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FAMIN Is a Multifunctional Purine Enzyme Enabling the Purine Nucleotide Cycle.

Cell (2020-01-25)
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 Iglesias-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.

MATERIALS
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