thymidine-5'-diphosphate-3-amino-2,3,6-trideoxy-3-C-methyl-D-erythro-hexopyranos-4-ulose | 321847-72-7

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷酸
• 英文名称: thymidine-5'-diphosphate-3-amino-2,3,6-trideoxy-3-C-methyl-D-erythro-hexopyranos-4-ulose
• 英文别名: deoxythymidine diphosphate 3-amino-2,3,6-trideoxy-4-keto-3-methyl-D-glucose；dTDP-3-amino-2,3,6-trideoxy-4-keto-3-methyl-D-glucose；dTDP-3-amino-2,3,6-trideoxy-C-methyl-D-erythro-hexopyranos-4-ulose；[(2R,4S,6R)-4-amino-4,6-dimethyl-5-oxooxan-2-yl] [hydroxy-[[(2R,3S,5R)-3-hydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy]phosphoryl] hydrogen phosphate
• CAS: 321847-72-7
• 化学式: C₁₇H₂₇N₃O₁₃P₂
• 分子量: 543.361
• InChiKey: LXNLHPYBLNFMEH-XXXNSVIPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -5.7
• 重原子数：
  35
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  234
• 氢给体数：
  5
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  thymidine-5'-diphosphate-3-amino-2,3,6-trideoxy-3-C-methyl-D-erythro-hexopyranos-4-ulose 在 recombinant Amycolatopsis orientalis EvaD 、 recombinant Amycolatopsis orientalis EvaE 、 还原型辅酶II(NADPH)四钠盐 作用下， 反应 2.0h， 以55%的产率得到thymidine 5'-(3-amino-2,3,6-trideoxy-3C-methyl-β-L-arabino-hexopyranosyl diphosphate)
  参考文献：
  名称：

  依维尼诺霉素生物合成中的氨基糖氧化酶 ORF36 的结构和机制，

  摘要：

  Everninomicin 是一种高度修饰的八糖，属于抗生素正霉素家族，具有强效的革兰氏阳性抗生素活性，包括对多重耐药肠球菌和金黄色葡萄球菌的广谱功效。其独特的结构特征之一是硝基糖，即l- evernitrose，它的类似物装饰了各种天然产品。最近，我们从Micromonospora carbonacea var. 中鉴定了一种由orf36编码的亚硝基合酶。AFRICANA介导合成产生的胸苷二磷酸（TDP）的依赖黄素的双氧化-升-外延-vancosamine 到相应的亚硝基糖。在此，我们利用五酶体外途径来验证 ORF36 催化生物源性TDP - 1 - epi- vancosamine 的氧化，并确定 ORF36 是否对其任何生物合成祖细胞表现出催化能力，这些祖细胞是体内亚硝基合酶的候选底物. 祖细胞仅经历单氧化反应并终止于羟胺氧化态。在18 O 2存在下进行体外反应确定分子氧，而不是来自水中的氧，被结合到

  DOI：

  10.1021/bi101336u
• 作为产物：
  描述：

  thymidine 5'-diphospho-β-D-glucose 在 L-谷氨酸 、 N-(2-hydroxyethyl)piperazine-N'-methanesulfonic acid 、 2,3-dehydratase EvaA 、 3-aminotransferase TcaB₈ 、 4,6-dehydratase RmlB 、 C-3-methyltransferase KijD₁ 、 (S,S)-S-adenosyl-L-methionine 、 甘油 、 sodium chloride 、 magnesium chloride 作用下， 反应 16.0h， 以5%的产率得到thymidine-5'-diphosphate-3-amino-2,3,6-trideoxy-3-C-methyl-D-erythro-hexopyranos-4-ulose
  参考文献：
  名称：

  X-ray Structure of KijD3, a Key Enzyme Involved in the Biosynthesis of d-Kijanose

