. Nukui;Sunnhild Salmen;Julia Hoechstetter;G. Bernhardt;S. Dove;M. J. Jedrzejas;A. Buschauer
透明质酸酶是降解透明质酸的酶，透明质酸是细胞外基质的重要组成部分。哺乳动物透明质酸酶被认为参与许多（病理）生理过程，如受精、肿瘤生长和转移。细菌透明质酸酶，也称为透明质酸裂解酶，有助于微生物在组织中的传播。透明质酸酶的这种作用表明抑制剂可能是有用的药理学工具。尽管据报道 L-抗坏血酸是肺炎链球菌透明质酸裂解酶 (SpnHL) 的弱抑制剂，但迄今为止尚不清楚有效的选择性抑制剂。与 L-抗坏血酸复合的 SpnHL 的 X 射线结构已被阐明，表明额外的疏水相互作用可能会增加抑制活性。在这里，我们证明 L-抗坏血酸 6-十六烷酸酯 (Vcpal) 是链球菌和牛睾丸透明质酸酶 (BTH) 的有效抑制剂。 Vcpal 对无乳链球菌透明质酸裂解酶具有较强的抑制作用，IC50 为 4 μm，对 SpnHL 和 BTH 具有较弱的抑制作用，IC50 值分别为 100 和 56 μm。迄今为止，Vcpal 已被证明是最有效的透明质酸酶抑制剂之一。我们还确定了 SpnHL-Vcpal 复合物的 X 射线结构，并证实了这样的假设：活性位点中与 Phe-343、His-399 和 Thr-400 的额外疏水相互作用导致抑制增加。还生成了 BTH 的同源结构模型以表明 Vcpal 与该透明质酸酶的结合模式。长烷基链似乎与 BTH 中大部分保守氨基酸 Ala-84、Leu-91、Tyr-93、Tyr-220 和 Leu-344 形成的延伸疏水通道相互作用。
Hyaluronidases are enzymes that degrade hyaluronan, an important component of the extracellular matrix. The mammalian hyaluronidases are considered to be involved in many (patho)physiological processes like fertilization, tumor growth, and metastasis. Bacterial hyaluronidases, also termed hyaluronate lyases, contribute to the spreading of microorganisms in tissues. Such roles for hyaluronidases suggest that inhibitors could be useful pharmacological tools. Potent and selective inhibitors are not known to date, although l-ascorbic acid has been reported to be a weak inhibitor of Streptococcus pneumoniae hyaluronate lyase (SpnHL). The x-ray structure of SpnHL complexed with l-ascorbic acid has been elucidated suggesting that additional hydrophobic interactions might increase inhibitory activity. Here we show that l-ascorbic acid 6-hexadecanoate (Vcpal) is a potent inhibitor of both streptococcal and bovine testicular hyaluronidase (BTH). Vcpal showed strong inhibition of Streptococcus agalactiae hyaluronate lyase with an IC50 of 4 μm and weaker inhibition of SpnHL and BTH with IC50 values of 100 and 56 μm, respectively. To date, Vcpal has proved to be one of the most potent inhibitors of hyaluronidase. We also determined the x-ray structure of the SpnHL-Vcpal complex and confirmed the hypothesis that additional hydrophobic interactions with Phe-343, His-399, and Thr-400 in the active site led to increased inhibition. A homology structural model of BTH was also generated to suggest binding modes of Vcpal to this hyaluronidase. The long alkyl chain seemed to interact with an extended, hydrophobic channel formed by mostly conserved amino acids Ala-84, Leu-91, Tyr-93, Tyr-220, and Leu-344 in BTH.
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肺炎链球菌透明质酸裂解酶催化裂隙中疏水残基的功能。
DOI：
10.1074/jbc.m204999200
发表时间：
2003
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Nukui,Masatoshi;Taylor,KennethB;McPherson,DavidT;Shigenaga,MarkK;Jedrzejas,MarkJ
通讯作者：
Jedrzejas,MarkJ
影响因子：
--
作者：
R. Sánchez;Andrej Sali
通讯作者：
R. Sánchez;Andrej Sali
影响因子：
9.7
作者：
Lin, G;Stern, R
通讯作者：
Stern, R
DOI：
10.1016/s0925-4439(00)00009-0
发表时间：
2000-04-15
影响因子：
6.2
作者：
Simpson, GLW;Ortwerth, BJ
通讯作者：
Ortwerth, BJ