Manganese Stimulation and Stereospecificity of the Dopa (3,4-Dihydroxyphenylalanine)/Tyrosine-sulfating Activity of Human Monoamine-form Phenol Sulfotransferase

Pai, Tongkun; Ohkimoto, Kei; Sakakibara, Yoichi; Suiko, Masahito; Sugahara, Takuya; Liu, Ming‐Cheh

doi:10.1074/jbc.m200785200

Cited by 11 publications

(17 citation statements)

References 42 publications

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“…In contrast to the dopaminesulfating activity, the Dopa/tyrosine-sulfating activity can be stimulated much more dramatically by Mn 2ϩ and, intriguingly, displays stereospecificity for the D-form Dopa/tyrosine enantiomers (13). As discussed before, our recent kinetic studies (15) suggested that Dopa and tyrosine form complexes with Mn 2ϩ (the pH dependence of the reaction forming the complex may explain the different pH optimum for the Dopa/tyrosine-sulfating activity compared with that for the dopamine sulfation, which does not involve such a complex) that serve either as the obligatory (in the case of tyrosine) or as a better (in the case of Dopa) substrate. The log K for the formation of the tyrosineMn 2ϩ complex is 1.5, whereas that for the tyrosine-Mn 2ϩ -tyrosine complex is 5.0 (30, 31).…”

Section: Resultsmentioning

confidence: 78%

“…1B) for their sulfation activities toward the Dopa and tyrosine enantiomers, in the presence or absence of Mn 2ϩ . Our previous kinetic studies (15) had confirmed that Mn 2ϩ could stimulate dramatically the sulfation activity of wild-type SULT1A3 toward the tyrosine enantiomers. Mn 2ϩ , when added at a 5 mM concentration to the assay mixture, stimulated the sulfation activity of SULT1A3 toward D-tyrosine by two orders of magnitude in comparison with the basal activity determined without Mn 2ϩ , whereas the activity toward L-tyrosine was stimulated about ten times (15).…”

Section: Differential Roles Of Variable Regions I and Ii Of Sult1a3 Imentioning

confidence: 76%

“…Our previous kinetic studies (15) had confirmed that Mn 2ϩ could stimulate dramatically the sulfation activity of wild-type SULT1A3 toward the tyrosine enantiomers. Mn 2ϩ , when added at a 5 mM concentration to the assay mixture, stimulated the sulfation activity of SULT1A3 toward D-tyrosine by two orders of magnitude in comparison with the basal activity determined without Mn 2ϩ , whereas the activity toward L-tyrosine was stimulated about ten times (15). The same assay conditions were used to evaluate the stimulatory effect of Mn 2ϩ on the sulfation activities of wild-type SULT1A3 and SULT1A1 and their various chimeras.…”

Section: Differential Roles Of Variable Regions I and Ii Of Sult1a3 Imentioning

confidence: 76%

“…The sulfating activity toward dopamine, which presumably helps to regulate the levels of this endogenous compound, has a pH optimum of ϳ7.0 and a K m of 2 M (in the physiological range) (14,28). Mn 2ϩ stimulated this activity to a comparatively smaller extent (ϳ2-to 3-fold) (13) but appeared to increase the K m for dopamine slightly (15). The Dopa/tyrosine-sulfating activity of SULT1A3, on the other hand, has the hallmarks of a detoxifying activity, with a pH optimum between 8 and 9 (29) and a K m (if we consider the substrate rather than substrate-Mn 2ϩ complex) in the millimolar or sub-millimolar range (7,13).…”

Section: Resultsmentioning

confidence: 99%

“…SULT1A3 is present as a homodimer in its native state (14). Kinetic studies of the Dopa/tyrosine-sulfating activity of SULT1A3 (15) suggested that, in the case of D-tyrosine, where a 4-hydroxyphenyl group is to be sulfated, the tyrosineMn 2ϩ and tyrosine-Mn 2ϩ -tyrosine complexes may be the real and obligatory substrates. In the case of D-Dopa, where we had shown that sulfation takes place exclusively at the 3-hydroxyphenyl group (16), the substrate-Mn 2ϩ complexes appeared to be better substrates than D-Dopa.…”

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confidence: 99%

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Structure-Function Relationships in the Stereospecific and Manganese-dependent 3,4-Dihydroxyphenylalanine/ Tyrosine-sulfating Activity of Human Monoamine-form Phenol Sulfotransferase, SULT1A3

