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Effect of Sulfotransferase Structural Rearrangements in Fulvestrant Sulfation
Author(s) -
Falany Charles Napoleon,
Cook Ian T,
Kadlubar Susan A,
Leyh Thomas S
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.850.11
Subject(s) - sulfation , chemistry , sulfotransferase , enzyme , biochemistry , stereochemistry
Fulvestant (FUL) sulfation by SULTs 1A1 and 1E1 is influenced by structural rearrangements in the enzymes elicited by PAPS binding. FUL, a chemotherapeutic used to treat estrogen positive breast cancer, is sulfated by both isoforms in vitro; however, FUL sulfation in vivo may be modulated by PAPS levels. PAPS binding to the SULTs results in structural changes that significantly decrease the volume of the substrate binding pocket resulting in differential binding in the presence or absence of PAPS. FUL shows a random Bi‐Bi reaction mechanism with SULT1E1. In contrast, with SULT1A1 FUL displays an apparent ordered reaction mechanism with FUL binding first. FUL docked competently to SULT1E1 in the presence and absence of bound PAP. FUL docked to SULT1A1 only in the absence of PAPS. SULT1E1 bound FUL with a Kd of 0.2 μM in the presence or absence of PAP, whereas FUL bound SULT1A1 with a Kd of 2.4 μM in the absence of PAP and no binding was detectable in the presence of PAP. PAP was an uncompetitive inhibitor of FUL sulfation by SULT1A1 consistent with an ordered reaction mechanism. In summary, PAPS elicited structural changes in SULT1A1 and 1E1 may significantly affect the kinetics and apparent reaction mechanism of FUL sulfation suggesting that cellular PAPS levels may inhibit FUL sulfation in tissues with high SULT1A1 activity. Supported by PHS grants GM38953 to CNF and CA128897 to SAK.