FAMIN Is a Multifunctional Purine Enzyme Enabling the Purine Nucleotide Cycle PMID: 31978345

ADC Targets in Oncology

2026-04-10

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

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: [email protected].

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.