Fig. 6: Proposed catalytic and inhibitory mechanism of Chs1.
From: Structure, catalysis, chitin transport, and selective inhibition of chitin synthase
a Chs1 in the apo state has an open active site and a transmembrane channel sealed by a switch loop and TMH4. The sugar donor (UDP-GlcNAc) binding and subsequent hydrolysis primed the first acceptor molecule (GlcNAc) in the binding site. The priming process opens the chitin transport channel on the cytosolic side by flipping the switch loop and triggers the downward movement of the GT domain to push the product out. Then, UDP is released, and a new donor molecule binds to the active site for chitin elongation. To transport the chitin product outside, TMH4 is shifted outward, resulting in an open channel on the exoplasmic side. More details are provided in the text. b Peptidyl nucleoside inhibitors inhibit Chs1 by competing with UDP binding, occupying the sugar acceptor binding site, and blocking the chitin transport channel. c The domain swapping loop in one subunit regulates the other subunit’s activity by inhibiting and releasing its GTD. This allows the chitin synthesis of two subunits in the Chs1 dimer simultaneously and facilitates chitin fiber formation. During chitin synthesis, the switch loop and TMH4 of each subunit shift to open the chitin transporting channel.
