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. 2006 Oct;386(3):666-74.
doi: 10.1007/s00216-006-0495-1. Epub 2006 May 25.

Identification of sulfation sites of metabolites and prediction of the compounds' biological effects

Lin Yi  1 , Joe Dratter, Chao Wang, Jon A Tunge, Heather Desaire
Affiliations

Identification of sulfation sites of metabolites and prediction of the compounds' biological effects

Lin Yi et al. Anal Bioanal Chem. 2006 Oct.

Abstract

Characterizing the biological effects of metabolic transformations (or biotransformation) is one of the key steps in developing safe and effective pharmaceuticals. Sulfate conjugation, one of the major phase II biotransformations, is the focus of this study. While this biotransformation typically facilitates excretion of metabolites by making the compounds more water soluble, sulfation may also lead to bioactivation, producing carcinogenic products. The end result, excretion or bioactivation, depends on the structural features of the sulfation sites, so obtaining the structure of the sulfated metabolites is critically important. We describe herein a very simple, high-throughput procedure for using mass spectrometry to identify the structure-and thus the biological fate-of sulfated metabolites. We have chemically synthesized and analyzed libraries of compounds representing all the biologically relevant types of sulfation products, and using the mass spectral data, the structural features present in these analytes can be reliably determined, with a 97% success rate. This work represents the first example of a high-throughput analysis that can identify the structure of sulfated metabolites and predict their biological effects.

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Figures

Fig. 1
Fig. 1
Mechanism of forming bioactive carbocation or nitrenium ion intermediates from sulfated products. Substrates a, b and c undergo the bioactivation process while d–g do not. a sulfated benzylic alcohol; b sulfated allylic alcohol; c sulfated aromatic hydroxylamine; d) sulfated aliphatic alcohol; e sulfated phenol; f sulfated aliphatic amine; g sulfated aromatic amine
Fig. 2
Fig. 2
Structures of selected sulfated compounds a sulfated aromatic alcohols or enols; b sulfated aliphatic alcohols with β hydrogens on sp3carbons; c sulfated benzylic or allylic alcohols; d sulfated hydroxylamines; e sulfated amines
Fig. 3
Fig. 3
Characteristic (-) ESI-MS/MS data for compounds in this study: a sulfated aromatic alcohol, from group a; b sulfated aliphatic alcohol with β hydrogen on sp3carbon, from group b; c sulfated benzylic alcohol, from group c; d sulfated aliphatic hydroxylamine, from group d; e sulfated aromatic hydroxylamine, from group d; f sulfated aliphatic amine, from group e; g sulfated aromatic amine, from group e
Scheme 1
Scheme 1
Sulfated aromatic alcohols or enols (group a) dissociate to produce a characteristic ion with neutral loss of 80 Da. Group b: sulfated aliphatic alcohols with β hydrogens on sp3carbons
Scheme 2
Scheme 2
Sulfated aliphatic alcohols (group b) produce the characteristic ion m/z 97
Scheme 3
Scheme 3
Sulfated benzylic and allylic alcohols (group c) produce the characteristic ion m/z 96
Scheme 4
Scheme 4
Fragmentation mechanism producing m/z 97 from compound 16
Scheme 5
Scheme 5
Sulfated hydroxylamines (group d) produce the characteristic ion m/z 96
Scheme 6
Scheme 6
Fragmentation mechanism producing m/z 96 from compound 8
Scheme 7
Scheme 7
Sulfated amines (group e) produce the characteristic ion m/z 80
Fig. 4
Fig. 4
The method for characterizing unknown sulfated metabolites
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References

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    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PubMed', 'value': '9443165', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/9443165/'}]}
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