Structure of enzyme that converts neurotransmitter dopamine to norepinephrine revealed for the first time

A first glimpse of the three-dimensional structure of the human enzyme that converts the neurotransmitter dopamine to norepinephrine comes courtesy of X-ray crystallography and a team led by Hans E. M. Christensen of the Technical University of Denmark (Sci. Adv. 2016, DOI: 10.1126/sciadv.1500980). The enzyme, dopamine β-hydroxylase, modulates the relative brain concentrations of dopamine and norepinephrine. That balance has been implicated in a large number of physiological, neurological, and psychiatric diseases, Christensen notes. Examples include congestive heart failure, hypertension, Alzheimer’s and Parkinson’s diseases, and depression. The structure of the human enzyme, which has been determined at a resolution of 2.9 Å, is the first of its kind for any organism. It shows the enzyme can adopt open and closed conformations and features a catalytic site with two copper atoms about 4 Å apart in the closed conformation. The proximity of the copper atoms is a welcome surprise, Christensen says, because prior studies placed the catalytically important metals about 14 Å apart. Disrupting the closed conformation with small molecules might offer a new strategy for drug developers devising therapeutics aimed at the enzyme.