Structural Basis of the Inhibition of L-Methionine ?-Lyase from Fusobacterium nucleatum

Fusobacterium nucleatum is a lesion-associated obligate anaerobic pathogen of destructive periodontal disease; it is also implicated in the progression and severity of colorectal cancer. Four genes (FN0625, FN1055, FN1220, and FN1419) of F. nucleatum are involved in producing hydrogen sulfide (H2S), which plays an essential role against oxidative stress. The molecular functions of Fn1419 are known, but their mechanisms remain unclear. We determined the crystal structure of Fn1419 at 2.5 A, showing the unique conformation of the PLP-binding site when compared with L-methionine gamma-lyase (MGL) proteins. Inhibitor screening for Fn1419 with L-cysteine showed that two natural compounds, gallic acid and dihydromyricetin, selectively inhibit the H2S production of Fn1419. The chemicals of gallic acid, dihydromyricetin, and its analogs containing trihydroxybenzene, were potentially responsible for the enzyme-inhibiting activity on Fn1419. Molecular docking and mutational analyses suggested that Gly112, Pro159, Val337, and Arg373 are involved in gallic acid binding and positioned close to the substrate and pyridoxal-5'-phosphate-binding site. Gallic acid has little effect on the other H2S-producing enzymes (Fn1220 and Fn1055). Overall, we proposed a molecular mechanism underlying the action of Fn1419 from F. nucleatum and found a new lead compound for inhibitor development.

Automated summary

This study discovered that the pathogen Fusobacterium nucleatum, which is associated with destructive periodontal disease and colorectal cancer, has four genes that produce hydrogen sulfide, which helps protect against oxidative stress. By examining the structure and conducting inhibitor screening, two natural compounds were found to selectively inhibit the production of hydrogen sulfide by Fn1419. This research revealed the molecular mechanism of Fn1419 and identified a new potential inhibitor.