S-inosyl-L-homocysteine | 17298-56-5

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 5'-脱氧核糖核苷
• 英文名称: S-inosyl-L-homocysteine
• 英文别名: S-inosyl-homocysteine；S-inosyl-Hcy；5-Hypoxanthinyl-L-homocystein；S-inosin-5'-yl-L-homocysteine；9-{5-S-[(3S)-3-azaniumyl-3-carboxylatopropyl]-5-thio-beta-D-ribofuranosyl}-9H-purin-6-ol；(2S)-2-azaniumyl-4-[[(2S,3S,4R,5R)-3,4-dihydroxy-5-(6-oxo-1H-purin-9-yl)oxolan-2-yl]methylsulfanyl]butanoate
• CAS: 17298-56-5
• 化学式: C₁₄H₁₉N₅O₆S
• 分子量: 385.401
• InChiKey: VNPWVMVYUSNFAW-WFMPWKQPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.8
• 重原子数：
  26
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  198
• 氢给体数：
  5
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  S-inosyl-L-homocysteine 在 高氯酸 、 ammonium molybdate 、 双氧水 作用下， 以14%的产率得到S-inosyl-L-homocysteine sulfone
  参考文献：
  名称：

  SAM结合核糖开关的分子识别特征。

  摘要：

  DOI：

  10.1002/anie.200503198
• 作为产物：
  描述：

  S-(5'-腺苷)-L-高半胱氨酸 在 Sav₂₅₉₅ from Steptomyces avermitilis MA-4680 、 水 作用下， 反应 16.0h， 生成 S-inosyl-L-homocysteine
  参考文献：
  名称：

  Deamination of 6-Aminodeoxyfutalosine in Menaquinone Biosynthesis by Distantly Related Enzymes

  摘要：

  Proteins of unknown function belonging to cog1816 and cog0402 were characterized. Sav2595 from Steptomyces avermitilis MA-4680, Ace10264 from Acidothermus cellulolyticus 11B, Nis0429 from Nitratiruptor sp. SB155-2 and Dr0824 from Deinococcus radiodurans R1 were cloned, purified, and their substrate profiles determined. These enzymes were previously incorrectly annotated as adenosine deaminases or chlorohydrolases. It was shown here that these enzymes actually deaminate 6-aminodeoxyfutalosine. The deamination of 6-aminodeoxyfutalosine is part of an alternative menaquinone biosynthetic pathway that involves the formation of futalosine. 6-Aminodeoxyfutalosine is deaminated by these enzymes with catalytic efficiencies greater than 106 M-1 s(-1), Km values of 0.9-6.0 mu M, and k(cat) values of 1.2-8.6 Adenosine, 2'-deoxyadenosine, thiomethyladenosine, and S-adenosylhomocysteine are deaminated at least an order of magnitude slower than 6-aminodeoxyfutalosine. The crystal structure of Nis0429 was determined and the substrate, 6-aminodeoxyfutalosine, was positioned in the active site on the basis of the presence of adventitiously bound benzoic acid. In this model, Ser-145 interacts with the carboxylate moiety of the substrate. The structure of.Dr0824 was also determined, but a collapsed active site pocket prevented docking of substrates. A computational model of Sav2595 was built on the basis of the crystal structure of adenosine deaminase and substrates were docked. The model predicted a conserved arginine after beta-strand 1 to be partially responsible for the substrate specificity of Sav2595.

  DOI：

  10.1021/bi400750a

文献信息

• Determinants of cofactor binding to DNA methyltransferases: insights from a systematic series of structural variants of S-adenosylhomocysteine
  作者：Helen M. Cohen、Andrew D. Griffiths、Dan S. Tawfik、David Loakes

  DOI：10.1039/b415446k

  日期：——

  tested them for the ability to inhibit methylation by HhaI and HaeIII DNA methyltransferase. Comparison of the Ki values highlights the structural determinants for cofactor binding, and indicates which nucleoside and amino acid functional groups contribute significantly to AdoMet binding. An understanding of the binding of AdoHyc to methyltransferases will greatly assist the design of AdoMet inhibitors

