guanidinoacetate甲基转移酶催化机理:guanidinoacetate甲基转移酶三元配合物的晶体结构。

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山田Komoto J, T,中国人Y, Konishi K,小川H,无味,Fujioka M, Takusagawa F

guanidinoacetate甲基转移酶催化机理:guanidinoacetate甲基转移酶三元配合物的晶体结构。

生物化学。2004年11月16日,43 (45):14385 - 94。

PubMed ID

15533043 (在PubMed

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文摘

Guanidinoacetate甲基转移酶(GAMT)是酶,催化肌酸生物合成的最后一步。丰富的酶被发现所有脊椎动物的肝脏。的完整GAMT重组大鼠肝脏被结晶抑制剂S-adenosylhomocysteine (SAH)和基质guanidinoacetate(棉酚),长官和抑制剂胍(枪)。这些三元复杂的结构已经确定在2.0一项决议。GAMT有α/β单片三明治结构,氨基端部分(残留1-42)涵盖了活跃的站点入口,这样活跃的站点是不可见的。与GAMT SAH有着丰富的交互通过H-bonds和疏水相互作用。棉酚的胍基组和两双枪形式H-bonds E45和D134,分别。棉酚的羧基与骨干酰胺L170和T171组。GAMT的模型结构包含两个基板(山姆和棉酚)是由附加一个甲基(C (E))的S (D)绑定长官。该模型结构的基础上,提出了GAMT的催化机理。 The active site entrance is opened when the N-terminal section is moved out. GAA and SAM enter the active site and interact with the amino acid residues on the surface of the active site by polar and nonpolar interactions. O(D1) of D134 and C(E) of SAM approach N(E) of GAA from the tetrahedral directions. The O(D1)...N(E) and C(E)...N(E) distances are 2.9 and 2.2 A, respectively. It is proposed that three slightly negatively charged carbonyl oxygen atoms (O of T135, O of C168, and O(B) of GAA) around O(D1) of D134 increase the pK(a) of O(D1) so that O(D1) abstracts the proton on N(E). A strong nucleophile is generated on the deprotonated N(E) of GAA, which abstracts the methyl group (C(E)) from the positively charged S(D) of SAM, and creatine (methyl-GAA) and SAH (demethyl-SAM) are produced. E45, D134, and Y221 mutagenesis studies support the proposed mechanism. A mutagenesis study and the inhibitory mechanism of guanidine analogues support the proposed mechanism.

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药物靶点

药物	目标	类	生物	药理作用	行动
胍	Guanidinoacetate N-methyltransferase	蛋白质	人类	未知的	不可用	细节