February 2011

Ruma V. Banerjee and Stephen W. Ragsdale: deciphering sulfur and carbon metabolism

Vitamin B12 is an essential cofactor that is both reactive and rare. Research in the Banerjee laboratory is revealing how an intricate network of proteins tailor and escort the vitamin from its point of entry to its target enzymes in cells.

Molecular traffic patterns

Banerjee, who also serves as a member of the American Society for Biochemistry and Molecular Biology council, has focused her efforts on looking at how sulfur enzymes operate in the framework of a network. “What are the traffic lights that govern the flow of sulfur to help furnish cells with some very important reagents?”

In recent years, her group has been particularly interested in the trafficking of vitamin B12, an essential vitamin that requires 30 dedicated enzymes to synthesize in bacteria. Although humans only have two B12-requiring enzymes, both of which support sulfur metabolism (methylmalonyl-CoA mutase and methionine synthase), this rare vitamin is extremely important for every cell, as evidenced by a complex protein network involved in B12 trafficking.

Banerjee’s group has been busy identifying and assigning functions to the genes involved in B12 maintenance, which include chaperones that escort this highly reactive molecule to various destinations and some novel enzymes that tailor the cobalamin molecule to its enzyme-specific active form. For example, she recently solved a long-standing mystery by revealing that a B12 chaperone called MMACHC also was responsible for cleaving off the cyanide group in cyanocobalamin, the form that’s most prevalent in vitamin supplements.

Ragsdale has expanded his field of research to include methanogenesis in addition to acetogenesis, and his group recently elucidated the reaction for the final step in methane synthesis, demonstrating that the process is nickel-dependent.

“I’ve been getting excited about that area because not only does methane have many wonderful chemical properties, but it could be a great source of future energy,” Ragsdale says. “There’s lots of stored methane available, it’s got a great energy potential and it’s clean burning.”

Following an eye-opening Gordon Conference on metals in biology, the formerly inorganic-adverse Ragsdale also has become interested in other classes of metalloproteins. One intriguing area his lab has just started investigating involves a potentially novel type of metabolic regulation in which thiol/disulfide redox switches regulate a protein’s affinity for heme; these heme-regulatory motifs respond to conditions like oxidative stress and subsequently adjust protein function. The heme functionality also allows the protein to respond to gas-signaling molecules like carbon monoxide and nitric oxide.

And, in a discovery that definitely pleased his music-loving soul, Ragsdale even found one such thiol/disulfide redox switch on a key nuclear hormone receptor involved in the circadian cycle called Rev-erb. “It was not a planned occurrence, and I didn’t name the protein,” he says, “but it kind of highlights the wonders of science and how the right protein, or person, seems to find you.”

References

Banerjee, R. V., Harder, S. R., Ragsdale, S. W., and Matthews, R. G. (1990) Mechanism of reductive activation of cobalamin-dependent methionine synthase: an electron paramagnetic resonance spectroelectrochemical study. Biochemistry 29, 1129 – 1135.

Kim, J., Gherasim, C., and Banerjee, R. (2008) Decyanation of vitamin B12 by a trafficking chaperone. Proc. Nat. Acad. Sci. 105, 14551 – 14554.

Padovani, D., Labunska, T., Palfey, B. A., Ballou, D. P., and Banerjee, R. (2008) Adenosyltransferase tailors and delivers coenzyme B12. Nature Chem. Biol. 4, 194 – 196.

Li, X., Telser, J., Hoffman, B. M., Gerfen, G., and Ragsdale, S. W. (2010) Observation of organometallic and radical intermediates formed during the reaction of methyl-coenzyme M reductase with bromoethanesulfonate. Biochemistry 49, 6866 – 6876.

Gupta, N., and Ragsdale, S. W. (2010) Thiol-disulfide redox dependence of heme binding and heme ligand switching in a nuclear hormone receptor Rev-erb{beta}. J. Biol. Chem. [Epub Dec 1 ahead of print].

Nick Zagorski (nicozags@gmail.com) is a freelance science writer.

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