Structural Characterization of a Human-Type Corrinoid Adenosyltransferase Confirms That Coenzyme B12 Is Synthesized through a Four-Coordinate Intermediate

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• 作者：Martin St. Maurice ; Paola Mera ; Kiyoung Park ; Thomas C. Brunold ; Jorge C. Escalante-Semerena ; Ivan Rayment
• 刊名：Biochemistry
• 出版年：2008
• 出版时间：May 27, 2008
• 年：2008
• 卷：47
• 期：21
• 页码：5755 - 5766
• 全文大小：9944K
• 年卷期：v.47,no.21(May 27, 2008)
• ISSN：1520-4995

文摘

ATP:cob(I)alamin adenosyltransferases (ACAs) catalyze the transfer of the 5′-deoxyadenosyl moiety from ATP to the upper axial ligand position of cobalamin in the synthesis of coenzyme B₁₂. For the ACA-catalyzed reaction to proceed, cob(II)alamin must be reduced to cob(I)alamin in the enzyme active site. This reduction is facilitated through the generation of a four-coordinate cob(II)alamin intermediate on the enzyme. We have determined the high-resolution crystal structure of a human-type ACA from Lactobacillus reuteri with a four-coordinate cob(II)alamin bound in the enzyme active site and with the product, adenosylcobalamin, partially occupied in the active site. The assembled structures represent snapshots of the steps in the ACA-catalyzed formation of the cobalt−carbon bond of coenzyme B₁₂. The structures define the corrinoid binding site and provide visual evidence for a base-off, four-coordinate cob(II)alamin intermediate. The complete structural description of ACA-mediated catalysis reveals the molecular features of four-coordinate cob(II)alamin stabilization and provides additional insights into the molecular basis for dysfunction in human patients suffering from methylmalonic aciduria.