Enzymes for Detoxification – a Matter of Life and Death

A rendering of a human with a highlighted liver.

Although we live in a world that is more developed than ever, toxins are omnipresent in our environment. During evolution, the human bodies developed ways to cope with many harmful compounds; most of them are degraded enzymatically. A project at the Austrian Centre of Industrial Biotechnology (acib) revealed new insights into life saving processes – especially into the enzymatic detoxification by a special class of enzymes called flavin containing monooxygenases (FMO).

The human being is constantly exposed to xenobiotics, substances that don’t occur naturally in our metabolism. Herbicides, pesticides, drugs, exhaust gases, naturally occurring toxins, and many more substances cause problems for human health. The detoxification is generally performed by an “oxidative action” of two enzyme families called “cytochrome P450 monooxygenases” and “flavin-containing monooxygenases” (FMO). While P450 monooxygenases are studied quite well, there still was a lack of information according to the activity of the FMO-enzymes – although they have been attributed to some key biological process like health and longevity, arteriosclerosis or cholesterol regulation. This type of enzymes is active in liver, kidneys, lungs, or in the brain in five different forms called FMO1-5. Researchers at acib uncovered the function of the yet unexplored FMO5 that plays a major role in detoxification processes in the human liver.

In order to study the human FMO5, acib researchers together with their partners from University of Pavia (Andrea Mattevi) established a protocol for the production using bacteria (Escherichia coli) and the purification of the enzyme.They discovered a broad range of substrates that is degraded by FMO5, e.g. flavoring components in food like 2-heptanone that is used in cheese, banana or even coconut flavors. Additionally, FMO5 is active in breaking down pharmaceutical ingredients that are common in cancer treatments or in antibacterial applications.

Liver in a Test Tube

These findings are an important contribution to an acib-project called the “liver in a test tube”.  As most pharmaceutical compounds are degraded in the human liver, acib thrives to discover and produce all enzymes that are active in the degradation process. Using this collection of enzymes – like a liver in a test tube – the pharmaceutical industry can simulate the decomposition of drug molecules like it is done in the human body. This way, the real metabolites are accessible that had to be guessed in former times which facilitates the test procedures of new active agents and speeds up the development of new drugs.

This work is based on:
Filippo Fiorentini, Martina Geier, Claudia Binda, Margit Winkler, Kurt Faber, Mélanie Hall, and Andrea Mattevi: Biocatalytic Characterization of Human FMO5; Unearthing Baeyer-Villiger Reactions in Humans. ACS Chem. Biol., 2016, 11 (4), pp 1039–1048. doi: 10.1021/acschembio.5b01016

Picture credits: Dreamtime