Newly discovered enzyme may hold the key to childhood inflammatory bowel disease
Imperial researchers have discovered a novel enzyme that may explain some of the underlying immune mechanisms associated with a range of diseases.
The research shows that mutations in FAMIN enzyme can cause arthritis and inflammatory bowel disease in early childhood, as well as a common genetic variant that increases the risk for Crohn's disease and leprosy.
The work, from the Section of Biomolecular Medicine’s Griffin group and in collaboration with colleagues at the Department of Medicine, University of Cambridge, stemmed from the observation that a protein with an unknown function was linked to a range of diseases associated with either over-active or impaired immune function.
The four-year study, published in Cell, looked into the function of this unknown protein, which is named Fatty Acid Metabolism-Immunity Nexus (FAMIN). The team used an unbiased novel mass spectrometry screen to identify what metabolites were affected by overexpression and knock-down of the protein. Using this approach, the team demonstrated the protein had an unusual impact on purine nucleotide metabolism.
Speaking about the study, Professor Julian Griffin said: "This has been a real biochemical mystery to understand how a newly discovered protein, FAMIN, had such a major impact on metabolism in immune cells. Part of the confusion was caused by the fact that the enzyme didn't have a single function but is involved in three important pathways which have a central role in macrophage function. To add to the mystery FAMIN is involved in a range of diseases including inflammatory bowel disease, arthritis, Crohn's disease and leprosy. We now think we know the mechanism behind this complex set of metabolic interactions."
Most enzymes in metabolism act on one or two metabolites and produce either one or two products. The first major surprise with FAMIN is that it acts on a range of purine nucleosides and these different reactions help recycle important metabolites, particularly within immune cells such as macrophages.
Furthermore, this contribution to the nucleotide salvage pathway helps the cell prevent acidification and plays a role in regulating the interface between glycolysis and oxidative metabolism, explaining why FAMIN plays such an important role in the immune system.
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