2. Academic Validation
  3. FAMIN Is a Multifunctional Purine Enzyme Enabling the Purine Nucleotide Cycle

FAMIN Is a Multifunctional Purine Enzyme Enabling the Purine Nucleotide Cycle

  • Cell. 2020 Jan 23;180(2):278-295.e23. doi: 10.1016/j.cell.2019.12.017.
M Zaeem Cader 1,  Rodrigo Pereira de Almeida Rodrigues 1,  James A West 2,  Gavin W Sewell 1,  Muhammad N Md-Ibrahim 1,  Stephanie Reikine 3,  Giuseppe Sirago 1,  Lukas W Unger 1,  Ana Belén Iglesias-Romero 1,  Katharina Ramshorn 1,  Lea-Maxie Haag 1,  Svetlana Saveljeva 1,  Jana-Fabienne Ebel 4,  Philip Rosenstiel 4,  Nicole C Kaneider 1,  James C Lee 1,  Trevor D Lawley 5,  Allan Bradley 6,  Gordon Dougan 7,  Yorgo Modis 3,  Julian L Griffin 8,  Arthur Kaser 9
Affiliations

Affiliations

  • 1 Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  • 2 Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK; Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge CB2 1GA, UK.
  • 3 Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
  • 4 Institute of Clinical Molecular Biology, Christian Albrechts University, Campus Kiel, 24105 Kiel, Germany.
  • 5 Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
  • 6 Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
  • 7 Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Division of Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
  • 8 Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge CB2 1GA, UK.
  • 9 Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. Electronic address: ak729@cam.ac.uk.
PMID: 31978345 DOI: 10.1016/j.cell.2019.12.017
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.

Keywords

C13orf31; Crohn's disease; FAMIN; LACC1; Still's disease; immunometabolism; pH homeostasis; purine metabolism; purine nucleotide cycle; redox homeostasis.

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