Arthur C. Cope Scholar: Squire J. Booker

Described by colleagues as fearless for his willingness to tackle intractable biochemical problems, Squire J. Booker is being honored with an Arthur C. Cope Scholar Award for his efforts to understand enzymes that catalyze “kinetically challenged” reactions.

The enzymes that Booker studies typically use S-adenosyl-l-methionine (SAM), iron-sulfur clusters, or both to generate cellular oxidants under anaerobic conditions. The pathways arose during primordial times, when cells had to work without oxygen, Booker says. His studies require special experimental care, because much of the work must be done anaerobically—including growing crystals for X-ray crystallography.

Booker’s work is “always highly original and rigorously designed and executed,” one colleague says. “I expect him to become one of the most highly regarded authorities on biological mechanisms.”

An associate professor of chemistry and biochemistry and molecular biology at Pennsylvania State University, Booker started his research program by studying lipoic acid synthase, an enzyme that had stymied other researchers, says his Penn State colleague J. Martin Bollinger Jr. The enzyme produces lipoic acid, a cofactor used by several other enzymes, by inserting sulfur atoms into octanoic acid through a mechanism involving a SAM-derived radical. Booker and coworkers found that the sulfur atoms are sourced from a sacrificed iron-sulfur cluster.

More recently, Booker studied SAM-dependent methylation of RNA carbon atoms that are normally considered inert to such reactions. Both of the enzymes he studied methylate RNA in bacterial ribosomes; one group promotes normal ribosome function and the other promotes antibiotic resistance. Booker and colleagues found that the methylation mechanism involves a ping-pong reaction in which the enzymes first transfer a methyl group from SAM to a cysteine residue, then a second SAM generates a 5’-deoxyadenosyl radical that relocates the methyl from the cysteine to the adenosine base through a radical-addition mechanism.

Booker has also studied a bacterial enzyme that uses iron-sulfur clusters to make quinolinic acid as part of the bacterial biosynthetic pathway for nicotinamide adenine dinucleotide (NAD⁺), a common cellular cofactor. One of his findings is that the amount of oxygen available regulates one of the enzymes in the NAD⁺ synthetic pathway through a dithiol/disulfide redox switch: In the disulfide form, the enzyme activity is 10 times as much as when it’s in the dithiol form. That makes sense, Booker says, because bacteria require higher concentrations of NAD⁺ to grow in aerobic conditions. His group continues to tease out the details of the switch and the enzyme’s catalytic chemistry.

Booker, 46, earned a B.A. degree with a concentration in chemistry from Austin College in 1987 and a Ph.D. in chemistry from Massachusetts Institute of Technology in 1994.

Aside from Booker’s laboratory successes, he is lauded for his mentorship and ability to turn students into outstanding scientists. Booker’s combination of critical analysis and interpersonal skills also puts him in demand for service to Penn State as well as the broader chemistry community. Booker rarely refuses a request for his time, Bollinger says, “he is as unselfish and community-minded as he is scientifically gifted.”