Inhibition of human glutamine synthetase by L-methionine-S,R-sulfoximine-relevance to the treatment of neurological diseases.
Inhibition of human glutamine synthetase by L-methionine-S,R-sulfoximine-relevance to the treatment of neurological diseases.
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DOI：
10.1007/s11011-013-9439-6
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发表时间：
2014-12
影响因子：
3.6
通讯作者：
Cooper, Arthur J. L.
中科院分区：
文献类型：
--
作者：
Jeitner, Thomas M.;Cooper, Arthur J. L.
高浓度时，谷氨酰胺合成酶抑制剂l -蛋氨酸-s， r -亚砜胺是一种惊厥药，特别是对狗。然而，亚惊厥剂量的MSO对高氨血症、急性肝病和肌萎缩侧索硬化症的啮齿动物模型具有神经保护作用，这表明MSO可能在临床上有用。先前的研究也表明，与灵长类动物相比，狗产生抽搐所需的MSO剂量要低得多。20世纪中期的证据表明，人类也不那么敏感。在目前的研究中，MSO对重组人谷氨酰胺合成酶的抑制是双相的——最初是可逆的竞争性抑制（Ki 1.19 mM），随后是快速的不可逆失活。人类酶的Ki值在一定程度上解释了灵长类动物对MSO相对不敏感的原因，并表明这种抑制剂可以用于安全地抑制人类谷氨酰胺合成酶的活性。
At high concentrations, the glutamine synthetase inhibitor L-methionine-S,R-sulfoximine is a convulsant, especially in dogs. Nevertheless, sub-convulsive doses of MSO are neuroprotective in rodent models of hyperammonemia, acute liver disease, and amyotrophic lateral sclerosis and suggest MSO may be clinically useful. Previous work has also shown that much lower doses of MSO are required to produce convulsions in dogs than in primates. Evidence from the mid-20th century suggests that humans are also less sensitive. In the present work, the inhibition of recombinant human glutamine synthetase with MSO is shown to be biphasic – an initial reversible competitive inhibition (Ki 1.19 mM) is followed by rapid irreversible inactivation. This Ki value for the human enzyme accounts, in part, for relative insensitivity of primates to MSO and suggests that this inhibitor could be used to safely inhibit glutamine synthetase activity in humans.
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影响因子：
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