Work

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

Year: 2016

Type: article

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 - 14 C and 36 S and secondary methyl - 3 H, 5′- 3 H, and 5′- 14 C 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 N 2 transition state in which methyl transfer is rate-limiting.

Source: ACS Chemical Biology

DOI: 10.1021/acschembio.6b00922

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

Institution: Albert Einstein College of Medicine

Language: English

Topic: Chemical Reaction Mechanisms

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: green

Funders: National Institutes of Health, National Institute of General Medical Sciences

Awards: Transition State Analysis of Enzymatic Reactions, Transition State Analysis of Enzymatic Reactions, G521541070