Abstract
Demethylases play a pivitol role in numerous biological processes from covalent histone modification and DNA repair to specialized metabolism in plants and microorganisms. Enzymes that catalyze O- and N-demethylation include 2-oxoglutarate (2OG)/Fe(II)-dependent dioxygenases, cytochromes P450, Rieske-domain proteins and flavin adenine dinucleotide (FAD)-dependent oxidases. Proposed mechanisms for demethylation by 2OG/Fe(II)-dependent enzymes involve hydroxylation at the O- or N-linked methyl group followed by formaldehyde elimination. Members of this enzyme family catalyze a wide variety of reactions in diverse plant metabolic pathways. Recently, we showed that 2OG/Fe(II)-dependent dioxygenases catalyze the unique O-demethylation steps of morphine biosynthesis in opium poppy, which provides a rational basis for the widespread occurrence of demethylases in benzylisoquinoline alkaloid metabolism.
Highlights
Demethylation is a key aspect of many diverse biological processes including epigenetic regulation, DNA repair, toxin degradation, and the metabolism of bioactive metabolites
SUMMARY AND PROSPECTS Enzymes that catalyze demethylation reactions belong to several different protein families including cytochromes P450, FADdependent oxidases, Rieske-domain proteins and others with non-heme irons centers
Of particular interest are 2OG/Fe(II)dependent dioxygenases owing to their capacity to catalyze the O- and N-demethylation of various substrates, and because of their diverse roles in plant metabolic pathways
Summary
Demethylation is a key aspect of many diverse biological processes including epigenetic regulation, DNA repair, toxin degradation, and the metabolism of bioactive metabolites. We showed that 2OG/Fe(II)-dependent dioxygenases catalyze the unique O-demethylation steps of morphine biosynthesis in opium poppy, which provides a rational basis for the widespread occurrence of demethylases in benzylisoquinoline alkaloid metabolism. Our recent isolation of thebaine 6-O-demethylase (T6ODM) and codeine O-demethylase (CODM) from opium poppy (Figure 1A) represent two of only a small number of plant enzymes capable of catalyzing an O-demethylation reaction (Hagel and Facchini, 2010).
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