Alpha1-Antitrypsin Deficiency in COPD: Clinical Implications

, College of Physicians and Surgeons, Columbia University, NY

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Normal Synthesis and Function of Alpha1-Antitrypsin

Alpha1-antitrypsin is synthesized by hepatocytes, and is a serine protease inhibitor (serpin). Alpha1-AT is a member of a large supergene family of "suicide serpins" that inactivate a specific group of proteases. Among these, alpha1-AT has a very high association rate constant for neutrophil elastase, and is therefore the major physiologic inhibitor for this enzyme. The secondary structure of the alpha1-AT molecule includes a loop containing a reactive Met358-Ser359 site that extends from a five stranded alpha (A) sheet (Fig. 1A), two hinged regions, and a shutter region.[6] Combination with elastase at the active site is a very avid process resulting in irreversible binding and conformational changes that "lock" the protease within the A sheets of the molecule (Figs. 1B, 1C). These reactions ensure the mutual inactivation of both the protease and its inhibitor.

Figure 1A,B,C. Conformational change occurring in a serpin molecule reactive loop after binding to its target protease. The structure of the alpha 1-AT molecule: the five stranded A sheet is shown in black and the reactive loop is shown in red. The active site is represented as a red circle. In the circulating quiescent form of the molecule (A), the reactive loop extends outside the structure of the main molecule. During combination with the target protease, the reactive loop is incorporated between the strands of the A sheet (B,C). The site of the Z mutation of alpha 1-ATD is shown as a green circle on the proximal hinge region and would likely cause spontaneous incorporation of the reactive loop into other molecules of alpha 1-AT and lead to polymerization of the protein. Adapted with permission from Carrell RW, Lomas DA, Sidhar S, et al: Alpha 1-antitrypsin deficiency. A conformational disease. Chest 110(6 Suppl):243S-247S, 1996 Dec.

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