Identifying androsterone (ADT) as a cognate substrate for human dehydroepiandrosterone sulfotransferase (DHEA-ST) important for steroid homeostasis: structure of the enzyme-ADT complex.
In steroid biosynthesis, human dehydroepiandrosterone sulfotransferase (DHEA-ST) in the adrenals has been reported to catalyze the transfer of the sulfonate group from 3'-phosphoadenosine-5'-phosphosulfate to dehydroepiandrosterone (DHEA). DHEA and its sulfate play roles as steroid precursors; however, the role of the enzyme in the catabolism of androgens is poorly understood. Androsterone sulfate is clinically recognized as one of the major androgen metabolites found in urine. Here it is demonstrated that this enzyme recognizes androsterone (ADT) as a cognate substrate with similar kinetics but a 2-fold specificity and stronger substrate inhibition than DHEA. The structure of human DHEA-ST in complex with ADT has been solved at 2.7 A resolution, confirming ADT recognition. Structural analysis has revealed the binding mode of ADT differs from that of DHEA, despite the similarity of the overall structure between the ADT and the DHEA binary complexes. Our results identify that this human enzyme is an ADT sulfotransferase as well as a DHEA sulfotransferase, implying an important role in steroid homeostasis for the adrenals and liver.
Canadian Institutes of Health Research Group in Oncology and Molecular Endocrinology Laboratory, CHUL Research Center and Laval University, Sainte-Foy, Quebec G1V 4G2, Canada.
Ho-Jin
HJ
Chang
Rong
R
Shi
Peter
P
Rehse
Sheng-Xiang
SX
Lin
D000311:Adrenal Glands / Q000378:metabolism; D000738:Androsterone / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D015238:Sulfotransferases / Q000737:chemistry* / Q000378:metabolism
D000738:Androsterone; D015238:Sulfotransferases; C019998:dehydroepiandrosterone sulfotransferase