  S-腺苷甲硫氨酸（AdoMet）是一种常用的辅因子，在其参与的各种反应中仅次于ATP。它是大多数甲基转移反应中的甲基供体，包括DNA，RNA，蛋白质和小分子的甲基化。几乎所有结构特征化的甲基转移酶都具有保守的AdoMet依赖性甲基转移酶折叠，其中AdoMet以相同的方向结合。虽然辅助因子和甲基转移酶之间的潜在相互作用已从晶体结构中推断出来，但尚未系统地研究每个官能团对结合的贡献。为了探索结合相互作用，我们合成了甲基转移酶抑制剂S-腺苷同型半胱氨酸（AdoHcy）的一系列七个类似物，每个类似物包含一个修饰，并测试了它们抑制HhaI和HaeIII DNA甲基转移酶甲基化的能力。Ki值的比较突出了辅因子结合的结构决定因素，并指出了哪些核苷和氨基酸官能团对AdoMet结合起了重要作用。对AdoHyc与甲基转移酶结合的理解将大大有助于AdoMet抑制剂的设计。
• Structure-based activity prediction for an enzyme of unknown function
  作者：Johannes C. Hermann、Ricardo Marti-Arbona、Alexander A. Fedorov、Elena Fedorov、Steven C. Almo、Brian K. Shoichet、Frank M. Raushel

  DOI：10.1038/nature05981

  日期：2007.8.16

  With many genomes sequenced, a pressing challenge in biology is predicting the function of the proteins that the genes encode. When proteins are unrelated to others of known activity, bioinformatics inference for function becomes problematic. It would thus be useful to interrogate protein structures for function directly. Here, we predict the function of an enzyme of unknown activity, Tm0936 from Thermotoga maritima, by docking high-energy intermediate forms of thousands of candidate metabolites. The docking hit list was dominated by adenine analogues, which appeared to undergo C6-deamination. Four of these, including 5-methylthioadenosine and S-adenosylhomocysteine (SAH), were tested as substrates, and three had substantial catalytic rate constants (105 M-1s-1). The X-ray crystal structure of the complex between Tm0936 and the product resulting from the deamination of SAH, S-inosylhomocysteine, was determined, and it corresponded closely to the predicted structure. The deaminated products can be further metabolized by T. maritima in a previously uncharacterized SAH degradation pathway. Structure-based docking with high-energy forms of potential substrates may be a useful tool to annotate enzymes for function. Though it is often possible to infer the function of a newly discovered protein by comparing its sequence to those of other characterized proteins, it can be extremely difficult to predict the function of an enzyme that is unrelated to other studied proteins. Hermann et al. now show that it is possible to use a computational approach to predict the function of an enzyme of unknown activity. They 'docked' high-energy intermediate forms of thousands of candidate metabolites to the X-ray crystal structure of Tm0936, a member of the amidohydrolase superfamily. These experiments predicted that the enzyme would deaminate 5-methylthioadenosine and S-adenosylhomocysteine; this was borne out biochemically, and the X-ray crystal structure of one of the products bound to Tm0936 corresponded closely to the predicted structure. These results suggest that structure-based docking using high-energy forms of potential substrates may be a useful tool to annotate enzymes for function. A computational approach is used to predict the function of an uncharacterized enzyme by docking high-energy intermediate forms of candidate metabolites into its purported binding site. The docking experiments predicted that the enzyme would be able to deaminate intermediates of 5-methylthioadenosine and S-adenosylhomocysteine, a prediction confirmed by biochemical experiments and examination of the X-ray crystal structure of the protein.

