Trans-cyclosulfamidate mannose-configured cyclitol allows isoform-dependent inhibition of GH47 α-d-mannosidases through a bump–hole strategy

MALES, Alexandra, KOK, Ken, NIN-HILL, Alba, DE KOSTER, Nicky, VAN DEN BEUKEL, Sija, BEENAKKER, Thomas J.M., VAN DER MAREL, Gijsbert A., CODÉE, Jeroen D.C., AERTS, Johannes M.F.G., OVERKLEEFT, Herman S., ROVIRA, Carme, DAVIES, Gideon J. and ARTOLA, Marta (2023). Trans-cyclosulfamidate mannose-configured cyclitol allows isoform-dependent inhibition of GH47 α-d-mannosidases through a bump–hole strategy. Chemical Science.

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Abstract

Class I inverting exo-acting α-1,2-mannosidases (CAZY family GH47) display an unusual catalytic itinerary featuring ring-flipped mannosides, 3S1 → 3H4‡ → 1C4. Conformationally locked 1C4 compounds, such as kifunensine, display nanomolar inhibition but large multigene GH47 mannosidase families render specific “isoform-dependent” inhibition impossible. Here we develop a bump-and-hole strategy in which a new mannose-configured 1,6-trans-cyclic sulfamidate inhibits α-D-mannosidases by virtue of its 1C4 conformation. This compound does not inhibit the wild-type GH47 model enzyme by virtue of a steric clash, a “bump”, in the active site. An L310S (a conserved residue amongst human GH47 enzymes) mutant of the model Caulobacter GH47 awoke 574 nM inhibition of the previously dormant inhibitor, confirmed by structural analysis of a 0.97 Å structure. Considering that L310 is a conserved residue amongst human GH47 enzymes, this work provides a unique framework for future biotechnological studies on N-glycan maturation and ER associated degradation by isoform-specific GH47 α-D-mannosidase inhibition through a bump-and-hole approach.

Item Type:	Article
Uncontrolled Keywords:	03 Chemical Sciences; 34 Chemical sciences
Identification Number:	https://doi.org/10.1039/d3sc05016e
SWORD Depositor:	Symplectic Elements
Depositing User:	Symplectic Elements
Date Deposited:	28 Nov 2023 13:15
Last Modified:	28 Nov 2023 13:15
URI:	https://shura.shu.ac.uk/id/eprint/32776

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