A missense mutation in a patient with developmental delay affects the activity and structure of the hexosamine biosynthetic pathway enzyme AGX1

DOI: 10.1002/1873-3468.13968

Authors: Xiping Chen (University of Dundee) , Olawale Raimi (University of Dundee) , Andrew T. Ferenbach (University of Dundee) , Daan M. F. Van Aalten (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Febs Letters

State: Published (Approved)
Published: October 2020

Abstract: O‐GlcNAcylation is a post‐translational modification catalysed by O‐GlcNAc transferase (OGT). Missense mutations in OGT have been associated with developmental disorders, OGT‐linked Congenital Disorders of Glycosylation (OGT‐CDG), which are characterized by intellectual disability. OGT relies on the hexosamine biosynthetic pathway (HBP) for provision of its UDP‐GlcNAc donor. We considered whether mutations in UDP‐N‐acetylhexosamine pyrophosphorylase (UAP1), which catalyses the final step in the HBP, would phenocopy OGT‐CDG mutations. A de novo mutation in UAP1 (NM_001324114:c.G685A:p.A229T) was reported in a patient with intellectual disability. We show that this mutation is pathogenic and decreases the stability and activity of the UAP1 isoform AGX1 in vitro. X‐ray crystallography reveals a structural shift proximal to the mutation, leading to a conformational change of the N‐terminal domain. These data suggest that the UAP1A229T missense mutation could be a contributory factor to the patient phenotype.

Journal Keywords: O‐GlcNAcylation; enzyme mutation; pathogenesis; protein structure; neurodevelopment

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 02/11/2020 14:41

Documents:
FEBS Letters - 2020 - Chen - A missense mutation in a patient with developmental delay affects the activity and structure.pdf

Discipline Tags:

Health & Wellbeing Biochemistry Genetics Catalysis Neurology Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)