Structure of a sedoheptulose 7-phosphate cyclase: ValA from Streptomyces hygroscopicus.
Structure of a sedoheptulose 7-phosphate cyclase: ValA from Streptomyces hygroscopicus.
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DOI：
10.1021/bi5003508
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发表时间：
2014-07-08
期刊：
影响因子：
2.9
通讯作者：
Karplus PA
中科院分区：
文献类型：
--
作者：
Kean KM;Codding SJ;Asamizu S;Mahmud T;Karplus PA
七糖7-磷酸环化酶(SH7PC)包括三种酶，参与产生拟糖苷类和类似生物活性天然产物的核心环醇结构。一种这样的酶是来自吸湿链霉菌亚种的Vala。2-epi-5-epi-valiolone作为农用抗真菌药物validamcin A生物合成的一部分。作为第一个SH7PC结构，Vala与NAD+和Zn2+辅因子形成的络合物具有2.1？分辨率的晶体结构。Vala具有类似于糖磷酸环化酶脱氢奎尼酸合成酶(DHQS)的折叠和活性部位组织，并且包含两个以前未被发现的显著的NAD+和Asp侧链之间的相互作用，这些作用在所有可能影响催化的糖磷酸环化酶中保守。由于Vala的结构域即使在没有糖底物的情况下也采用几乎封闭的构象，因此与配体结合的DHQS的比较为底物结合的方面提供了一个模型。一个显著的活性位点差异是由于Asp Arg Asn相对于DHQS的改变而采用不同构象的环，并改变了关键→残基的身份和取向。这一差异和Vala中其他活性部位的差异大多局限于Vala底物与DHQS不同的区域。与第二个SH7PC生产具有不同立体化学的产品的序列比较使我们假设，给定的SH7PC的产品立体化学不是催化过程中发生的事件的结果，而是通过选择性结合底物的α或β吡喃糖异构体完成的。
Sedoheptulose 7-phosphate cyclases (SH7PCs) encompass three enzymes involved in producing the core cyclitol structures of pseudoglycosides and similar bioactive natural products. One such enzyme is ValA from Streptomyces hygroscopicus subsp. jinggangensis 5008, which makes 2-epi-5-epi-valiolone as part of the biosynthesis of the agricultural antifungal agent validamycin A. We present, as the first SH7PC structure, the 2.1 Å resolution crystal structure of ValA in complex with NAD+ and Zn2+ cofactors. ValA has a fold and active site organization resembling those of the sugar phosphate cyclase dehydroquinate synthase (DHQS) and contains two notable, previously unrecognized interactions between NAD+ and Asp side chains conserved in all sugar phosphate cyclases that may influence catalysis. Because the domains of ValA adopt a nearly closed conformation even though no sugar substrate is present, comparisons with a ligand-bound DHQS provide a model for aspects of substrate binding. One striking active site difference is a loop that adopts a distinct conformation as a result of an Asp → Asn change with respect to DHQS and alters the identity and orientation of a key Arg residue. This and other active site differences in ValA are mostly localized to areas where the ValA substrate differs from that of DHQS. Sequence comparisons with a second SH7PC making a product with distinct stereochemistry lead us to postulate that the product stereochemistry of a given SH7PC is not the result of events taking place during catalysis but is accomplished by selective binding of either the α or β pyranose anomer of the substrate.
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DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
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通讯作者：
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影响因子：
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DOI：
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发表时间：
2008-08-15
影响因子：
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作者：
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