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 i s an excellent candidate as a hepatic proprotein convertase. Here we s how that purified recombinant furin has the same proalbumin specificit y 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 specific ally inhibited by alpha(1)-antitrypsin Pittsburgh (358 Met-->Arg), (K1 /2 = 3 mu M) but not by 50 mu M normal antitrypsin M or by antithrombi n, however, antithrombin/heparin was a good inhibitor (K1/2 = 9 mu M). The pH optimum for proalbumin cleavage was between pH 5.5 and 6.0, in dicating that furin is potentially fully active within secretory vesic les, the site of proalbumin cleavage.