8IL7

Structure of human soluble Adenylyl Cyclase in complex with lactate

Summary for 8IL7

• Entry DOI: 10.2210/pdb8il7/pdb
• Descriptor: Adenylate cyclase type 10, (2S)-2-HYDROXYPROPANOIC ACID, GLYCEROL, ... (4 entities in total)
• Functional Keywords: sac, lyase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 54636.02

Authors

Li, Q.J.,Li, Z.L.,Gao, P. (deposition date: 2023-03-02, release date: 2023-07-26, Last modification date: 2024-08-14)

Primary citation

Liu, W.,Zhang, S.,Li, Q.,Wu, Y.,Jia, X.,Feng, W.,Li, Z.,Shi, Y.,Hou, Q.,Ma, J.,Liu, Y.,Gao, P.,Ganz, T.,Liu, S.
Lactate modulates iron metabolism by binding soluble adenylyl cyclase.
Cell Metab., 35:1597-1612.e6, 2023

PubMed Abstract: Overproduction of lactate (LA) can occur during exercise and in many diseases such as cancers. Individuals with hyperlactatemia often display anemia, decreased serum iron, and elevated hepcidin, a key regulator of iron metabolism. However, it is unknown whether and how LA regulates hepcidin expression. Here, we show LA binds to soluble adenylyl cyclase (sAC) in normal hepatocytes and affects systemic iron homeostasis in mice by increasing hepcidin expression. Comprehensive in vitro, in vivo, and in silico experiments show that the LA-sAC interaction raises cyclic adenosine monophosphate (cAMP) levels, which activates the PKA-Smad1/5/8 signaling pathway to increase hepcidin transcription. We verified this regulatory axis in wild-type mice and in mice with disordered iron homeostasis. LA also regulates hepcidin in humans at rest and subjected to extensive exercise that produce elevated LA. Our study links hyperlactatemia to iron deficiency, offering a mechanistic explanation for anemias seen in athletes and patients with lactic acidosis.

PubMed: 37480842
DOI: 10.1016/j.cmet.2023.06.017

Experimental method

X-RAY DIFFRACTION (1.95 Å)