  随着许多基因组被测序，生物学中的一个紧迫挑战是预测基因编码蛋白质的功能。当蛋白质与其他已知活性的蛋白质不相关时，生物信息学的功能推断就成了问题。因此，直接询问蛋白质结构以了解其功能是非常有用的。在这里，我们通过对接数千种候选代谢物的高能中间形式，预测了一种未知活性的酶--来自海洋嗜热菌（Thermotoga maritima）的 Tm0936 的功能。对接命中列表主要是腺嘌呤类似物，它们似乎会发生 C6-脱氨反应。其中四种腺嘌呤类似物，包括 5-甲硫基腺苷和 S-腺苷高半胱氨酸（SAH），被作为底物进行了测试，其中三种具有很高的催化速率常数（105âM-1s-1）。测定了 Tm0936 与 SAH 脱氨基产物 S-腺苷高半胱氨酸之间复合物的 X 射线晶体结构，该结构与预测结构非常吻合。脱氨基产物可被 T. maritima 在之前未表征的 SAH 降解途径中进一步代谢。基于结构与潜在底物的高能形式对接可能是注释酶功能的有用工具。虽然通常可以通过比较新发现蛋白质的序列和其他特征蛋白质的序列来推断其功能，但要预测一种与其他已研究蛋白质无关的酶的功能却非常困难。Hermann 等人现在证明，使用计算方法预测未知活性酶的功能是可能的。他们将数千种候选代谢物的高能中间形式与酰胺水解酶超家族成员 Tm0936 的 X 射线晶体结构 "对接"。这些实验预测，该酶将对 5-甲硫基腺苷和 S-腺苷高半胱氨酸进行脱氨基处理；生化实验证实了这一点，与 Tm0936 结合的一种产物的 X 射线晶体结构与预测结构非常吻合。这些结果表明，利用潜在底物的高能形式进行基于结构的对接可能是注释酶功能的有用工具。通过将候选代谢物的高能中间形式与酶的所谓结合位点对接，利用计算方法预测了一种未表征酶的功能。对接实验预测该酶能够使 5-甲硫基腺苷和 S-腺苷高半胱氨酸的中间体脱氨基，这一预测得到了生化实验和蛋白质 X 射线晶体结构检查的证实。
• Purification and characterization of S-adenosylhomocysteine deaminase from streptonigrin-producing Streptomyces flocculus
  作者：J J Zulty、M K Speedie

  DOI：10.1128/jb.171.12.6840-6844.1989

  日期：1989.12

  An S-adenosylhomocysteine deaminase has been isolated and purified from streptonigrin-producing Streptomyces flocculus ATCC 13257. Deamination represents the major metabolic route of S-adenosylhomocysteine in this organism. The protein was found to be monomeric with a molecular weight of 56,100 +/- 1,600. The activity was optimal at pH 7.0 and 37 degrees C, and the deaminase was inactivated by p-chloromercuribenzoate but not by metal chelators. The Km for S-adenosylhomocysteine is 2.5 mM, and the Ki for inhibition by deoxycoformycin is 1.6 nM.

  一种S-腺苷同型半胱氨酸脱氨酶已经从产生链霉菌素的Streptomyces flocculus ATCC 13257中分离和纯化。在这种生物体内，脱氨作用是S-腺苷同型半胱氨酸的主要代谢途径。发现该蛋白是单体，分子量为56,100 +/- 1,600。该酶的活性在pH 7.0和37摄氏度时最佳，被对氯硫代苯甲酸钠失活，但不被金属螯合剂失活。S-腺苷同型半胱氨酸的Km为2.5 mM，被脱氧考察霉素抑制的Ki为1.6 nM。
• <i>S</i> -Inosyl- <scp>l</scp> -Homocysteine Hydrolase, a Novel Enzyme Involved in <i>S</i> -Adenosyl- <scp>l</scp> -Methionine Recycling
  作者：Danielle Miller、Huimin Xu、Robert H. White

  DOI：10.1128/jb.00080-15

  日期：2015.7.15

  S -Adenosyl- l -homocysteine, the product of S -adenosyl- l -methionine (SAM) methyltransferases, is known to be a strong feedback inhibitor of these enzymes. A hydrolase specific for S -adenosyl- l -homocysteine produces l -homocysteine, which is remethylated to methionine and can be used to regenerate SAM. Here, we show that the annotated S -adenosyl- l -homocysteine hydrolase in Methanocaldococcus jannaschii is specific for the hydrolysis and synthesis of S -inosyl- l -homocysteine, not S -adenosyl- l -homocysteine. This is the first report of an enzyme specific for S -inosyl- l -homocysteine. As with S -adenosyl- l -homocysteine hydrolase, which shares greater than 45% sequence identity with the M. jannaschii homologue, the M. jannaschii enzyme was found to copurify with bound NAD ⁺ and has K _m values of 0.64 ± 0.4 mM, 0.0054 ± 0.006 mM, and 0.22 ± 0.11 mM for inosine, l -homocysteine, and S -inosyl- l -homocysteine, respectively. No enzymatic activity was detected with S -adenosyl- l -homocysteine as the substrate in either the synthesis or hydrolysis direction. These results prompted us to redesignate the M. jannaschii enzyme an S -inosyl- l -homocysteine hydrolase (SIHH). Identification of SIHH demonstrates a modified pathway in this methanogen for the regeneration of SAM from S -adenosyl- l -homocysteine that uses the deamination of S -adenosyl- l -homocysteine to form S -inosyl- l -homocysteine.

