Prevention of polymerization of M and Z alpha(1)-antitrypsin (alpha(1)-AT)with trimethylamine N-oxide - Implications for the treatment of alpha(1)-AT deficiency

alpha (1)-Antitrypsin (alpha (1)-AT) is the most abundant circulating prote inase inhibitor. The Z variant results in profound plasma deficiency as the mutant polymerizes within hepatocytes. The retained polymers are associate d with cirrhosis, acid 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 no rmal M and disease-associated Z alpha (1)-AT. TMAO stabilized both M and Z alpha (1)-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, T MAO did not aid the refolding of denatured alpha (1)-AT to a native conform ation; instead, it enhanced polymerization. These data show that TMAO can b e used to control the conformational transitions of folded alpha (1)-AT but that it is ineffective in promoting folding of the polypeptide chain withi n the secretory pathway.