8QF2

Beta-L-Arabinofurano-cyclitol Aziridines are Cysteine-directed Broad-spectrum Inhibitors and Activity-based Probes for Retaining Beta-L-arabinofuranosidases

This is a non-PDB format compatible entry.

Summary for 8QF2

• Entry DOI: 10.2210/pdb8qf2/pdb
• Descriptor: Non-reducing end beta-L-arabinofuranosidase, ZINC ION, (1~{S},2~{S},3~{S},4~{R})-4-azanyl-3-(hydroxymethyl)cyclopentane-1,2-diol, ... (4 entities in total)
• Functional Keywords: arabinofuranosidase, activity-based probe, cyclophellitol aziridine, hydrolase
• Biological source: Bifidobacterium longum
• Total number of polymer chains: 1
• Total formula weight: 74670.49

Authors

Borlandelli, V.,Offen, W.A.,Moroz, O.,Nin-Hill, A.,McGregor, N.,Binkhorst, L.,Armstrong, Z.,Ishiwata, A.,Artola, M.,Rovira, C.,Davies, G.J.,Overkleeft, H. (deposition date: 2023-09-02, release date: 2023-12-13, Last modification date: 2023-12-27)

Primary citation

Borlandelli, V.,Offen, W.,Moroz, O.,Nin-Hill, A.,McGregor, N.,Binkhorst, L.,Ishiwata, A.,Armstrong, Z.,Artola, M.,Rovira, C.,Davies, G.J.,Overkleeft, H.S.
beta-l- Arabino furano-cyclitol Aziridines Are Covalent Broad-Spectrum Inhibitors and Activity-Based Probes for Retaining beta-l-Arabinofuranosidases.
Acs Chem.Biol., 18:2564-2573, 2023

PubMed Abstract: GH127 and GH146 microorganismal retaining β-l-arabinofuranosidases, expressed by human gut microbiomes, feature an atypical catalytic domain and an unusual mechanism of action. We recently reported that both GH146 and HypBA1 are inhibited by β-l-furanosyl cyclophellitol epoxide, supporting the action of a zinc-coordinated cysteine as a catalytic nucleophile, where in most retaining GH families, an aspartate or glutamate is employed. This work presents a panel of β-l-furanosyl cyclophellitol epoxides and aziridines as mechanism-based GH146/HypBA1 inhibitors and activity-based probes. The β-l-furanosyl cyclophellitol aziridines both inhibit and label β-l-arabinofuranosidase efficiently (however with different activities), whereas the epoxide-derived probes favor GH146 over HypBA1. These findings are accompanied by X-ray structural analysis of the unmodified β-l-furanosyl cyclophellitol aziridine in complex with both isozymes, which were shown to react by nucleophilic opening of the aziridine, at the pseudoanomeric carbon, by the active site cysteine nucleophile to form a stable thioether bond. Altogether, our activity-based probes may serve as chemical tools for the detection and identification of low-abundance β-l-arabinofuranosidases in complex biological samples.

PubMed: 38051515
DOI: 10.1021/acschembio.3c00558

Experimental method

X-RAY DIFFRACTION (2.35 Å)