  摘要：

  D-Kijanose is an unusual nitrosugar found attached to the antibiotic kijanimicin. Ten enzymes are required for its production in Actinomodura kijaniata, a soil-dwelling actinomycete. The focus of this investigation is on the protein encoded by the kijd3 gene and hereafter referred to as KijD3. On the basis of amino acid sequence analyses, KijD3 has been proposed to be an FAD-dependent oxidoreductase, which catalyzes the sixth step in D-kijanose biosynthesis by converting dTDP-3-amino-2,3,6-trideoxy-4-keto-3-methyl-D-glucose into its C-3' nitro derivative. This putative activity, however, has never been demonstrated in vivo or in vitro. Here we report the first structural study of this enzyme. For our investigation, crystals of KijD3 were grown in the presence of dTDP, and the structure was solved to 2.05-angstrom resolution. The enzyme is a tetramer with each subunit folding into three distinct regions: a five a-helical bundle, an eight-stranded beta-sheet, and a second five a-helical bundle. The dTDP moiety is anchored to the protein via the side chains of Glu 113, Gln 254, and Arg 330. The overall fold of KijD3 places it into the well-characterized fatty acyl-CoA dehydrogenase superfamily. There is a decided cleft in each subunit with the appropriate dimensions to accommodate a dTDP-linked sugar. Strikingly, the loop defined by Phe 383 to Ala 388, which projects into the active site, contains two adjacent cis-peptide bonds, Pro 386 and Tyr 387. Activity assays demonstrate that KijD3 requires FAD for activity and that it produces a hydroxylamino product. The molecular architecture of KijD3 described in this report serves as a paradigm for a new family of enzymes that function on dTDP-linked sugar substrates.

  DOI：

  10.1021/bi100318v

文献信息

• Nitrososynthase-Triggered Oxidative Carbon–Carbon Bond Cleavage in Baumycin Biosynthesis
  作者：Ahmad Al-Mestarihi、Anthony Romo、Hung-wen Liu、Brian O. Bachmann

  DOI：10.1021/ja404987r

  日期：2013.8.7

  sugar. Notably, the dnmZ gene in the dox gene cluster possesses high translated sequence similarity to nitrososynthases, which are flavin-dependent amine monooxygenases involved in the four-electron oxidation of amino sugars to nitroso sugars. Herein we demonstrate that DnmZ is an amino sugar nitrososynthase that initiates the conversion of thymidine-5'-diphosphate-l-epi-vancosamine to a ring-opened product

  鲍霉素与临床上重要的抗癌次级代谢产物柔红霉素和多柔比星共同产生，它们是从 Streptomyces peucetius 中分离出来的糖基化蒽环类药物。鲍霉素的显着特征是存在附加到柔红胺的不寻常的缩醛部分，柔红霉素在从发酵液中酸提取柔红霉素的过程中会水解。鲍霉素缩醛的结构表明它很可能来自在 C3" 和 C4" 位置之间切割的未知 C3"-甲基脱氧糖。这得到了对鲍霉素/柔红霉素生物合成基因簇 (dox) 的分析的支持，该基因簇也编码与含有支链糖的蒽环类双糖的生产一致的推定蛋白质。尤其，dox 基因簇中的 dnmZ 基因与亚硝基合酶具有高度的翻译序列相似性，亚硝基合酶是一种黄素依赖性胺单加氧酶，参与氨基糖的四电子氧化为亚硝基糖。在本文中，我们证明 DnmZ 是一种氨基糖亚硝基合酶，它通过以前未表征的逆肟-醛醇反应启动 thymidine-5'-diphosphate-l-epi-vancosamine
• Molecular Architecture of a <i>C-</i>3′-Methyltransferase Involved in the Biosynthesis of <scp>d</scp>-Tetronitrose
  作者：Nathan A. Bruender、James B. Thoden、Manpreet Kaur、Marie K. Avey、Hazel M. Holden

  DOI：10.1021/bi100782b

  日期：2010.7.20

  S-Adenosylmethionine (SAM)-dependent methyltransferases are involved in a myriad of biological processes, including signal transduction, chromatin repair, metabolism, and biosyntheses, among others. Here we report the high-resolution structure of a novel C-3'-methyltransferase involved in the production of D-tetronitrose, an unusual sugar found attached to the antitumor agent tetrocarcin A or the antibiotic kijanimicin. Specifically, this enzyme, referred to as TcaB9 and cloned from Micromonospora chalcea, catalyzes the conversion of dTDP-3-amino-2,3,6-trideoxy-4-keto-D-glucose to dTDP-3-amino-2,3,6-trideoxy-4-keto-3-methyl-D-glucose. For this analysis, two structures were determined to 1.5 angstrom resolution: one in which the enzyme was crystallized in the presence of SAM and dTMP and the other with the protein complexed to S-adenosylhomocysteine and its dTDP-linked sugar product. The overall fold of the monomeric enzyme can be described in terms of three domains. The N-terminal domain harbors the binding site for a zinc ion that is ligated by four cysteines. The middle domain adopts the canonical "SAM-binding" fold with a seven-stranded mixed beta-sheet flanked on either side by three alpha-helices. This domain is responsible for anchoring the SAM cofactor to the protein. Strikingly, the C-terminal domain also contains a seven-stranded beta-sheet, and it appears to be related to the middle domain by an approximate 2-fold rotational axis, thus suggesting TcaB9 arose via gene duplication. Key residues involved in sugar binding include His 181, Glu 224, His 225, and Tyr 222. Their possible roles in catalysis are discussed.
• X-ray Structure of KijD3, a Key Enzyme Involved in the Biosynthesis of <scp>d</scp>-Kijanose
  作者：Nathan A. Bruender、James B. Thoden、Hazel M. Holden

