ENZYME TARGETED IMAGING AGENTS FOR NEUROPSYCHIATRY

用于神经精神病学的酶靶向成像剂

基本信息

批准号：
6120914
负责人：
Onofre DeJesus
金额：
$ 0.22万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-03-01 至 2000-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6120914
关键词：
biological products biomaterials biomedical resource enzymes nuclear magnetic resonance spectroscopy

项目摘要

Low-barrier hydrogen bonds have been recently hypothesized to be involved in providing the energy required by enzymes for catalysis. These very strong, low-barrier hydrogen bonds exhibit very low field proton NMR signals (16-20 ppm) and low deuterium fractionation factors. The mechanism of enolase is believed to pass through a carbanion intermediate, which may be stabilized by such a low-barrier hydrogen bond present in the intermediate but not ground state. It has been demonstrated by Weiss, et al. (JACS, 1987) that the fractionation factor for the proton transferred from C-2 of D-TSP (a competitive inhibitor of enolase) to the catalytic base is far below unity. Because no cysteine residues are present in the catalytic site to explain this finding, as observed from x-ray crystal structure, it has been hypothesized that this result suggests the presence of a low-barrier hydrogen bond. Thus, proton NMR will be used to search for a low field signal indicative of such a low-barrier hydrogen bond. Methylene phosphoenolpyruvate, a slow substrate for enolase, and tartronate semialdehyde phosphate, a dead end inhibitor, will be employed for the studies. The use of such inhibitors in which the intermediate may be present in appreciable amounts is hoped to allow one to observe the low field signal representative of a low-barrier hydrogen bond. A low field proton NMR signal has been observed in chymotrypsin by Robillard, et al. (J. Mol. Biol., 1972), which has been postulated to represent a low-barrier hydrogen bond.

低势垒氢键最近被假设为参与提供酶催化所需的能量。这些非常强、低势垒的氢键表现出非常低的场质子 NMR 信号 (16-20 ppm) 和低氘分馏因素。烯醇化酶的作用机制被认为是通过碳负离子中间体，可以通过这种低势垒来稳定氢键存在于中间态但不存在基态。它 Weiss 等人已证明。（JACS，1987）从 D-TSP 的 C-2 转移的质子的分馏因子（a 烯醇化酶的竞争性抑制剂）对催化碱的影响远远低于统一。因为催化位点不存在半胱氨酸残基为了解释这一发现，从 X 射线晶体结构观察到，假设这一结果表明存在低势垒氢键。因此，质子核磁共振将用于搜索用于指示这种低势垒氢键的低场信号。亚甲基磷酸烯醇丙酮酸，烯醇酶的慢底物，以及酒石酸半醛磷酸盐，一种死端抑制剂，将受雇于研究。使用此类抑制剂时，中间体可能以可观的量存在，希望能够观察代表低势垒的低场信号氢键。观察到低场质子核磁共振信号胰凝乳蛋白酶，Robillard 等人。（J. Mol. Biol.，1972），其中有被假定代表低势垒氢键。