SYNTHESIS AND PROPERTIES OF ORGANOCOBALT COMPLEXES

有机钴配合物的合成及性质

• 批准号: 3276773
• 负责人: LUIGI G. MARZILLI
• 金额: $ 11.86万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-09-01 至 1990-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3276773
• 关键词: Raman spectrometry; adenine; alkylation; catalyst; chemical chain length; chemical cleavage; chemical kinetics; chemical synthesis; circular dichroism; cobalt; conformation; electron spin resonance spectroscopy; isomer; ligands; metal complex; metalloenzyme; model design /development; nuclear magnetic resonance spectroscopy; physical chemical interaction; spectrometry; vitamin B12; vitamin B12 coenzyme; vitamin analog

Important unanswered questions concerning B12-dependent enzymic processes are: What are the conformational changes which promote the rate of homolytic cleavage of the Co-C bond of coenzyme B12 by a factor of 10-10 and which favor homolytic over heterolytic cleavage in B12 holoenzymes? Why is the Co- N(DMBz) bond so long and what is the role of DMBz in these processes? If the contribution of the enzyme to rearrangement processes (e.g. methylmalonyl-CoA to succinylCoA) is restricted to insuring the existence of long-lived substrate radicals, how do the enzymes prevent radical combination with B12? These and other questions have not been fully answered for several reasons. The B12-dependent enzymes are large, making X-ray and some spectroscopic studies difficult. The cofactor generally lies tightly bound in a protected enzyme pocket inaccessible to probe reagents. Only four alkylcobaltcorrin X-ray structures including coenzyme B12 and methyl B12 have been reported. The molecules are complex and unique and spectroscopic methods are limited by this complexity and by a lack of background data. Therefore, the conformations of well studied coenzyme analogues are unknown. One consequence of this limited information is that there are few clear relationships between structure and spectra. Also, there remains an inadequate background with which to assess the steric factors leading to Co-C bond cleavage. To continue to address these questions, we propose a three-pronged approach. Detailed studies of (i) alkylcobaltcorrins, (ii) synthetic organocobalt species, and (iii) ribonucleotide reductase (RR) are contemplated. The range of conformations possible for alkylcobalamins will be defined via the synthesis of modified or sterically strained alkylcobaltcorrins (cobalamins, cobinamides and other side chain- modified derivatives) and additional organocobalt compounds with sterically or electronically modified equatorial ligands based on the Cosaloph and "Costa" systems. The effect of structural changes induced in these systems will be assessed by X-ray crystallography, modern spectroscopic methods (CD, 2D and HMQC NMR, Raman) and by reaction rates and mechanistic studies (DMBz dissociation, ligand exchange). Application of some of these methods has produced a wealth of information and provided new insight during this grant period. These methods will be extended to the study of RR. RR is relatively small, with a loosely bound accessible, B12 site and a mechanism of action related to the Fe enzymes. Thus, RR has special advantages and significance. Steric strain in the alkyl linkage between Co and adenine in coenzyme analogues will also be varied and the interaction of the analogues and coenzyme B12 with RR will be investigated. For NMR studies, we will employ cobalamins containing isotopically enriched sites. The spectroscopic (CD, vis, NMR (2D, HMQC)), background to be developed will be generally useful in studies on other B12 holoenzymes and on B12 transport systems.

有关B12依赖性的重要未解决的问题 酶过程是：构象变化是什么 促进了Co-C键的均质裂解速率 辅酶B12的含量为10-10，并且有利于均利性 B12全酶中的杂裂裂解？ 为什么共同 n（DMBZ）债券这么长，DMBZ在这些键中的作用是什么 过程？ 如果酶对重排的贡献 过程（例如甲基甲硅烷-COA至琥珀酸）受到限制 为了确保长期存在的底物自由基的存在，如何 这些酶可以防止与B12的自由基组合？ 这些和 由于几个原因，其他问题尚未得到充分回答。 B12依赖性酶很大，制作X射线，有些 光谱研究困难。 辅助因子通常紧紧地位于 绑在一个受保护的酶口袋中，无法访问 试剂。 只有四个烷基钙蛋白X射线结构包括 辅助B12和甲基B12已有报道。 分子 复杂且独特，光谱法受到限制 这种复杂性和缺乏背景数据。 因此， 研究经过的辅酶类似物的构象未知。 这个有限信息的结果是很少 结构与光谱之间的明确关系。 另外，那里 仍然是评估空间的背景不足 导致Co-C键裂解的因素。 继续解决 这些问题，我们提出了一种三管齐下的方法。 详细的 （i）烷基钙蛋白的研究，（ii）合成有机体 考虑了（iii）核糖核苷酸还原酶（RR）。 烷基卡明蛋白可能的构象范围将是 通过合成修饰或空间紧张的合成定义 烷基钙蛋白酶（钴胺素，cobinamides和其他侧链 - 修饰的衍生物）和其他有机库型化合物， 基于空间或电子修饰的赤道配体 宇宙和“ Costa”系统。 结构的效果 这些系统中诱导的变化将通过X射线评估 晶体学，现代光谱法（CD，2D和 HMQC NMR，拉曼）以及反应速率和机械 研究（DMBZ解离，配体交换）。 应用 其中一些方法产生了大量信息， 在此赠款期间提供了新的见解。 这些方法将 扩展到RR的研究。 RR相对较小，有 松散绑定的可访问，B12站点和动作机理 与Fe酶有关。 因此，RR具有特殊优势，并且 意义。 CO和CO之间的烷基连接中的空间应变 辅酶类似物中的腺嘌呤也将变化，并且 类似物和辅酶B12与RR的相互作用将是 调查。 对于NMR研究，我们将采用钴胺素 包含同位素富集的位点。 光谱学（CD，VIS， NMR（2D，HMQC）），通常会开发背景 在其他B12全酶和B12转运的研究中有用 系统。