Kinetic Isotope Effects and Transition State Structure for Human Phenylethanolamine N-Methyltransferase

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• 作者：Christopher F. Stratton ; Myles B. PoulinQuan Du ; Vern L. Schramm
• 刊名：ACS Chemical Biology
• 出版年：2017
• 出版时间：February 17, 2017
• 年：2017
• 卷：12
• 期：2
• 页码：342-346
• 全文大小：330K
• ISSN：1554-8937

文摘

Phenylethanolamine N-methyltransferase (PNMT) catalyzes the S-adenosyl-l-methionine (SAM)-dependent conversion of norepinephrine to epinephrine. Epinephrine has been associated with critical processes in humans including the control of respiration and blood pressure. Additionally, PNMT activity has been suggested to play a role in hypertension and Alzheimer’s disease. In the current study, labeled SAM substrates were used to measure primary methyl-¹⁴C and ³⁶S and secondary methyl-³H, 5′-³H, and 5′-¹⁴C intrinsic kinetic isotope effects for human PNMT. The transition state of human PNMT was modeled by matching kinetic isotope effects predicted via quantum chemical calculations to intrinsic values. The model provides information on the geometry and electrostatics of the human PNMT transition state structure and indicates that human PNMT catalyzes the formation of epinephrine through an early S_N2 transition state in which methyl transfer is rate-limiting.