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Design and Interpretation of Human Sulfotransferase 1A1 Assays.

ABSTRACT: The human sulfotransferases (SULTs) regulate the activities of hundreds, if not thousands, of small molecule metabolites via transfer of the sulfuryl-moiety (-SO3) from the nucleotide donor, 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to the hydroxyls and amines of the recipients. Our understanding of the molecular basis of SULT catalysis has expanded considerably in recent years. The basic kinetic mechanism of these enzymes, previously thought to be ordered, has been redefined as random for SULT2A1, a representative member of the superfamily. An active-site cap whose structure and dynamics are highly responsive to nucleotides was discovered and shown to be critical in determining SULT selectivity, a topic of longstanding interest to the field. We now realize that a given SULT can operate in two specificity modes-broad and narrow-depending on the disposition of the cap. More recent work has revealed that the caps of the SULT1A1 are controlled by homotropic allosteric interactions between PAPS molecules bound at the dimer's active sites. These interactions cause the catalytic efficiency of SULT1A1 to vary in a substrate-dependent fashion by as much as two orders of magnitude over a range of PAPS concentrations that spans those found in human tissues. SULT catalysis is further complicated by the fact that these enzymes are frequently inhibited by their substrates. This review provides an overview of the mechanistic features of SULT1A1 that are important for the design and interpretation of SULT1A1 assays.

SUBMITTER: Wang T

PROVIDER: S-EPMC4810762 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Design and Interpretation of Human Sulfotransferase 1A1 Assays.

Wang Ting T Cook Ian I Leyh Thomas S TS

Drug metabolism and disposition: the biological fate of chemicals 20151209 4

The human sulfotransferases (SULTs) regulate the activities of hundreds, if not thousands, of small molecule metabolites via transfer of the sulfuryl-moiety (-SO3) from the nucleotide donor, 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to the hydroxyls and amines of the recipients. Our understanding of the molecular basis of SULT catalysis has expanded considerably in recent years. The basic kinetic mechanism of these enzymes, previously thought to be ordered, has been redefined as random for SU ...[more]

PMID: 26658224

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Project description:BACKGROUND:Sulfotransferase 1A1 (SULT1A1) gene expression is tissue specific, with little to no expression in normal breast epithelia. Expression in breast tumors has been documented, but the transcriptional regulation of SULT1A1 in human breast tissue is poorly understood. We identified Nuclear Factor I (NFI) as a transcription factor family involved in the regulation of SULT1A1 expression. METHODS:Transcription Factor Activation Profiling Plate Array assay was used to identify the possible transcription factors that regulate the gene expression of SULT1A1in normal breast MCF-10A cells and breast cancer ZR-75-1 cells. Expression levels of NFI-C and SULT1A1 were determined by real-time RT-PCR using total RNA isolated from 84 human liver samples. Expression levels of SULT1A1, NFI-A, NFI-B, NFI-C, and NFI-X were also determined in different human breast cancer cell lines (MCF-7, T-47D, ZR-75-1, and MDA-MB-231), in the transformed human epithelial cell line MCF-10A, and in ZR-75-1 cells that were transfected with siRNAs directed against NFI-A, NFI-B, NFI-C, or NFI-X for 48 h. The copy numbers of SULT1A1 in cell lines ZR-75-1, MCF-7, T-47D, MDA-MB-231, and MCF-10A were determined using a pre-designed Custom Plus TaqMan® Copy Number kit from Life Technologies. RESULTS:In normal human liver samples, SULT1A1 mRNA level was positively associated with NFI-C. In different human breast cancer and normal epithelial cell lines, SULT1A1 expression was positively correlated with NFI-B and NFI-C. SULT1A1 expression was decreased 41% and 61% in ZR-75-1 cells treated with siRNAs against NFI-A and NFI-C respectively. SULT1A1 gene expression was higher in cells containing more than one SULT1A1 copy numbers. CONCLUSIONS:Our data suggests that SULT1A1 expression is regulated by NFI, as well as SULT1A1 copy number variation in human breast cancer cell lines. These data provide a mechanistic basis for the differential expression of SULT1A1 in different tissues and different physiological states of disease.

Dataset Information

Design and Interpretation of Human Sulfotransferase 1A1 Assays.

Publications

Design and Interpretation of Human Sulfotransferase 1A1 Assays.

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