Researchers unearth new metabolic pathways

Researchers at Case Western Reserve University School of Medicine, led by Henri Brunengraber, MD, PhD, professor and Mt. Sinai Auxiliary Commemorative Chair in Nutrition Research in the Department of Nutrition, have shed new light on how 4-hydroxy-n-acids, including gamma hydroxybutyrate (GHB, also called 4-hydroxybutyrate or 4-HB), are metabolized by the body—and, in so doing, have discovered two new metabolic pathways. A naturally occurring brain metabolite, GHB can be abused or used as a date-rape drug when taken orally.

The research team used a combination of metabolomics and mass isotopomer analysis to evaluate the chemicals produced when GHB and similar compounds are broken down—and identified previously unknown pathways that act on the chemical. Guo-Fang Zhang, PhD, a research associate in the Department of Nutrition working on the project, says the findings will lead to further studies that will increase the understanding of metabolic disturbances that occur during oxidative stress—which are part of the pathology of diseases such as heart attacks, strokes, diabetes and inflammation. “We hope that future studies will result in the design of new treatments that minimize the effects of oxidative stress,” he says.

The work was supported by several funding sources, including a RoadMap grant from the National Institutes of Health, a grant from the National Institute of Environmental Health and Sciences and a grant from the Cleveland Mt. Sinai Health Care Foundation. The discovery was published in the Nov. 27, 2009, issue of the Journal of Biological Chemistry as the “Paper of the Week.”

“Paving a Catabolic Highway,” an editorial about this landmark study, concluded, “Overall, this study represents an exemplary prototype for any projects that aim to identify incomplete or unknown metabolic pathways.”