Cell
Volume 180, Issue 2, 23 January 2020, Pages 278-295.e23
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Article
FAMIN Is a Multifunctional Purine Enzyme Enabling the Purine Nucleotide Cycle

https://doi.org/10.1016/j.cell.2019.12.017Get rights and content
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Highlights

  • An unbiased LC-MS screen reveals FAMIN as a purine nucleoside enzyme

  • FAMIN combines adenosine phosphorylase with ADA-, PNP-, and MTAP-like activities

  • FAMIN enables a purine nucleotide cycle (PNC) preventing cytoplasmic acidification

  • The FAMIN-dependent PNC balances the glycolysis-mitochondrial redox interface

Summary

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

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

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These authors contributed equally

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