  IMPORTANCE In strictly anaerobic methanogenic archaea, such as Methanocaldococcus jannaschii , canonical metabolic pathways are often not present, and instead, unique pathways that are deeply rooted on the phylogenetic tree are utilized by the organisms. Here, we discuss the recycling pathway for S -adenosyl- l -homocysteine, produced from S -adenosyl- l -methionine (SAM)-dependent methylation reactions, which uses a hydrolase specific for S -inosyl- l -homocysteine, an uncommon metabolite. Identification of the pathways and the enzymes involved in the unique pathways in the methanogens will provide insight into the biochemical reactions that were occurring when life originated.

  摘要 S -腺苷 l -高半胱氨酸的产物 S -腺苷 l 众所周知，高半胱氨酸是 S-腺苷-l-蛋氨酸（SAM）甲基转移酶的产物，是这些酶的强反馈抑制剂。一种专门针对 S -腺苷 l -同型半胱氨酸产生 l -高半胱氨酸，后者被再甲基化为蛋氨酸，可用于再生 SAM。在这里，我们展示了注释的 S -腺苷- l -同型半胱氨酸水解酶。 甲烷球菌中的 的水解和合成具有特异性。 S -半胱氨酸 l -高半胱氨酸，而不是 S -腺苷 l -高半胱氨酸。这是首次报道一种特异于 S -腺苷- l -高半胱氨酸的特异性酶。与 S -腺苷 l -高半胱氨酸水解酶一样，它与 M. jannaschii 的 S -腺苷-l-高半胱氨酸水解酶有超过 45% 的序列相同性。 同源物 同源物 同源物 酶与结合的 NAD + 并具有 K m 值分别为 0.64 ± 0.4 mM、0.0054 ± 0.006 mM 和 0.22 ± 0.11 mM、 l -高半胱氨酸和 S -肌苷 l -高半胱氨酸。没有检测到 S -腺苷 l -高半胱氨酸作为底物时，无论是合成方向还是水解方向都没有检测到酶活性。这些结果促使我们将 M. jannaschii 酶重新命名为 S -氨基- l -高半胱氨酸水解酶（SIHH）。SIHH 的鉴定表明，这种甲烷发生器中的 SAM 从 S -腺苷- l -高半胱氨酸的脱氨作用。 S -腺苷 l -形成 S -腺苷 l -高半胱氨酸。 重要意义 在严格厌氧的产甲烷古菌中，如 甲烷醛球菌（Methanocaldococcus jannaschii 等严格厌氧的甲烷发生古菌中，通常不存在典型的代谢途径，而是利用在系统发育树上根深蒂固的独特途径。在这里，我们将讨论 S -腺苷 l -高半胱氨酸的循环途径。 S -腺苷 l -甲硫氨酸（SAM）依赖性甲基化反应产生的，它使用一种特异于 S -腺苷- l -同型半胱氨酸（一种不常见的代谢物）的水解酶。鉴定甲烷菌中的独特途径和参与途径的酶将有助于深入了解生命起源时发生的生化反应。
• ASSAYS FOR S-ADENOSYLMETHIONINE-DEPENDENT METHYLTRANSFERASES
  申请人：Zhou Zhaohui

  公开号：US20100291605A1

  公开（公告）日：2010-11-18

  Disclosed are novel methyltransferase assay methods, comprising: including, in a reaction mixture for a methyltransferase activity, a purified or recombinant adenosine nucleosidase activity that catalyses release of an adenine or adenine derivative moiety from a transmethylation product, and a purified or recombinant adenine deaminase activity that catalyses deamination of the released moiety to hypoxanthine or respective derivative and ammonia, wherein the methyltransferase activity is rate-limiting; and determining the methyltransferase activity by spectrophotometric or chromatographic monitoring of the coupled deamination reaction products, or of subsequent enzymatic or chemical reactions coupled thereto. Coupled oxidation of the hypoxanthine to uric acid and hydrogen peroxide is optionally affected using purified or recombinant xanthine oxidase, wherein the methyltransferase activity is rate-limiting, and wherein determining the methyltransferase activity comprises monitoring of the coupled oxidation reaction. Variations are disclosed comprises monitoring of reaction products (e.g., to detect NH3, Hypoxanthine, H2O2, and Uric Acid).