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首页> 外文期刊>Journal of Molecular Biology >Crystal structure of an enzyme displaying both inositol-polyphosphate-1-phosphatase and 3'-phosphoadenosine-5'-phosphate phosphatase activities: a novel target of lithium therapy.
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Crystal structure of an enzyme displaying both inositol-polyphosphate-1-phosphatase and 3'-phosphoadenosine-5'-phosphate phosphatase activities: a novel target of lithium therapy.

机译：既显示肌醇多磷酸-1-磷酸酶又显示3'-磷酸腺苷-5'-磷酸磷酸酶活性的酶的晶体结构：锂治疗的新目标。

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摘要

Lithium cations exert profound and selective psychopharmacological effects on ameliorate manic-depressive psychosis. Although lithium is an effective drug for both treatment and prophylaxis of bipolar disorder, the precise mechanism of action is not well understood. Lithium acts as both an uncompetitive and non-competitive inhibitor of several lithium- sensitive phosphatases with regard to substrate and magnesium cofactor, respectively. In this work, we report the crystal structure and reaction mechanism of Rattus norvegicus 3'-phosphoadenosine 5'-phosphate and inositol 1,4-bisphosphate phosphatase (RnPIP), a recently identified target of lithium therapy. This Li(+)-sensitive enzyme plays a crucial role in several cellular processes, such as RNA processing, sulphation reactions and probably inositol recycling. RnPIP specifically removes the 3'-phosphate group of 3'-phosphoadenosine 5'-phosphate (PAP) and the 1'-phosphate group of inositol 1,4-bisphosphate (I(1),(4)P(2)) producing AMP and inositol 4'-phosphate, respectively. The crystal structure of RnPIP complexed with AMP, Pi and magnesium ions at 1.69 A resolution provides insight into the reaction mechanism of the hydrolysis of PAP. The core fold of the enzyme is equivalent to that found in other Li(+)-sensitive phosphatases, such as inositol monophosphatase, but molecular modelling of I(1),(4)P(2) in the RnPIP active site reveals important structural determinants that accommodate this additional substrate. RnPIP is potently inhibited by lithium and, as the accumulation of PAP inhibits a variety of proteins, including sulphotransferases and RNA processing enzymes, this dual specificity enzyme represents a potential target of lithium action, in addition to inositol monophosphatases. Copyright 2002 Academic Press.
机译：锂阳离子对减轻躁狂抑郁症的精神病具有深远和选择性的心理药理作用。尽管锂是用于治疗和预防双相情感障碍的有效药物，但确切的作用机理尚不十分清楚。在底物和镁辅因子方面，锂分别充当几种对锂敏感的磷酸酶的非竞争性和非竞争性抑制剂。在这项工作中，我们报告了褐家鼠的3'-磷酸腺苷5'-磷酸和肌醇1,4-双磷酸磷酸酶（RnPIP）的晶体结构和反应机理，这是最近确定的锂治疗靶标。这种对Li（+）敏感的酶在一些细胞过程中起着至关重要的作用，例如RNA加工，硫酸化反应以及可能的肌醇再循环。 RnPIP专门去除3'-磷酸腺苷5'-磷酸（PAP）的3'-磷酸基团和肌醇1,4-双磷酸（I（1），（4）P（2））的1'-磷酸基团AMP和肌醇4'-磷酸。 RnPIP的晶体结构在1.69 A的分辨率下与AMP，Pi和镁离子络合，可深入了解PAP水解的反应机理。该酶的核心折叠与其他对Li（+）敏感的磷酸酶（如肌醇单磷酸酶）中的核心折叠相同，但RnPIP活性位点中的I（1），（4）P（2）的分子模型揭示了重要的结构决定因素是否适合这种额外的底物。 RnPIP被锂有效地抑制，并且由于PAP的积累抑制了各种蛋白质，包括磺基转移酶和RNA处理酶，因此这种双重特异性酶除了肌醇单磷酸酶外，还代表了锂作用的潜在靶标。版权所有2002学术出版社。

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