HPE Alpha 1 Antitrypsin Deficiency | Page 6

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