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.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / metabolism
  • Adenosine / metabolism
  • Adenosine Deaminase / metabolism
  • Chromatography, Liquid / methods
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins / physiology
  • Mass Spectrometry / methods
  • Multifunctional Enzymes / genetics
  • Phosphorylation
  • Proteins / genetics
  • Purine Nucleotides / metabolism
  • Purines / metabolism


  • Intracellular Signaling Peptides and Proteins
  • LACC1 protein, human
  • Multifunctional Enzymes
  • Proteins
  • Purine Nucleotides
  • Purines
  • Adenosine Deaminase
  • Adenine
  • Adenosine