Chemistry PhD Final Defense — Joelle Wu

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Title: The Pathway for Coenzyme M Biosynthesis in Bacteria

Abstract: Mercaptoethane sulfonate or coenzyme M (CoM) is the smallest known organic cofactor, and is most commonly associated with the methane forming step in all methanogenic archaea. It has also been found in a small number of bacteria capable of the metabolism of small organics. Although many of the steps for CoM biosynthesis in methanogenic archaea have been elucidated, a complete pathway for the biosynthesis of CoM in archaea or bacteria has not been reported. Here we present the complete CoM biosynthesis pathway in bacteria, revealing distinct chemical steps relative to CoM biosynthesis in methanogenic archaea. The existence of two unique pathways represents a profound instance of convergent evolution. The five-step pathway (XcbA-E) in bacteria involves addition of sulfite, elimination of vi phosphate, decarboxylation, thiolation, and reduction to affect the sequential conversion of phosphoenolpyruvate to CoM. Interestingly, the bacterial CoM biosynthetic pathway has evolved from members of large aspartase/fumarase and pyridoxal 5’-phosphate-dependent enzyme families. XcbC and XcbD enzymes belong to aspartase/fumarase superfamily (AFS), and catalyze the phosphate elimination reaction of phosphosulfolactate to yield sulfoacrylic acid and the β-addition reaction of cysteine on sulfoacrylic acid to produce 3-sulfo propionyl cysteine, respectively. It is intriguing that both reactions have never been reported in this family before, suggesting both XcbC and XcbD catalyze unique reactions and represent new members of this enzyme family. Moreover, both XcbC and XcbD require discrimination of sulfonate moiety from carboxylate moiety, indicating both enzymes can recognize and place substrates in the proper orientation. With this work, we have made significant strides toward understanding bacterial CoM biosynthesis, which has evaded characterization in previous years.