Enantioselective sulfation of β2‐receptor agonists by the human intestine and the recombinant M‐form phenolsulfotransferase

Hartman, Andrew P.; Wilson, Anne A.; Wilson, Hugh M.; Åberg, Gunnar; Falany, Charles N.; Walle, Thomas

doi:10.1002/(sici)1520-636x(1998)10:9<800::aid-chir4>3.3.co;2-m

Cited by 3 publications

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“…For these reasons, we considered it significant to determine the substrate enantioselectivity of the sulfonation of normetanephrine enantiomers by SULT1A3 and find out whether their substitution by the racemic sulfated calibrator we previously described does or does not influence the results. [9][10][11][12][13][14] Extrapolating from the existing literature, we therefore expected the sulfoconjugation of synthetic (1R)normetanephrine and (1S)-normetanephrine to be notably enantioselective and used recombinant human SULT1A3 to challenge this hypothesis. 6 The important role of Glu146 in the substrate specificity of SULT1A3 was demonstrated, 7,8 and the crystal structure of SULT1A3-PAPS-ligand complexes confirmed that residues Glu146 and Asp86 are crucial to the L-DOPA/tyrosinesulfonating activity of SULT1A3 and play also a role in the stereoselectivity of the reaction.…”

Section: Introductionmentioning

confidence: 99%

Lack of Enantioselectivity in the SULT1A3‐catalyzed Sulfoconjugation of Normetanephrine Enantiomers: An In Vitro and Computational Study

et al. 2012

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(1R)-Normetanephrine is the natural stereoisomeric substrate for sulfotransferase 1A3 (SULT1A3)-catalyzed sulfonation. Nothing appears known on the enantioselectivity of the reaction despite its potential significance in the metabolism of adrenergic amines and in clinical biochemistry. We confronted the kinetic parameters of the sulfoconjugation of synthetic (1R)-normetanephrine and (1S)-normetanephrine by recombinant human SULT1A3 to a docking model of each normetanephrine enantiomer with SULT1A3 and the 3'-phosphoadenosine-5'-phosphosulfate cofactor on the basis of molecular modeling and molecular dynamics simulations of the stability of the complexes. The K(M), V(max), and k(cat) values for the sulfonation of (1R)-normetanephrine, (1S)-normetanephrine, and racemic normetanephrine were similar. In silico models were consistent with these findings as they showed that the binding modes of the two enantiomers were almost identical. In conclusion, SULT1A3 is not substrate-enantioselective toward normetanephrine, an unexpected finding explainable by a mutual adaptability between the ligands and SULT1A3 through an "induced-fit model" in the catalytic pocket.

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Section: Introductionmentioning

confidence: 99%

Lack of Enantioselectivity in the SULT1A3‐catalyzed Sulfoconjugation of Normetanephrine Enantiomers: An In Vitro and Computational Study

et al. 2012

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“…Sulfation catalyzed by aryl (phenol) sulfotransferases is a significant route of conjugation for a wide variety of drugs and their hydroxylated metabolites. Characteristic examples include the sulfation of acetaminophen, , isoproterenol, 4-hydroxypropranolol, minoxidil, , albuterol, and many others.…”

Section: Introductionmentioning

confidence: 99%

Comparative Molecular Field Analysis of Substrates for an Aryl Sulfotransferase Based on Catalytic Mechanism and Protein Homology Modeling

Sharma

Duffel

2002

J. Med. Chem.

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Comparative Molecular Field Analysis (CoMFA) methods were used to produce a 3D-QSAR model that correlated the catalytic efficiency of rat hepatic aryl sulfotransferase (AST) IV, expressed as log(k(cat)/K(m)), with the molecular structures of its substrates. A total of 35 substrate molecules were used to construct a CoMFA model that was evaluated on the basis of its leave-one-out cross-validated partial least-squares value (q(2)) and its ability to predict the activity of six additional substrates not used in the training set. The model was constructed using substrate conformations that favored (1) proton abstraction by the catalytic histidine residue, (2) an in-line sulfuryl-group transfer mechanism, and (3) constraints imposed by the residues lining the substrate binding pocket of a homology model of AST IV. This CoMFA model had a q(2) value of 0.691, and it successfully predicted the activities of the six molecules not used in the training set. A final CoMFA model was constructed using the same methodology but with molecules from both the training set and the test set. Its q(2) value was 0.701, and it had a non-cross-validated r(2) value of 0.922. The contour coefficient map generated by this CoMFA was overlaid on the amino acids in the substrate-binding pocket of the homology model of AST IV and found to show a good fit. Additionally external validation was obtained by using the CoMFA model to design substrates that show high activities. These results establish a methodology for prediction of the substrate specificity of this sulfotransferase based on CoMFA methods that are guided by both the homology model and the catalytic mechanism of the enzyme.

