标题：Quantum chemistry studies of the catalysis mechanism differences between the two isoforms of glutamic acid decarboxylase
作者：Chunling Wang;Rongxiu Zhu;Hainan Sun;Baiqing Li
作者机构：[Wang, C] Institute of Theoretical Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan Shandong 250100, China;[ Zhu, R 更多
通讯作者地址：[Li, BQ]Shandong Univ, Inst Theoret Chem, Sch Chem & Chem Engn, Key Lab Colloid & Interface Chem,Minist Educ, Jinan 250100, Shandong, Peoples R China.
来源：Journal of molecular modeling
关键词：Density functional theory;Glutamic acid decarboxylase;Proton transfer;Pyridoxal 5′-phosphate;Transition state theory
摘要：The production of gamma-aminobutyric acid (GABA) is catalyzed by two isoforms of glutamic acid decarboxylase (GAD), using pyridoxal 5′-phosphate (PLP) as the cofactor. Between the two enzymes, GAD67 accounts for normal GABA requirement, while GAD65 stays inactive until emergent demand for GABA. Recent crystal structure findings revealed that the distinct conformation of a common catalytic loop of the enzymes may account for their different functions (Fenalti et al Nat Struct Mol Biol, 14:280-286, 2007). Enlightened by their inferences, we studied the underlying reaction mechanism of the two GAD isoforms using density functional theory (DFT). A rather complete reaction pathway is identified, including nine transition state (TS) structures and 14 intermediate (IM) structures. The rate limiting step occurs early during the reaction and involves a proton transfer. In the late stage, there are two pathways that involve C_4\' and Cα protonation by Tyr or Lys. Our calculations show that the reaction barriers corroborate the conjecture made by Fenalti et al.