Diverse clinical compounds alter the quaternary structure and inhibit the activity of an essential enzyme.
Diverse clinical compounds alter the quaternary structure and inhibit the activity of an essential enzyme.
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DOI：
10.1002/cmdc.201100009
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发表时间：
2011-06-06
期刊：
影响因子：
3.4
通讯作者：
Jaffe, Eileen K.
中科院分区：
文献类型：
--
作者：
Lawrence, Sarah H.;Selwood, Trevor;Jaffe, Eileen K.
约翰霍普金斯临床化合物库的体外评估表明，某些药物可以改变人体必需蛋白质的四级结构。人胆色素原合酶（HsPBGS）是血红素生物合成中必需的酶;它以高活性八聚体、低活性六聚体和交替二聚体构型的平衡存在，所述平衡决定了进一步组装的化学计量和结构。降低的HsPBGS活性与铅中毒和ALAD卟啉症相关的毒性有关，后者涉及六聚体有利的HsPBGS变体。一个中等通量的天然PAGE迁移率变动筛选，再加上作为HsPBGS抑制剂的评价命中，揭示了12种药物，稳定HsPBGS六聚体和抑制HsPBGS活性在体外。这些影响的详细表征。通过诱导六聚体形成来抑制体内HsPBGS的药物将构成前所未有的副作用机制。我们认为，小分子扰动的四级结构平衡被认为是药物作用和副作用的一般机制。
An in vitro evaluation of the Johns Hopkins Clinical Compound Library demonstrates that certain drugs can alter the quaternary structure of an essential human protein. Human porphobilinogen synthase (HsPBGS) is an essential enzyme involved in heme biosynthesis; it exists as an equilibrium of high activity octamers, low activity hexamers, and alternate dimer configurations that dictate the stoichiometry and architecture of further assembly. Reduced HsPBGS activity is implicated in toxicities associated with lead poisoning and ALAD porphyria, the latter of which involves hexamer-favoring HsPBGS variants. A medium-throughput native PAGE mobility shift screen, coupled with evaluation of hits as HsPBGS inhibitors, revealed twelve drugs that stabilize the HsPBGS hexamer and inhibit HsPBGS activity in vitro. A detailed characterization of these effects is presented. Drug inhibition of HsPBGS in vivo by inducing hexamer formation would constitute an unprecedented mechanism for side effects. We suggest that small molecule perturbation of quaternary structure equilibria be considered as a general mechanism for drug action and side effects.
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影响因子：
4.8
作者：
Lawrence, Sarah H.;Ramirez, Ursula D.;Jaffe, Eileen K.
通讯作者：
Jaffe, Eileen K.
DOI：
10.1073/pnas.93.26.15051
发表时间：
1996-12-24
影响因子：
11.1
作者：
Miroy, GJ;Lai, ZH;Kelly, JW
通讯作者：
Kelly, JW
影响因子：
3.1
作者：
Feuerstein, Tamar;Schauder, Avital;Malik, Zvi
通讯作者：
Malik, Zvi
影响因子：
4.8
作者：
Ronen, Daniel;Rosenberg, Masha M.;Ravid, Shoshana
通讯作者：
Ravid, Shoshana
DOI：
10.1001/jama.1933.02740280013006
发表时间：
1933-07-01
影响因子：
--
作者：
Cutting, WC;Mehrtens, HG;Tainter, ML
通讯作者：
Tainter, ML