Furin has the proalbumin substrate specificity and serpin inhibitory properties of an in situ hepatic convertase.

Furin, a KEX2 protease homolog with high RNA expression in the liver is an excellent candidate as a hepatic proprotein convertase. Here we show that purified recombinant furin has the same proalbumin specificity and serpin inhibitory properties as the in situ hepatic convertase. There was rapid cleavage at the -RRD- site of normal human proalbumin but there no significant cleavage of natural unprocessed variants with cleavage site sequences of -RRV-, -HRD-, -RQD-, or -CRD-. Cleavage of the latter was not increased by S-aminoethylation. Furin was specifically inhibited by alpha 1-antitrypsin Pittsburgh (358 Met-->Arg), (K1/2 = 3 microM) but not by 50 microM normal antitrypsin M or by antithrombin, however, antithrombin/heparin was a good inhibitor (K1/2 = 9 microM). The pH optimum for proalbumin cleavage was between pH 5.5 and 6.0, indicating that furin is potentially fully active within secretory vesicles, the site of proalbumin cleavage.