8il7 | pdb_00008il7

Structure of human soluble Adenylyl Cyclase in complex with lactate

spinqualitylabelsall models 8il7, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8il7 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.95Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease ADCYA_HUMAN Idiopathic hypercalciuria. Disease susceptibility is associated with variations affecting the gene represented in this entry. Function ADCYA_HUMAN Soluble adenylyl cyclase that has a critical role in mammalian spermatogenesis. Produces the cAMP which mediates in part the cAMP-responsive nuclear factors indispensable for maturation of sperm in the epididymis. Induces capacitation, the maturational process that sperm undergo prior to fertilization. May be the bicarbonate sensor. Involved in ciliary beat regulation. Publication Abstract from PubMed 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. Lactate modulates iron metabolism by binding soluble adenylyl cyclase.,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 Cell Metab. 2023 Sep 5;35(9):1597-1612.e6. doi: 10.1016/j.cmet.2023.06.017. Epub , 2023 Jul 21. PMID:37480842 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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