Mechanism of Inactivation of Escherichia coli Aspartate Aminotransferase by (S)-4-Amino-4,5-dihydro-2-furancarboxylic Acid,

Dali Liu Edwin Pozharski Mengmeng Fu Richard B. Silverman and Dagmar Ringe

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Mechanism of Inactivation of Escherichia coli Aspartate Aminotransferase by (S)-4-Amino-4,5-dihydro-2-furancarboxylic Acid,

机译：（S）-4-氨基-4,5-二氢-2-呋喃甲酸灭活大肠杆菌天门冬氨酸氨基转移酶的机理，

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As a potential drug to treat neurological diseases, themechanism-based inhibitor (S)-4-amino-4,5-ndihydro-2-furancarboxylic acid (S-ADFA) has been found to inhibit the γ-aminobutyric acid aminotransfer-nase (GABA-AT) reaction. To circumvent the difficulties in structural studies of a S-ADFA-enzyme complexnusing GABA-AT, L-aspartate aminotransferase (L-AspAT) from Escherichia coli was used as a model PLP-ndependent enzyme. Crystal structures of the E. coli aspartate aminotransferase with S-ADFA bound to thenactive site were obtained via cocrystallization at pH 7.5 and 8. The complex structures suggest that S-ADFAninhibits the transamination reaction by forming adducts with the catalytic lysine 246 via a covalent bond whilenproducing 1 equiv of pyridoxamine 50n-phosphate (PMP). Based on the structures, formation of the K246-S-nADFA adducts requires a specific initial binding configuration of S-ADFA in the L-AspAT active site, as wellnas deprotonation of the ε-amino group of lysine 246 after the formation of the quinonoid and/or ketiminenintermediate in the overall inactivation reaction.

机译：作为治疗神经系统疾病的潜在药物，已发现基于机理的抑制剂（S）-4-氨基-4,5-ndihydro-2-呋喃羧酸（S-ADFA）可以抑制γ-氨基丁酸氨基转移酶（ GABA-AT）反应。为了规避使用GABA-AT进行S-ADFA-酶复合物结构研究的困难，将大肠杆菌的L-天冬氨酸转氨酶（L-AspAT）用作模型PLP依赖性酶。通过在pH 7.5和8下共结晶，获得结合了S-ADFA的大肠杆菌天冬氨酸转氨酶的晶体结构。复杂的结构表明，S-ADFAn通过与赖氨酸246的催化作用通过共价键形成加合物来抑制氨基转移反应。同时生产1当量的吡ido胺50n-磷酸（PMP）。基于该结构，K246-S-nADFA加合物的形成需要在L-AspAT活性位点具有特定的S-ADFA初始结合构型，因为醌类化合物形成后赖氨酸246的ε-氨基的质子去质子化和/或酮亚胺在整个灭活反应中处于中间状态。

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《Biochemistry》 |2010年第49期|p.10507-10515|共9页
作者
Dali Liu Edwin Pozharski Mengmeng Fu Richard B. Silverman and Dagmar Ringe;
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§Departments of Biochemistry and Chemistry and Rosenstiel Basic Sciences Research Center MS029, Brandeis University,Waltham, Massachusetts 02454-9110, United States, and ) Department of Chemistry andDepartment of Biochemistry, Molecular Biology, and Cell Biology, Center for Molecular Innovation and Drug Discovery andChemistry of Life Processes Institute, Northwestern University, Evanston, Illinois 60208-3113, United States.^Present address:Department of Chemistry, Loyola University Chicago, 1032 Sheridan Road, Chicago, IL 60626.#Present address: Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201.4Present address: Dardi & Herbert, PLLC, 3490 Piedmont Road, Suite 400, Atlanta, GA 30305.;

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1. Mechanism of Inactivation of Escherichia coli Aspartate Aminotransferase by (S)-4-Amino-4,5-dihydro-2-furancarboxylic Acid [J] . Liu DL, Pozharski E, Fu MM, Biochemistry . 2010,第49期

机译：（S）-4-氨基-4,5-二氢-2-呋喃甲酸使大肠杆菌天门冬氨酸氨基转移酶失活的机理
2. Inactivation of Escherichia coli L-aspartate aminotransferase by (S)-4-Amino-4,5-dihydro-2-thiophenecarboxylic acid reveals "A tale of two mechanisms" [J] . Liu DL, Pozharski E, Lepore BW, Biochemistry . 2007,第37期

机译：（S）-4-氨基-4,5-二氢-2-噻吩羧酸对大肠杆菌L-天门冬氨酸氨基转移酶的灭活揭示了“两个机理的故事”
3. Inactivation of gamma-aminobutyric acid aminotransferase by (S)-4-amino-4,5-dihydro-2-furancarboxylic acid does not proceed by the expected aromatization mechanism. [J] . Fu M, Silverman RB Bioorganic and Medicinal Chemistry Letters . 2004,第1期

机译：（S）-4-氨基-4,5-二氢-2-呋喃羧酸使γ-氨基丁酸氨基转移酶失活不会通过预期的芳构化机理进行。
4. Mechanism of Escherichia coli inactivation on plasma sprayed Ca_2ZnSi_2O_7 coating [C] . Kai Li, Youtao Xie, Liping Huang, World biomaterials congress . 2012

机译：等离子体喷涂Ca_2ZnSi_2O_7涂层上大肠杆菌失活的机理
5. Aspartate aminotransferase and aromatic-amino-acid aminotransferase in Escherichia coli. [D] . Orr, Winson M. S. 1977

机译：大肠杆菌中的天冬氨酸转氨酶和芳香族氨基酸转氨酶。
6. Mechanism of inactivation of E. coli aspartate aminotransferase by (S)-4-amino-45-dihydro-2-furancarboxylic acid (S-ADFA) [O] . Dali Liu, Edwin Pozharski, Mengmeng Fu, -1

机译：大肠杆菌天冬氨酸氨基转移酶的灭活机制（S）-4-氨基-45-二氢-2-呋喃甲酸（S-ADFA）
7. Mechanism of Inactivation ofEscherichia coliAspartate Aminotransferase by (S)-4-Amino-4,5-dihydro-2-furancarboxylic Acid, [O] . Dali Liu, Edwin Pozharski, Mengmeng Fu, 2010

机译：（S）-4-氨基-4,5-二氢-2-二叔转移酶的蛋白酶蛋白氨基氨基氨硅酸氨基氨基氨基氨基氨基转移酶的机制

Mechanism of Inactivation of Escherichia coli Aspartate Aminotransferase by (S)-4-Amino-4,5-dihydro-2-furancarboxylic Acid,

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