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Taxadiene synthase structure and evolution of modular architecture in terpene biosynthesis

机译：萜烯生物合成中紫杉二烯合酶的结构及其模块结构的演变

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摘要

With more than 55,000 members identified so far in all forms of life, the family of terpene or terpenoid natural products represents the epitome of molecular biodiversity. A well-known and important member of this family is the polycyclic diterpenoid Taxol (paditaxel), which promotes tubulin polymerization and shows remarkable effi-cacy in cancer chemotherapy. The first committed step of Taxol biosynthesis in the Pacific yew (Taxus brevifolia) is the cydization of the linear isoprenoid substrate geranyigeranyi diphosphate (GGPP) to form taxa-4(5),11(12)diene, which is catalysed by taxa-diene synthase. The full-length form of this diterpene cydase con-tains 862 residues, but a roughly 80-residue amino-terminal transit sequence is cleaved on maturation in plastids. We now report the X-ray crystal structure of a truncation variant lacking the transit sequence and an additional 27 residues at the N terminus, hereafter designated TXS. Specifically, we have determined structures of TXS complexed with 13-aza-13,14-dihydrocopalyl diphosphate (1.82 A resolution) and 2-fluorogeranylgeranyl diphosphate (2.25 A resolu-tion). The TXS structure reveals a modular assembly of three a-helical domains. The carboxy-terminal catalytic domain is a class I terpenoid cydase, which binds and activates substrate GGPP with a three-metal ion duster. The N-terminal domain and a third 'inser-tion' domain together adopt the fold of a vestigial dass II terpenoid cydase. A dass II cydase activates the isoprenoid substrate by proto-nation instead of ionization, and the TXS structure reveals a defin-itive connection between the two distinct cydase classes in the evolution of terpenoid biosynthesis.
机译：到目前为止，已鉴定出超过55,000个成员存在于各种生活方式中，萜烯或萜类天然产物家族代表着分子生物多样性的缩影。该家族中一个众所周知的重要成员是多环二萜类紫杉醇（paditaxel），它促进微管蛋白聚合并在癌症化学疗法中显示出显着的功效。紫杉（Taxus brevifolia）中紫杉醇生物合成的第一步是将线性类异戊二烯底物geranyigeranyi diphosphate（GGPP）氰化，形成taxa-4（5），11（12）二烯，并由taxa-diene催化合酶。该二萜环化酶的全长形式包含862个残基，但是在质体中成熟时会切割出约80个残基的氨基末端转运序列。现在，我们报告了一个截断变体的X射线晶体结构，该结构缺少转运序列，并且在N末端（此后称为TXS）另外有27个残基。具体而言，我们已经确定了与13-氮杂-13,14-二氢枯基二磷酸酯（1.82 A分辨率）和2-氟香叶基香叶烷基二磷酸酯（2.25 A分辨率）复合的TXS结构。 TXS结构揭示了三个a螺旋域的模块化组装。羧基末端催化结构域是I类萜类环化酶，它通过三金属离子喷粉器结合并激活底物GGPP。 N-末端结构域和第三个“插入”结构域共同采用残留的dass II萜类胱氨酸蛋白酶的折叠。 dass II胞苷酶通过质子化而不是离子化激活类异戊二烯底物，TXS结构揭示了萜类生物合成过程中两种不同的胞苷酶之间的确定性联系。

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  • 来源
    《Nature》 |2011年第7328期|p.116-120|共5页
  • 作者

    Mustafa Koksal; Yinghua Jin; Robert M. Coates; Rodney Croteau; David W. Christianson;

  • 作者单位

    Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, USA;

    Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA,Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309, USA;

    Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA;

    Institute of Biological Chemistry, Washington State University, Pullman, Washington 99164-6340, USA;

    Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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