Enzyme catalyzes cross-membrane reaction

Hydrophilic and hydrophobic molecules tend to avoid each other. But phosphoglycosyl transferases, enzymes that reside on bacterial cell membranes, can bring these odd couples together and catalyze reactions between them.

Barbara Imperiali of Massachusetts Institute of Technology, Karen N. Allen of Boston University, and coworkers report the 2.7-Å-resolution crystal structure of a phosphoglycosyl transferase called PglC. The structure allowed them to uncover the enzyme’s unique mechanism, which permits hydrophilic and hydrophobic molecules to interact without ever having to leave their natural environments (Nat. Chem. Biol. 2018, DOI: 10.1038/s41589-018-0054-z).

These enzymes catalyze reactions that are key steps in the assembly of glycoconjugates like glycoproteins, glycolipids, and peptidoglycans—sugar-linked molecules that are required for bacterial survival and virulence. So understanding PglC’s mechanism could aid antibiotic drug discovery.

The study shows that PglC has three structural parts. One part sticks outside the cell membrane into the watery cytoplasm of the cell and captures a hydrophilic molecule, a sugar nucleotide diphosphate. A second part, a helix with a bent serine-proline sequence, pokes halfway into the greasy membrane bilayer, where it binds a hydrophobic molecule, polyprenol phosphate. PglC then brings the two molecules together in the third part of the enzyme, which is located on the membrane surface and includes the active site.

In the active site, the enzyme links a phosophosugar from the sugar nucleotide diphosphate to polyprenol phosphate, while the hydrophobic molecule remains embedded in the membrane bilayer, except for its terminal phosphate.

David Christianson of the University of Pennsylvania comments that “PglC catalyzes a reaction at the membrane interface, so it has evolved with some striking features to function at this location,” such as the bent helix. “If you think of the enzyme as a boat sailing across a membrane sea, the serine-proline motif is the keel of the boat.” Overall, he says, “the work is important and promises to be very high-impact” for antimicrobial drug discovery.

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