BIOCHEMISTRY
Biochemical properties
of Alpha 1 Antitrypsin
This article focuses on the biochemical properties of Alpha1 Antitrypsin (AAT), its functional
inactivation in vivo, and how polymerisation of mutant ZAAT leads to lung and liver manifestations
in AAT deficiency
Oliver McElvaney
MB BCh BAO MRCPI
Noel McElvaney
MB FRCPI FRCPC
Irish Centre for Genetic
Lung Disease, Beaumont
Hospital, Royal College
of Surgeons in Ireland,
Dublin, Ireland
Alpha 1 Antitrypsin (AAT) is a member of the
serine protease inhibitor (serpin) family of
proteins. AAT is produced mainly by hepatocytes
and, to a lesser extent, by other cells in the body.
In the past, AAT has been recognised mainly as an
anti-protease and indeed has significant anti-
protease activity but, more recently, focus has
shifted somewhat to a better understanding of the
anti-inflammatory properties of AAT. 1 Here we focus
on the biochemical properties of AAT, both anti-
protease and anti-inflammatory, how AAT may be
functionally inactivated in vivo, and how
polymerisation of mutant ZAAT leads to a loss of
function in the lung due to reduced levels in that
compartment and gain of function in the liver due
to endoplasmic reticulum (ER) stress. The lessons
learnt from AAT deficiency (AATD) may translate
into other serpinopathies, with potential for better
understanding of basic mechanisms and therapies.
Anti-neutrophil properties of AAT
The predominant role of AAT is as a serine protease
inhibitor, mainly inhibiting neutrophil elastase (NE),
but also other serine proteases including cathepsin
6 | 2019 | hospitalpharmacyeurope.com
G (CathG), proteinase 3 (PR3), chymotrypsin and
thrombin. 2 AAT is composed of three beta sheets
(A, B and C), nine alpha helices and a reactive centre
loop (RCL) at its C-terminal end. AAT undergoes
post-translational modification with the addition of
N-linked oligosaccharides. 3–5 These glycosylations
have relatively little effect on the ability of AAT to
inhibit NE, PR3 or CathG but they do significantly
affect some of the anti-inflammatory properties of
AAT. The anti-protease activity of AAT lies within the
RCL, whereby AAT acts as a ‘mouse trap’ with the
RCL as its ‘bait’. NE cleaves between amino acids
358 and 359 of the RCL, resulting in the creation
of an AAT:NE complex. The covalently-bound
enzyme then leads to irreversible inactivation
of both molecules. 6
In the healthy lung, AAT exists in abundance,
and the epithelial lining fluid of the lung has
significant anti-NE capacity. In disease states such
as AATD, cystic fibrosis (CF), non-CF bronchiectasis,
COPD, pneumonia and others, this protease–anti-
protease balance is disrupted, leading to the
unopposed action of NE and other proteases in the
lung with resulting damage. This is unsurprising