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PMID:12471039

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Citation

Gamage, NU, Duggleby, RG, Barnett, AC, Tresillian, M, Latham, CF, Liyou, NE, McManus, ME and Martin, JL (2003) Structure of a human carcinogen-converting enzyme, SULT1A1. Structural and kinetic implications of substrate inhibition. J. Biol. Chem. 278:7655-62

Abstract

Sulfonation catalyzed by sulfotransferase enzymes plays an important role in chemical defense mechanisms against various xenobiotics but also bioactivates carcinogens. A major human sulfotransferase, SULT1A1, metabolizes and/or bioactivates many endogenous compounds and is implicated in a range of cancers because of its ability to modify diverse promutagen and procarcinogen xenobiotics. The crystal structure of human SULT1A1 reported here is the first sulfotransferase structure complexed with a xenobiotic substrate. An unexpected finding is that the enzyme accommodates not one but two molecules of the xenobiotic model substrate p-nitrophenol in the active site. This result is supported by kinetic data for SULT1A1 that show substrate inhibition for this small xenobiotic. The extended active site of SULT1A1 is consistent with binding of diiodothyronine but cannot easily accommodate beta-estradiol, although both are known substrates. This observation, together with evidence for a disorder-order transition in SULT1A1, suggests that the active site is flexible and can adapt its architecture to accept diverse hydrophobic substrates with varying sizes, shapes and flexibility. Thus the crystal structure of SULT1A1 provides the molecular basis for substrate inhibition and reveals the first clues as to how the enzyme sulfonates a wide variety of lipophilic compounds.

Links

PubMed Online version:10.1074/jbc.M207246200

Keywords

Amino Acid Sequence; Arylsulfotransferase; Binding Sites; Carcinogens; Crystallography, X-Ray; DNA, Complementary/metabolism; Dose-Response Relationship, Drug; Humans; Kinetics; Ligands; Models, Chemical; Models, Molecular; Molecular Sequence Data; Protein Binding; Protein Conformation; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Substrate Specificity; Sulfotransferases/chemistry; Xenobiotics/pharmacology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ST1A1

involved_in

GO:0050427: 3'-phosphoadenosine 5'-phosphosulfate metabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ST1A1

enables

GO:0050656: 3'-phosphoadenosine 5'-phosphosulfate binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:ST2A1

enables

GO:0050656: 3'-phosphoadenosine 5'-phosphosulfate binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:ST1A1

enables

GO:0004062: aryl sulfotransferase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:ST1A1

involved_in

GO:0006805: xenobiotic metabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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