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

Christopher F. Stratton, Myles B. Poulin, Quan Du, Vern L. Schramm

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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 SN2 transition state in which methyl transfer is rate-limiting.

Original languageEnglish (US)
Pages (from-to)342-346
Number of pages5
JournalACS Chemical Biology
Volume12
Issue number2
DOIs
Publication statusPublished - Feb 17 2017

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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