麦吉尔大学Lawrence Kazak小组的最新研究提出了甘油驱动的TNAP在产热和矿化中的激活。这一研究成果发表在2026年4月22日出版的国际学术期刊《自然》上。

在这里，课题组人员确定甘油是TNAP的变构激活剂。甘油与活性位点远端的表面袋结合，该研究组称之为甘油袋，以增强TNAP的活性。利用生物物理、结构、生物能量和生理学的方法，该研究组发现甘油袋是TNAP驱动的产热所必需的。通过这种机制，TNAP激活无效肌酸循环，作为UCP1的生理补充。甘油袋同样需要最佳的成骨细胞调节矿化。该位点的人类错义变异在体外降低了TNAP依赖性矿化，并与较低的碱性磷酸酶活性和骨矿物质密度相关，这为其破坏损害骨骼生理提供了遗传证据。

据了解，组织非特异性碱性磷酸酶（TNAP）通过水解焦磷酸促进骨骼矿化，并通过磷酸肌酸水解的无效肌酸循环与解偶联蛋白1 （UCP1）无关的脂肪细胞产热有关。尽管TNAP具有广泛的生理作用，但其活性的内源性调节因子尚未明确。此外，不依赖UCP1的产热作用的激活机制仍未得到解决。

附：英文原文

Title: Glycerol-driven TNAP activation in thermogenesis and mineralization

Author: Hussain, Mohammed Faiz, Krishnan, Shreya S., Carroll, Brittany L., Samborska, Bozena, Mousa, Aisha, Williamson, Alice, Delgado-Martin, Maria, Srinivasu, Bindu Y., Bunk, Jakub, Rahbani, Janane F., Oppong, Abel, Roesler, Anna, Kaiser, Zafir, Ersin, Mina, Zhang, Qiaoqiao, Guerra Martinez, Maria, Shaw, Abhirup, Cheng, Jonathan, Klemets, Hannah, Illes, Katalin Kocsis, DeMambro, Victoria E., Rosen, Clifford J., Milln, Jos Luis, Wales, Thomas E., Langenberg, Claudia, McKee, Marc D., Guarn, Alba, Kazak, Lawrence

Issue&Volume: 2026-04-22

Abstract: Tissue-nonspecific alkaline phosphatase (TNAP) promotes skeletal mineralization by hydrolysing pyrophosphate1 and has been linked to uncoupling protein 1 (UCP1)-independent adipocyte thermogenesis through the futile creatine cycle through phosphocreatine hydrolysis2,3. 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.

DOI: 10.1038/s41586-026-10396-9

Source: https://www.nature.com/articles/s41586-026-10396-9