FAMIN is a multifunctional purine enzyme enabling the purine nucleotide cycle
Accepted version
Peer-reviewed
Repository URI
Repository DOI
Type
Change log
Authors
Abstract
Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases 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 paralogues 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 synchronises mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H+ and phosphate recycling.
Description
Keywords
Journal Title
Conference Name
Journal ISSN
1097-4172
Volume Title
Publisher
Publisher DOI
Sponsorship
Wellcome Trust (103077/Z/13/Z)
Wellcome Trust (106260/Z/14/Z)
European Research Council (648889)
Wellcome Trust (101908/Z/13/Z)
Academy of Medical Sciences (SGL018/1119)
Wellcome Trust (105920/Z/14/Z)
Medical Research Council (MR/P011705/1)
Medical Research Council (MR/P01836X/1)
Wellcome Trust (217191/Z/19/Z)