Tb's Novel Path to Cysteine

Tuberculosis-causing bacteria can make the amino acid cysteine via a surprising route, according to work reported by Cornell University chemistry professor Tadhg P. Begley at this week’s American Chemical Society national meeting in Washington, D.C.

Unlike the microbe’s other routes to cysteine, the newly discovered path relies on an unusual sulfur donor that isn’t susceptible to oxidative damage—a feature that Begley thinks may be critical for the survival of Mycobacterium tuberculosis during infection.

At the meeting, Begley showed that M. tuberculosis can make cysteine with a protein-bound thiocarboxylate as the source of sulfur (J. Am. Chem. Soc. 2005, 127, 11602). This protein-bound thiocarboxylate displaces the acetate of O-acetylserine, resulting in a thioester that undergoes a rapid S–N acyl shift to give protein-bound cysteine. Cleavage of the linking amide bond yields the free amino acid.

The chemistry of the new route “shows a new role for enzyme-bound thiocarboxylates in microbial metabolism,” said Christopher A. Walsh of Harvard Medical School. Previous work from the Begley group and other labs has shown that many bacteria use protein-bound thiocarboxylates as sulfur sources in the biosynthesis of certain biologically important sulfur-containing natural products, including thiamine (vitamin B-1) and the enzyme cofactor molybdopterin.

Using comparative genome analysis and painstaking biochemical detective work, Begley, graduate student Kristin E. Burns, and their coworkers now have “extended the thiocarboxylate logic to cysteine biosynthesis in M. tuberculosis,” Walsh added. “The chemistry of thiocarboxylates continues to reveal novel biological attributes.”

The other two known ways that M. tuberculosis makes cysteine require thiols or free sulfide, both of which are easily inactivated by oxidation. Because the new route depends on an oxidation-resistant, protein-bound thiocarboxylate as a sulfur source, it “could be necessary for cysteine biosynthesis in M. tuberculosis in the oxidizing environment of the macrophage,” Begley suggested. If his hunch proves correct, the route could make an interesting target for the design of new tuberculosis drugs.