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2021-07-23

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cc by (c) Piniello, Beatriz et al., 2021
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/229830

Asparagine tautomerization in glycosyltransferase catalysis. The molecular mechanism of protein O-fucosyltransferase 1

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Recurs relacionat

https://doi.org/10.1021/acscatal.1c01785

Resum

O-glycosylation is a post-translational protein modification essential to life. One of the enzymes involved in this process is protein O-fucosyltransferase 1 (POFUT1), which fucosylates threonine or serine residues within a specific sequence context of epidermal growth factor-like domains (EGF-LD). Unlike most inverting glycosyltransferases, POFUT1 lacks a basic residue in the active site that could act as a catalytic base to deprotonate the Thr/Ser residue of the EGF-LD acceptor during the chemical reaction. Using quantum mechanics/molecular mechanics (QM/MM) methods on recent crystal structures, as well as mutagenesis experiments, we uncover the enzyme catalytic mechanism, revealing that it involves proton shuttling through an active site asparagine, conserved among species, which undergoes tautomerization. This mechanism is consistent with experimental kinetic analysis of Caenorhabditis elegans POFUT1 Asn43 mutants, which ablate enzyme activity even if mutated to Asp, the canonical catalytic base in inverting glycosyltransferases. These results will aid inhibitor development for Notch-associated O-glycosylation disorders.

Matèries

Glicoproteïnes, Cinètica enzimàtica

Matèries (anglès)

Glycoproteins, Enzyme kinetics

Citació

Col·leccions

Articles publicats en revistes (Química Inorgànica i Orgànica)

Citació

PINIELLO, Beatriz, et al. Asparagine tautomerization in glycosyltransferase catalysis. The molecular mechanism of protein O-fucosyltransferase 1. ACS Catalysis. 2021. Vol. 11, num. 9926-9932. ISSN 2155-5435. [consulted: 4 of August of 2026]. Available at: https://hdl.handle.net/2445/229830

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