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Crystal Structure of GenD2, an NAD-Dependent Oxidoreductase Involved in the Biosynthesis of Gentamicin.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-04-30 , DOI: 10.1021/acschembio.9b00115 Natalia Cerrone de Araújo 1 , Priscila Dos Santos Bury 1 , Maurício Temotheo Tavares 2 , Fanglu Huang 3 , Roberto Parise-Filho 2 , Peter Leadlay 3 , Marcio Vinicius Bertacine Dias 1, 4
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-04-30 , DOI: 10.1021/acschembio.9b00115 Natalia Cerrone de Araújo 1 , Priscila Dos Santos Bury 1 , Maurício Temotheo Tavares 2 , Fanglu Huang 3 , Roberto Parise-Filho 2 , Peter Leadlay 3 , Marcio Vinicius Bertacine Dias 1, 4
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Gentamicins are clinically relevant aminoglycoside antibiotics produced by several Micromonospora species. Gentamicins are highly methylated and functionalized molecules, and their biosynthesis include glycosyltransferases, dehydratase/oxidoreductases, aminotransferases, and methyltransferases. The biosynthesis of gentamicin A from gentamicin A2 involves three enzymatic steps that modify the hydroxyl group at position 3″ of the unusual garosamine sugar to provide its substitution for an amino group, followed by an N-methylation. The first of these reactions is catalyzed by GenD2, an oxidoreductase from the Gfo/Idh/MocA protein family, which reduces the hydroxyl at the C3″ of gentamicin A to produce 3''-dehydro-3''-oxo-gentamicin A2 (DOA2). In this work, we solved the structure of GenD2 in complex with NAD+. Although the structure of GenD2 has a similar fold to other members of the Gfo/Idh/MocA family, this enzyme has several new features, including a 3D-domain swapping of two β-strands that are involved in a novel oligomerization interface for this protein family. In addition, the active site of this enzyme also has several specialties which are possibly involved in the substrate specificity, including a number of aromatic residues and a negatively charged region, which is complementary to the polycationic aminoglycoside-substrate. Therefore, docking simulations provided insights into the recognition of gentamicin A2 and into the catalytic mechanism of GenD2. This is the first report describing the structure of an oxidoreductase involved in aminoglycoside biosynthesis and could open perspectives into producing new aminoglycoside derivatives by protein engineering.
中文翻译：
GenD2 的晶体结构，一种参与庆大霉素生物合成的 NAD 依赖性氧化还原酶。
庆大霉素是由几种小单孢菌属产生的临床相关的氨基糖苷类抗生素。庆大霉素是高度甲基化和功能化的分子，它们的生物合成包括糖基转移酶、脱水酶/氧化还原酶、氨基转移酶和甲基转移酶。从庆大霉素 A2 生物合成庆大霉素 A 涉及三个酶促步骤，这些步骤修饰不寻常的 garosamine 糖 3” 位置的羟基以提供其对氨基的取代，然后是 N-甲基化。这些反应中的第一个由 GenD2 催化，GenD2 是一种来自 Gfo/Idh/MocA 蛋白家族的氧化还原酶，它可以还原庆大霉素 A 的 C3″ 上的羟基，生成 3''-dehydro-3''-oxo-gentamicin A2（ DOA2). 在这项工作中，我们解决了与 NAD+ 复合的 GenD2 结构。尽管 GenD2 的结构与 Gfo/Idh/MocA 家族的其他成员有相似的折叠，但这种酶有几个新的特征，包括两个 β 链的 3D 结构域交换，这两个 β 链参与了该蛋白质的新寡聚化界面家庭。此外，该酶的活性位点还具有一些可能与底物特异性有关的特性，包括许多芳香族残基和带负电的区域，与聚阳离子氨基糖苷底物互补。因此，对接模拟为庆大霉素 A2 的识别和 GenD2 的催化机制提供了见解。
更新日期：2019-04-17
中文翻译：
GenD2 的晶体结构，一种参与庆大霉素生物合成的 NAD 依赖性氧化还原酶。
庆大霉素是由几种小单孢菌属产生的临床相关的氨基糖苷类抗生素。庆大霉素是高度甲基化和功能化的分子，它们的生物合成包括糖基转移酶、脱水酶/氧化还原酶、氨基转移酶和甲基转移酶。从庆大霉素 A2 生物合成庆大霉素 A 涉及三个酶促步骤，这些步骤修饰不寻常的 garosamine 糖 3” 位置的羟基以提供其对氨基的取代，然后是 N-甲基化。这些反应中的第一个由 GenD2 催化，GenD2 是一种来自 Gfo/Idh/MocA 蛋白家族的氧化还原酶，它可以还原庆大霉素 A 的 C3″ 上的羟基，生成 3''-dehydro-3''-oxo-gentamicin A2（ DOA2). 在这项工作中，我们解决了与 NAD+ 复合的 GenD2 结构。尽管 GenD2 的结构与 Gfo/Idh/MocA 家族的其他成员有相似的折叠，但这种酶有几个新的特征，包括两个 β 链的 3D 结构域交换，这两个 β 链参与了该蛋白质的新寡聚化界面家庭。此外，该酶的活性位点还具有一些可能与底物特异性有关的特性，包括许多芳香族残基和带负电的区域，与聚阳离子氨基糖苷底物互补。因此，对接模拟为庆大霉素 A2 的识别和 GenD2 的催化机制提供了见解。
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