Structure of mouse cytosolic sulfotransferase SULT2A8 provides insight into sulfonation of 7α-hydroxyl bile acids
| Autor: | Susanna S.T. Lee, Wing-Tai Cheung, Lu Feng, Kai Wang, Xing Liu, Yan-Chun Chan, Shannon Wing-Ngor Au, Pui-Kin So |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Sulfotransferase Lithocholic acid mSULT2A8 medicine.drug_class SULT sulfotransferase PAP adenosine 3’ 5’-diphosphate sulfotransferase QD415-436 030204 cardiovascular system & hematology liver Biochemistry Cofactor 7-hydroxyl Enzyme catalysis Bile Acids and Salts PB 3’-phosphate binding 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Endocrinology Protein structure Na CDC sodium chenodeoxycholate GST glutathione-S-transferase homeostasis medicine protein structure LCA lithocholic acid sulfonation X-ray crystallography CA cholic acid Bile acid biology bile acid metabolism Cholic acid Substrate (chemistry) PAPS 3’-phosphoadenosine-5’-phosphosulfate Cell Biology Na C sodium cholate Tm transition midpoint Na T-C sodium taurocholate 030104 developmental biology chemistry PSB 5’-phosphate-sulfate binding biology.protein DHEA dehydroepiandrosterone OH hydroxyl Research Article |
| Zdroj: | Journal of Lipid Research, Vol 62, Iss, Pp 100074-(2021) Journal of Lipid Research |
| ISSN: | 0022-2275 |
| DOI: | 10.1016/j.jlr.2021.100074 |
| Popis: | Cytosolic sulfotransferases (SULTs) catalyze the transfer of a sulfonate group from the cofactor 3’-phosphoadenosine 5’-phosphosulfate to a hydroxyl (OH) containing substrate and play a critical role in the homeostasis of endogenous compounds, including hormones, neurotransmitters, and bile acids. In human, SULT2A1 sulfonates the 3-OH of bile acids; however, bile acid metabolism in mouse is dependent on a 7α-OH sulfonating SULT2A8 via unknown molecular mechanisms. In this study, the crystal structure of SULT2A8 in complex with adenosine 3’,5’-diphosphate and cholic acid was resolved at a resolution of 2.5 Å. Structural comparison with human SULT2A1 reveals different conformations of substrate binding loops. In addition, SULT2A8 possesses a unique substrate binding mode that positions the target 7α-OH of the bile acid close to the catalytic site. Furthermore, mapping of the critical residues by mutagenesis and enzyme activity assays further highlighted the importance of Lys44 and His48 for enzyme catalysis and Glu237 in loop 3 on substrate binding and stabilization. In addition, limited proteolysis and thermal shift assays suggested that the cofactor and substrates have protective roles in stabilizing SULT2A8 protein. Together, the findings unveil the structural basis of bile acid sulfonation targeting 7α-OH and shed light on the functional diversity of bile acid metabolism across species. |
| Databáze: | OpenAIRE |
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