Prevention of Polymerization of M and Z α1-Antitrypsin ( α1-AT) with Trimethylamine N-Oxide: Implications for the Treatment of α1-AT Deficiency

GL Devlin, H Parfrey, DJ Tew, DA Lomas… - American journal of …, 2001 - atsjournals.org
GL Devlin, H Parfrey, DJ Tew, DA Lomas, SP Bottomley
American journal of respiratory cell and molecular biology, 2001atsjournals.org
α1-Antitrypsin (α1-AT) is the most abundant circulating proteinase inhibitor. The Z variant
results in profound plasma deficiency as the mutant polymerizes within hepatocytes. The
retained polymers are associated with cirrhosis, and the lack of circulating protein
predisposes to early onset emphysema. We have investigated the role of the naturally
occurring solute trimethylamine N-oxide (TMAO) in modulating the polymerization of normal
M and disease-associated Z α1-AT. TMAO stabilized both M and Z α1-AT in an active …
α1-Antitrypsin ( α1-AT) is the most abundant circulating proteinase inhibitor. The Z variant results in profound plasma deficiency as the mutant polymerizes within hepatocytes. The retained polymers are associated with cirrhosis, and the lack of circulating protein predisposes to early onset emphysema. We have investigated the role of the naturally occurring solute trimethylamine N-oxide (TMAO) in modulating the polymerization of normal M and disease-associated Z α1-AT. TMAO stabilized both M and Z α1-AT in an active conformation against heat-induced polymerization. Spectroscopic analysis demonstrated that this was due to inhibition of the conversion of the native state to a polymerogenic intermediate. However, TMAO did not aid the refolding of denatured α1-AT to a native conformation; instead, it enhanced polymerization. These data show that TMAO can be used to control the conformational transitions of folded α1-AT but that it is ineffective in promoting folding of the polypeptide chain within the secretory pathway.
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