Enzymatic conversion of the antibiotic metronidazole to an analog of thiamine.
We propose that adverse effects of the antibiotic metronidazole may be due, wholly or in part, to its conversion to a thiamine analog and consequent vitamin B1 antagonism. Consistent with this hypothesis, the drug is accepted as a substrate for the thiaminase (EC 2.5.1.2) elaborated as an exoenzyme by the human gut flora constituent Bacillus thiaminolyticus and is also a substrate for the intracellular thiaminase of the mollusk Venus mercenaria. The product, identified as the 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-hydroxyethyl)-2-methyl-4 - nitroimidazolium cation, is a close structural analog of thiamine and is an effective inhibitor of thiamine pyrophosphokinase in vitro. Due to its susceptibility to nucleophilic attack, the analog is unstable, releasing inorganic nitrite under mild conditions. Enzymatic alkylation reactions such as that effected by thiaminase may have general pharmacological significance as a route of increasing the electrophilicity and/or reduction potential of drugs which are heterocyclic weak bases.
Alston
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Graduate Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02254.
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D000818:Animals; D001407:Bacillus / Q000378:metabolism*; D001711:Biotransformation; D049872:Bivalvia / Q000201:enzymology; D006867:Hydrolases / Q000378:metabolism*; D008795:Metronidazole / Q000378:metabolism*; D010770:Phosphotransferases / Q000037:antagonists & inhibitors; D017856:Phosphotransferases (Phosphate Group Acceptor); D013831:Thiamine / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology
C053664:1-((4-amino-2-methyl-5-pyrimidinyl)methyl)-3-(2-hydroxyethyl)-2-methyl-4-nitroimidazolium; D008795:Metronidazole; D010770:Phosphotransferases; D017856:Phosphotransferases (Phosphate Group Acceptor); C022733:thiamin-diphosphate kinase; D006867:Hydrolases; C022731:thiaminase II; D013831:Thiamine