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FAMIN is a multifunctional purine enzyme enabling the purine nucleotide cycle

DOI: 10.1016/j.cell.2019.12.017 DOI Help

Authors: M. Zaeem Cader (University of Cambridge) , Rodrigo Pereira De Almeida Rodrigues (University of Cambridge) , James A. West (University of Cambridge) , Gavin W. Sewell (University of Cambridge) , Muhammad N. Md-Ibrahim (University of Cambridge) , Stephanie Reikine (University of Cambridge) , Giuseppe Sirago (University of Cambridge) , Lukas W. Unger (University of Cambridge) , Ana Belén Iglesias-Romero (University of Cambridge) , Katharina Ramshorn (University of Cambridge) , Lea-Maxie Haag (University of Cambridge) , Svetlana Saveljeva (University of Cambridge) , Jana-Fabienne Ebel (Christian Albrechts University) , Philip Rosenstiel (Christian Albrechts University) , Nicole C. Kaneider (University of Cambridge) , James C. Lee (University of Cambridge) , Trevor D. Lawley (Wellcome Trust Sanger Institute) , Allan Bradley (University of Cambridge; Wellcome Trust Sanger Institute) , Gordon Dougan (University of Cambridge) , Yorgo Modis (University of Cambridge) , Julian L. Griffin (University of Cambridge) , Arthur Kaser (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell , VOL 180 , PAGES 278 - 295.e23

State: Published (Approved)
Published: January 2020
Diamond Proposal Number(s): 15916

Open Access Open Access

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.

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

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 06/02/2020 11:21

Documents:
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Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Autoimmune Diseases Non-Communicable Diseases Structural biology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)