Title: FAMIN Is a Multifunctional Purine Enzyme Enabling the Purine Nucleotide Cycle
Author: M. Zaeem Cader, Rodrigo Pereira de Almeida Rodrigues, James A. West, Gavin W. Sewell, Muhammad N. Md-Ibrahim, Stephanie Reikine, Giuseppe Sirago, Lukas W. Unger, Ana Belén Inglesias-Romero, Katharina Ramshorn, Lea-Maxie Haag, Svetlana Saveljeva, Jana-Fabienne Ebel, Philip Rosenstiel, Nicole C. Kaneider, James C. Lee, Trevor D. Lawley, Allan Bradley, Gordon Dougan, Yorgo Modis, Julian L. Griffin, Arthur Kaser
Abstract: Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases the risk for Crohn's disease and leprosy. We developed an unbiased liquid chromatography-mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic orthologs additionally have adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5′-thioadenosine phosphorylase activity, hence, combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronizes mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H+ and phosphate recycling.