title: Increased outer arm and core fucose residues on the N-glycans of mutated alpha-1 antitrypsin protein from alpha-1 antitrypsin deficient individuals.
abstract: Alpha-1 antitrypsin (AAT) is the major physiological inhibitor of a range of serine proteases, and in the lung, it maintains a protease-antiprotease balance. AAT deficiency (AATD) is an autosomal co-dominant condition with the Z mutation being the most common cause. Individuals homozygous for Z (PiZZ) have low levels of circulating mutant Z-AAT protein leading to premature emphysematous lung disease. Extensive glycoanalysis has been performed on normal AAT (M-AAT) from healthy individuals and the importance of glycosylation in affecting the immune modulatory roles of AAT is documented. However, no glycoanalysis has been carried out on Z-AAT from deficient individuals to date. In this study, we investigate whether the glycans present on Z-AAT differ to those found on M-AAT from healthy controls. Plasma AAT was purified from 10 individuals: 5 AATD donors with the PiZZ phenotype and 5 PiMM healthy controls. Glycoanalysis was performed employing N-glycan release, exoglycosidase digestion and UPLC analysis. No difference in branched glycans was identified between AATD and healthy controls. However, a significant increase in both outer arm (α1-3) (p = 0.04) and core (α1-6) fucosylated glycans (p < 0.0001) was found on Z-AAT compared to M-AAT. This study has identified increased fucosylation on N-glycans of Z-AAT indicative of ongoing inflammation in AATD individuals with implications for early therapeutic intervention.
authors: Respiratory Research Division, Royal College of Surgeons in Ireland , Beaumont Hospital, Dublin 9, Ireland.
authors: Cormac
authors: C
authors: McCarthy
authors: Radka
authors: R
authors: Saldova
authors: M Emmet
authors: ME
authors: O'Brien
authors: David A
authors: DA
authors: Bergin
authors: Tomás P
authors: TP
authors: Carroll
authors: Joanne
authors: J
authors: Keenan
authors: Paula
authors: P
authors: Meleady
authors: Michael
authors: M
authors: Henry
authors: Martin
authors: M
authors: Clynes
authors: Pauline M
authors: PM
authors: Rudd
authors: Emer P
authors: EP
authors: Reeves
authors: Noel G
authors: NG
authors: McElvaney
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002853:Chromatography, Liquid; D015180:Electrophoresis, Gel, Two-Dimensional; D005643:Fucose / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D053719:Tandem Mass Spectrometry; D055815:Young Adult; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism*; D019896:alpha 1-Antitrypsin Deficiency / Q000378:metabolism*
chemical_list: D011134:Polysaccharides; D000515:alpha 1-Antitrypsin; D005643:Fucose