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Title: Structure of mouse cytosolic sulfotransferase SULT2A8 provides insight into sulfonation of 7α-hydroxyl bile acids
Authors: Wang, K
Chan, YC
So, PK 
Liu, X
Feng, L
Cheung, WT
Lee, SST
Au, SWN
Issue Date: 2021
Source: Journal of lipid research, 2021, v. 62, 100074
Abstract: 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.
Keywords: 7-hydroxyl
Bile acid metabolism
Homeostasis
Liver
MSULT2A8
Protein structure
Sulfonation
Sulfotransferase
X-ray crystallography
Publisher: Elsevier Inc.
Journal: Journal of lipid research 
ISSN: 0022-2275
EISSN: 1539-7262
DOI: 10.1016/J.JLR.2021.100074
Rights: © 2021 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
The following publication Wang, K., Chan, Y. C., So, P. K., Liu, X., Feng, L., Cheung, W. T., ... & Au, S. W. N. (2021). Structure of mouse cytosolic sulfotransferase SULT2A8 provides insight into sulfonation of 7α-hydroxyl bile acids. Journal of lipid research, 62 is available at https://doi.org/10.1016/J.JLR.2021.100074
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