Pai

Oxendine

Sugahara

et al. 2003

Journal of Biological Chemistry

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The human monoamine-form phenol sulfotransferase (PST), SULT1A3, has a unique 3,4-dihydroxyphenylalanine (Dopa)/tyrosine-sulfating activity that is stereospecific for their D-form enantiomers and can be stimulated dramatically by Mn 2؉ . This activity is not present in the simple phenol-form PST, SULT1A1, which is otherwise >93% identical to SULT1A3 in amino acid sequence. The majority of the differences between these two proteins reside in two variable regions of their sequences. Through the characterization of chimeric PSTs where these two regions were exchanged between them, it was demonstrated that variable Region II of SULT1A3 is required for the stereospecificity of its Dopa/tyrosine-sulfating activity, whereas variable Region I of SULT1A3 is required for the stimulation by Mn 2؉ of this activity. Further studies using point-mutated SULT1A3s mutated at amino acid residues in these two regions and deletional mutants missing residues 84 -86 and 84 -90 implicate residue Glu-146 (in variable Region II of SULT1A3), as well as the presence of residues 84 -90 of variable Region I, in the stereospecificity in the absence of Mn 2؉ . Residue Asp-86 (in variable Region I of SULT1A3), on the other hand, is critical in the Mn 2؉ stimulation of the Dopa/tyrosine-sulfating activity of SULT1A3. A model is proposed, with reference to the reported x-ray crystal structure of SULT1A3, to explain how the normal role of SULT1A3 in dopamine regulation may be subverted in the presence of Mn 2؉ . These studies could be relevant in understanding the stereoselective action of SULT1A3 on chiral drugs.The sulfotransferases (STs), 1 which are ubiquitous in both plants and animals, catalyze the sulfation of hydroxyl or amino groups on a variety of target acceptor molecules (1, 2). These enzymes all use adenosine 3Ј-phosphate,5Ј-phosphosulfate (PAPS) as the sulfonyl group donor (3) and share sequences responsible for PAPS binding (4). Although the membranebound STs use proteins, glycolipids, and other macromolecules as acceptor substrates, the cytosolic STs sulfate smaller molecules and are part of the Phase II detoxification pathway for the biotransformation/excretion of drugs and xenobiotics (1, 2). Increasingly, the cytosolic STs have also been shown to be important in regulating the levels and/or activities of endogenous compounds such as thyroid and steroid hormones, catecholamines, and bile acids (5, 6).Based on their sequences, the cytosolic STs have been classified into several gene families (4). Two human cytosolic STs, the monoamine-form and the simple phenol-form phenol sulfotransferases, named SULT1A3 and SULT1A1, respectively (4), show an extensive (Ͼ93%) identity in their amino acid sequences (cf. Fig. 1A) and yet vary widely in their substrate specificity and other properties (7-9). They have thus served as an ideal model system to study structure/function relationships in these proteins. Examination of their aligned sequences revealed that most of the differences between SULT1A3 and SULT1A1 occur in two variable regions, ...

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Section: Resultsmentioning

confidence: 78%

Section: Differential Roles Of Variable Regions I and Ii Of Sult1a3 Imentioning

confidence: 76%

Section: Differential Roles Of Variable Regions I and Ii Of Sult1a3 Imentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Structure-Function Relationships in the Stereospecific and Manganese-dependent 3,4-Dihydroxyphenylalanine/ Tyrosine-sulfating Activity of Human Monoamine-form Phenol Sulfotransferase, SULT1A3

Pai

Oxendine

Sugahara

et al. 2003

Journal of Biological Chemistry

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Sulfotransferases

Ma¹,

Schrag²

2012

Encyclopedia of Drug Metabolism and Interactions

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The sulfotransferases (SULTs) are a family of phase II enzymes that catalyze the transfer of a sulfonate group (‐SO 3− ) from the cofactor 3′‐phosphoadenosine‐5′‐phosphosulfate (PAPS) to an acceptor molecule or substrate. Since these enzymes can conjugate with a wide variety of xenobiotics and endogenous substrates, they function not only as drug‐metabolizing enzymes but also modulators of physiological activities through conjugations of endogenous molecules such as steroids, catecholamines, and thyroid hormones. This chapter aims to provide drug metabolism scientists with an introductory overview on various aspects of SULTs along with challenges and complications associated with SULT‐mediated biotransformations, particularly encountered during the drug discovery and development process. In recent years, commercially available hepatocyte preparations and recombinant SULT enzymes facilitate the determination of SULT involvement for compounds of interest. However, significant challenges do remain. For example, when conducting reaction‐phenotyping experiments for SULT‐catalyzed conjugations, there is currently a lack of well‐characterized isoform‐specific probe substrates and inhibitors, in addition to a lack of well‐established in vitro incubation conditions. Kinetic experiments, too, often require careful interpretation, as profound substrate inhibition is rather common for sulfation reactions. From the toxicology stand‐point, sulfation may pose liability concerns due to the potential formation of reactive electron‐deficient metabolite species. It is recommended that investigators should take the time to explore and understand the properties of SULT‐mediated conjugations and their implications.

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Aryl sulfotransferase

Springer Handbook of Enzymes

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Manganese Stimulation and Stereospecificity of the Dopa (3,4-Dihydroxyphenylalanine)/Tyrosine-sulfating Activity of Human Monoamine-form Phenol Sulfotransferase

Cited by 11 publications

References 42 publications

Structure-Function Relationships in the Stereospecific and Manganese-dependent 3,4-Dihydroxyphenylalanine/ Tyrosine-sulfating Activity of Human Monoamine-form Phenol Sulfotransferase, SULT1A3

Structure-Function Relationships in the Stereospecific and Manganese-dependent 3,4-Dihydroxyphenylalanine/ Tyrosine-sulfating Activity of Human Monoamine-form Phenol Sulfotransferase, SULT1A3

Sulfotransferases

Aryl sulfotransferase

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