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“…Both R-and S-enantiomers are metabolised by sulfotransferases, mainly in the gut and liver (Walle et al 1996); (Hartman et al 1998) to inactive metabolites. Sulfotransferases work more effectively with the R-enantiomer, hence the bioavailability of S-isomer by far exceeds that of the R-enantiomer, resulting in S-to R-salbutamol ratio in plasma exceeding one after administration to human beings.…”

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Metabolism of Salbutamol Differs between Asthmatic Patients and Healthy Volunteers

Sjöswärd¹,

Josefsson²,

Ahlner³

et al. 2003

Pharmacology & Toxicology

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Patients with asthma are a target group for medication with b2-agonists, often in combination with corticosteroids. Salbutamol is commonly marketed as racemate. R-Salbutamol carries b2-agonistic property whereas S-salbutamol does not. The racemate undergoes stereoselective sulphatisation by sulfotransferases mainly in the gut and liver, so that S-salbutamol rests for a longer time in the body and reaches higher plasma levels than R-salbutamol. Ten patients with mild stable asthma and at present without cortisone medication were given racemic salbutamol as ventoline 4 mg orally. Plasma and urine levels were estimated until 24 hr after ingestion. For comparison healthy volunteers were treated in the same way.The group of asthma patients was then treated with budesonide inhalations 800 mg daily for one week and the initial programme resumed. Non-cortisone-treated asthmatic patients displayed higher levels of both R-and S-salbutamol in plasma than did healthy volunteers after one single ingestion of racemic salbutamol (CMAX both comparisons PϽ0.05). Plasma levels of salbutamol isomers in cortisone-treated asthmatic patients resembled the levels in volunteers. The most plausible explanation for the discrepancy in values between asthmatic patients and volunteers is a defective metabolic function by asthmatic patients possibly enzymatic in origin.Racemic R,S salbutamol is used to relieve bronchial constriction, the b2-agonist effect being mediated by the Renantiomer. S-Salbutamol may also have a pharmacological effect, but distinctly different from that of R-salbutamol. In vitro experiments have indicated increased production of histamine in mast cells following S-salbutamol (Cho et al. 2001) and furthermore, increase of intracellular Ca 2π by muscarinic receptor activation has been shown in connection with the S-enantiomer (Mitra et al. 1998). The latter effect may be a possible link to enhanced bronchial hyperresponsiveness, suggested to occur after regular treatment with salbutamol in asthmatic patients, and suspected to be associated with the presence of S-salbutamol (Nelson 1999).Previous studies have shown a distinct stereoselective metabolism. Both R-and S-enantiomers are metabolised by sulfotransferases, mainly in the gut and liver (Walle et al. 1996);(Hartman et al. 1998) to inactive metabolites. Sulfotransferases work more effectively with the R-enantiomer, hence the bioavailability of S-isomer by far exceeds that of the R-enantiomer, resulting in S-to R-salbutamol ratio in plasma exceeding one after administration to human beings. Racemisation in the stomach accounts for a small degree (6%) of interconversion (Boulton & Fawcett 2001).Although a limited number of pharmacokinetic studies has been performed in asthmatic patients, most pharmacokinetic studies have been conducted on healthy volunteers. It seems more appropriate though, to study a target popula-

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Enantioselective sulfation of β2‐receptor agonists by the human intestine and the recombinant M‐form phenolsulfotransferase

Cited by 3 publications

References 0 publications

Lack of Enantioselectivity in the SULT1A3‐catalyzed Sulfoconjugation of Normetanephrine Enantiomers: An In Vitro and Computational Study

Lack of Enantioselectivity in the SULT1A3‐catalyzed Sulfoconjugation of Normetanephrine Enantiomers: An In Vitro and Computational Study

Comparative Molecular Field Analysis of Substrates for an Aryl Sulfotransferase Based on Catalytic Mechanism and Protein Homology Modeling

Metabolism of Salbutamol Differs between Asthmatic Patients and Healthy Volunteers

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