Pyridine coenzyme analogues. Synthesis and characterization of alpha- and beta-nicotinamide arabinoside adenine dinucleotides.
Pyridine coenzyme analogues. Synthesis and characterization of alpha- and beta-nicotinamide arabinoside adenine dinucleotides.
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吡啶辅酶类似物。
DOI：
10.1021/bi00386a031
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发表时间：
1987
期刊：
影响因子：
2.9
通讯作者：
Oppenheimer,NJ
中科院分区：
文献类型：
--
作者：
Kam,BL;Malver,O;Marschner,TM;Oppenheimer,NJ
Bernard L. Kam,** Olaf Malver, Thomas M. Marschner, and Norman J. Oppenheimer*加州大学药物化学系，San Francisco, California 94143摘要：报道了一种含有阿拉伯烟酰胺核苷酸片段的新型吡啶辅酶类似物的合成和表征。氧化烟酰胺阿糖苷腺嘌呤二核苷酸的氧化还原电位为339 mV，氧化烟酰胺腺嘌呤二核苷酸的氧化还原电位为319 mV，还原烟酰胺阿糖苷腺嘌呤二核苷酸（araNADH）的Xmax分别为346 nm和338 nm。在90℃时，还原类似物的异构化导致aranadh与aranadh /3-araNADH的比例为5:1。这些结果表明，2/-羟基与碱基的相对构型是Xmax构型依赖性变化的主要决定因素，吡啶核苷酸的氧化还原电位，以及被还原辅酶的首选端粒构型。报道了类似物与核糖辅酶的核磁共振和31P谱数据的比较，并讨论了构象分析。用酵母和马肝酒精脱氢酶对阿拉伯糖类似物的辅酶性质进行了评价。这两个«和/3-异构体都被发现起辅酶的作用，并且氢化物转移的酯化反应在这两个异构体中是相同的。吡啶辅酶的类似物在脱氢酶、adp -核糖基转移酶和其他辅酶利用酶的空间约束和机制的研究中一直具有重要意义。修饰主要集中在吡啶环上，特别强调3-取代基，因为它们易于合成（Anderson et al., 1959），并且在较小程度上对腺嘌呤部分进行了修饰[见Anderson（1982）的全面回顾]。很少有研究针对合成含有烟酰胺糖分子修饰的类似物（Goebbeler & Woenckhaus, 1966； Woenckhaus等人，1964;Woenckhaus & Jeck, 1970）。这种类似物的缺乏代表了一个重要的遗漏，因为糖部分可以直接影响辅酶的化学性质，可以改变辅酶与脱氢酶的结合，并且被认为发挥重要的机制作用（Oppenheimer, 1986a）。在本文中，我们介绍了一种含有烟酰胺阿拉伯核苷片段的新型NAD“1”类似物的a-和3-异位物的合成和生化表征，如结构1所示。该合成方法基于S'- o -三烷基戊呋喃胺中间体的一般性质（Kam & oppenheimer 1979a, b），代表了一种合成广泛的NAD“1”类似物的通用方法。struc -
Bernard L. Kam,** Olaf Malver, Thomas M. Marschner, and Norman J. Oppenheimer* Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94143 Received October 31, 1986; Revised Manuscript Received February 9, 1987 abstract: The synthesis and characterization of a new pyridine coenzyme analogue containing a nicotinamide arabinonucleotide moiety are reported. The redox potentials are-339 mV for/3-oxidized nicotinamide arabinoside adenine dinucleotide and-319 mV for «-oxidized nicotinamide adenine dinucleotide, and the Xmax is 346 and 338 nm for ß-and «-reduced nicotinamide arabinoside adenine dinucleotides (araNADH), respectively. Anomerization of the reduced analogues leads to a 5: 1 ratio of-araNADH to/3-araNADH at 90 C. These results establish that the relative configuration of the 2/-hydroxyl to the base is the primary determinant for the configuration-dependent changes in Xmax, the redox potential of the pyridine nucleotides, and the preferred anomeric configuration of thereduced coenzymes. Comparison of the and 31P NMR spectral data of the analogues with those for the ribo coenzymes is reported and the conformational analysis discussed. The coenzyme properties of the arabino analogues havebeen evaluated with yeast and horse liver alcohol dehydrogenases. Both the «-and/3-anomers are found to serve as coenzymes, and the ster-eochemistry of hydride transfer is identical for both anomers..^^. nalogues of pyridine coenzymes have long been important in the study of the steric constraints and mechanism of de-hydrogenases, ADP-ribosyltransferases, and other co-enzyme-utilizing enzymes. Modifications have focused primarily on the pyridine ring, with special emphasis on the 3-substituent because of their ease of synthesis (Anderson et al., 1959), andto a lesser extent on the adenine moiety [see Anderson (1982) for a comprehensive review]. There have been few investigations directed at synthesis of analogues containing modifications of the nicotinamide sugar moeity (Goebbeler & Woenckhaus, 1966; Woenckhaus et al., 1964; Woenckhaus & Jeck, 1970). Thelack of such analogues represents a significant omission since the sugar moiety can influence directly the chemical properties of the coenzyme, can alter coenzyme binding to dehydrogenases, and has been suggested toplay an important mechanistic role (Oppenheimer, 1986a).In this paper we present the synthesis and biochemical characterization of both the a-and 3-anomers of a new NAD" 1" analogue containing a nicotinamide arabinonucleoside moiety as shown inStructure I. The procedures developed for this synthesis, which are based on the general properties of S'-O-tritylpentofuranosylamine intermediates (Kam & Oppen-heimer 1979a, b), represent a generalized approach to the synthesis of a wide range of NAD" 1" analogues. The struc-