  DOI：10.1021/bi100318v

  日期：2010.5.4

  D-Kijanose is an unusual nitrosugar found attached to the antibiotic kijanimicin. Ten enzymes are required for its production in Actinomodura kijaniata, a soil-dwelling actinomycete. The focus of this investigation is on the protein encoded by the kijd3 gene and hereafter referred to as KijD3. On the basis of amino acid sequence analyses, KijD3 has been proposed to be an FAD-dependent oxidoreductase, which catalyzes the sixth step in D-kijanose biosynthesis by converting dTDP-3-amino-2,3,6-trideoxy-4-keto-3-methyl-D-glucose into its C-3' nitro derivative. This putative activity, however, has never been demonstrated in vivo or in vitro. Here we report the first structural study of this enzyme. For our investigation, crystals of KijD3 were grown in the presence of dTDP, and the structure was solved to 2.05-angstrom resolution. The enzyme is a tetramer with each subunit folding into three distinct regions: a five a-helical bundle, an eight-stranded beta-sheet, and a second five a-helical bundle. The dTDP moiety is anchored to the protein via the side chains of Glu 113, Gln 254, and Arg 330. The overall fold of KijD3 places it into the well-characterized fatty acyl-CoA dehydrogenase superfamily. There is a decided cleft in each subunit with the appropriate dimensions to accommodate a dTDP-linked sugar. Strikingly, the loop defined by Phe 383 to Ala 388, which projects into the active site, contains two adjacent cis-peptide bonds, Pro 386 and Tyr 387. Activity assays demonstrate that KijD3 requires FAD for activity and that it produces a hydroxylamino product. The molecular architecture of KijD3 described in this report serves as a paradigm for a new family of enzymes that function on dTDP-linked sugar substrates.
• Structure and Mechanism of ORF36, an Amino Sugar Oxidizing Enzyme in Everninomicin Biosynthesis,
  作者：Jessica L. Vey、Ahmad Al-Mestarihi、Yunfeng Hu、Michael A. Funk、Brian O. Bachmann、T. M. Iverson

  DOI：10.1021/bi101336u

  日期：2010.11.2

  products and identifies an off-pathway product that correlates with the oxidation product of a progenitor substrate. The 3.15 Å resolution X-ray crystal structure of ORF36 reveals a tetrameric enzyme that shares a fold with acyl-CoA dehydrogenases and class D flavin-containing monooxygenases, including the nitrososynthase KijD3. However, ORF36 and KijD3 have unusually open active sites in comparison to these

  Everninomicin 是一种高度修饰的八糖，属于抗生素正霉素家族，具有强效的革兰氏阳性抗生素活性，包括对多重耐药肠球菌和金黄色葡萄球菌的广谱功效。其独特的结构特征之一是硝基糖，即l- evernitrose，它的类似物装饰了各种天然产品。最近，我们从Micromonospora carbonacea var. 中鉴定了一种由orf36编码的亚硝基合酶。AFRICANA介导合成产生的胸苷二磷酸（TDP）的依赖黄素的双氧化-升-外延-vancosamine 到相应的亚硝基糖。在此，我们利用五酶体外途径来验证 ORF36 催化生物源性TDP - 1 - epi- vancosamine 的氧化，并确定 ORF36 是否对其任何生物合成祖细胞表现出催化能力，这些祖细胞是体内亚硝基合酶的候选底物. 祖细胞仅经历单氧化反应并终止于羟胺氧化态。在18 O 2存在下进行体外反应确定分子氧，而不是来自水中的氧，被结合到