Glycerol-driven TNAP activation in thermogenesis and mineralization
. Despite TNAP's broad physiological roles, endogenous regulators of its activity have not been defined. Furthermore, the activation mechanism of UCP1-independent thermogenesis has remained unresolved. Here we identify glycerol as an allosteric activator of TNAP. Glycerol binds to a surface pocket distal to the active site, which we term the glycerol pocket, to enhance TNAP activity. Using biophysical, structural, bioenergetic and physiological approaches, we show that the glycerol pocket is required for TNAP-driven thermogenesis. Through this mechanism, TNAP activates the futile creatine cycle, acting as a physiological complement to UCP1. The glycerol pocket is likewise required for optimal osteoblast-regulated mineralization. Human missense variants in this site reduce TNAP-dependent mineralization in vitro and are associated with lower alkaline phosphatase activity and bone mineral density, providing genetic evidence that its disruption impairs skeletal physiology.
Authors
- Jakub Bunk
- Victoria DeMambro (ORCID: https://orcid.org/0000-0002-4557-461X)
- Alba Guarné (ORCID: https://orcid.org/0000-0003-4906-9132)
- Mohammed Faiz Hussain (ORCID: https://orcid.org/0009-0006-9573-1069)
- Janane F. Rahbani (ORCID: https://orcid.org/0000-0003-4598-4683)
- Lawrence Kazak (ORCID: https://orcid.org/0000-0002-7591-2544)
- José Luís Millán (ORCID: https://orcid.org/0000-0002-1547-2671)
- Marc D. McKee (ORCID: https://orcid.org/0000-0001-8349-965X)
- Abel Oppong (ORCID: https://orcid.org/0000-0002-8006-1537)
- Abhirup Shaw (ORCID: https://orcid.org/0000-0003-3390-3364)
- Claudia Langenberg (ORCID: https://orcid.org/0000-0002-5017-7344)
- Alice Williamson (ORCID: https://orcid.org/0000-0002-7599-9301)
- Aisha Mousa
- Bindu Y. Srinivasu (ORCID: https://orcid.org/0000-0003-0875-2680)
- Bożena Samborska (ORCID: https://orcid.org/0000-0002-1871-4699)
- Thomas E. Wales (ORCID: https://orcid.org/0000-0001-6133-5689)
- Brittany L. Carroll (ORCID: https://orcid.org/0000-0002-4199-7762)
- Zafir Kaiser
- Maria Delgado-Martin
- Qiaoqiao Zhang (ORCID: https://orcid.org/0009-0001-0132-5398)
- Shreya S Krishnan
- Hannah Klemets
- Anna Roesler
- Clifford J. Rosen
- Jonathan Cheng (ORCID: https://orcid.org/0000-0001-7611-7801)
- Katalin Kocsis Illes
- Maria Guerra Martinez
- Mina Ersin
Institutions
- Northeastern University (US)
- Queen Mary University of London (GB)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Discovery Institute (US)
- University of Chicago (US)
- MaineHealth (US)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Max Planck Institute for Molecular Genetics (DE)
- McGill University (CA)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Nature
- Published
- 2026-04-22
- DOI
- https://doi.org/10.1038/s41586-026-10396-9
- Primary Topic
- Alkaline Phosphatase Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00