The Role and Importance of Glycosylation of Acute Phase Proteins with Focus on Alpha-1 Antitrypsin in Acute and Chronic Inflammatory Conditions

Abstract

Acute phase proteins (APPs) are a group of circulating plasma proteins which undergo changes quantitatively or qualitatively at the time of inflammation. Many of these APPs are glycosylated, and it has been shown that alterations in glycosylation may occur in inflammatory and malignant conditions. Changes in glycosylation have been studied as potential biomarkers in cancer and also in chronic inflammatory conditions and have been shown to correlate with disease severity in certain conditions. Serine protease inhibitors (serpins), many of which are also APPs, are proteins involved in the control of proteases in numerous pathways. Alpha-1 Antitrypsin (AAT) is the most abundant serpin within the circulation and is an APP which has been shown to increase in response to inflammation. The primary role of AAT is maintaining the protease/antiprotease balance in the lung, but it also possesses important anti-inflammatory and immune-modulating properties. Several glycoforms of AAT exist, and they possess differing properties in regard to plasma half-life and stability. Glycosylation may also be important in determining the immune modulatory properties of AAT. The review will focus on the role and importance of glycosylation in acute phase proteins with particular attention to AAT and its use as a biomarker of disease. The review describes the processes involved in glycosylation, how glycosylation changes in differing disease states, and the alterations that occur to glycans of APPs with disease and inflammation. Finally, the review explores the importance of changes in glycosylation of AAT at times of inflammation and in malignant conditions and how this may impact upon the functions of AAT.

Upper Airway Mucosal Inflammation : Proteomic Studies after Exposure to Irritants and Microbial Agents

“…The protein is highly glycosylated and expressed as several isoforms. The glycosylation of the protein has been shown to be important in various disease states and glycosylation levels can often be elevated during inflammatory processes [215]. This is in agreement with our findings since we found elevated levels of the most glycosylated isoform, indicating an ongoing inflammatory process among swimming pool personnel with airway symptoms.…”

“…Alpha-1-antitrypsin is normally present at inflammatory sites where it protects tissue against injury, especially by inhibition of neutrophil-derived elastase. This protein is also known to be highly glycosylated and present as several isoforms that can be altered during various inflammatory states [215]. Alpha-1-antitrypsin has a theoretical molecular weight of 47 kDa, but the increased isoforms we found had a higher molecular mass of 59 kDa, which probably is explained by glycosylation.…”

The BLT1 Inhibitory Function of α-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling

“…Glycosylated AAT was modeled as previously described (55). The structure of LTB 4 was based on the crystal structure of Ornithodoros moubata C inhibitor-bound LTB 4 (56).…”

Preparation of legionaminic acid analogs of sialo-glycoconjugates by means of mammalian sialyltransferases

“…We also report that a second enzyme, human ST6Gal1 can attach Leg5Ac7Ac to N-linked glycans on glycoproteins, as exemplified by modification of α1-antitrypsin. Natural and recombinant forms of this protein 4 have three N-glycosylation sites where the predominant glycoforms are bi-antennary sialylated structures [6][7][8]. Both of these glycoproteins are being produced for therapeutic purposes and modification of their glycans may alter their biological activity [9] and their pharmacodynamics [10].…”