Mechanism of Inactivation of GABA Aminotransferase by (E)- and (Z)-(1S,3S)-3-Amino-4-fluoromethylenyl-1-cyclopentanoic Acid,ACS Chemical Biology

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Mechanism of Inactivation of GABA Aminotransferase by (E)- and (Z)-(1S,3S)-3-Amino-4-fluoromethylenyl-1-cyclopentanoic Acid
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2015-07-06 00:00:00 , DOI: 10.1021/acschembio.5b00212
Hyunbeom Lee ₁ , Hoang V. Le ₁ , Rui Wu ₂ , Emma Doud ₃ , Ruslan Sanishvili ₄ , John F. Kellie ₃ , Phillip D. Compton ₃ , Boobalan Pachaiyappan ₁ , Dali Liu ₂ , Neil L. Kelleher ₃ , Richard B. Silverman ₁

Affiliation

When γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, falls below a threshold level, seizures occur. One approach to raise GABA concentrations is to inhibit GABA aminotransferase (GABA-AT), a pyridoxal 5′-phosphate-dependent enzyme that degrades GABA. We have previously developed (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115), which is 186 times more efficient in inactivating GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT. We also developed (E)- and (Z)-(1S,3S)-3-amino-4-fluoromethylenyl-1-cyclopentanoic acid (1 and 2, respectively), monofluorinated analogs of CPP-115, which are comparable to vigabatrin in inactivating GABA-AT. Here, we report the mechanism of inactivation of GABA-AT by 1 and 2. Both produce a metabolite that induces disruption of the Glu270–Arg445 salt bridge to accommodate interaction between the metabolite formyl group and Arg445. This is the second time that Arg445 has interacted with a ligand and is involved in GABA-AT inactivation, thereby confirming the importance of Arg445 in future inactivator design.

中文翻译：

（E）-和（Z）-（1 S，3 S）-3-氨基-4-氟亚甲基-1-环戊酸使GABA氨基转移酶失活的机理

当哺乳动物中枢神经系统中主要的抑制性神经递质γ-氨基丁酸（GABA）降至阈值以下时，会发生癫痫发作。提高GABA浓度的一种方法是抑制GABA氨基转移酶（GABA-AT），这是一种降解GABA的吡ido醛5'-磷酸盐依赖性酶。我们以前已经开发了（1 S，3 S）-3-氨基-4-二氟亚甲基-1-环戊酸（CPP-115），其灭活GABA-AT的效率比FDA批准的唯一灭活剂vigabatrin高186倍GABA-AT。我们还开发了（E）-和（Z）-（1 S，3 S）-3-氨基-4-氟亚甲基-1-环戊酸（1和2分别是CPP-115的单氟化类似物，在灭活GABA-AT方面与vigabatrin相当。在这里，我们报告了1和2灭活GABA-AT的机制。两者均产生代谢物，该代谢物引起Glu270–Arg445盐桥的破坏，以适应代谢物甲酰基和Arg445之间的相互作用。这是Arg445第二次与配体相互作用并参与GABA-AT灭活，从而证实了Arg445在未来灭活剂设计中的重要性。

更新日期：2015-07-06

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