ORNITHINE DECARBOXYLASE IN PNEUMOCYSTIS-CARINII AND IMPLICATIONS FOR THERAPY

Pneumocystis carinii pneumonia (PCP) can be treated with eflornithine (difluoromethylornithine, DFMO, Ornidyl), a competitive irreversible i nhibitor of ornithine decarboxylase (ODC), a key enzyme for polyamine biosynthesis. Because ODC has been reported to be absent from P. carin ii, it has been assumed that eflornithine affects P. carinii only indi rectly, by affecting host polyamine biosynthesis. If this is true, the n improvements in the selectivity of antipolyamine therapy for PCP wou ld be limited. Since the presence of ODC in P. carinii is an important issue, a new search for this enzyme was made. Not only were initial a ssays negative, but P. carinii extract reduced the background catalyti c action of pyridoxal-5'-phosphate, the coenzyme required by the enzym e. This suggested the presence of an inhibitor, which was further supp orted by the observation that a P. carinii extract could suppress a so urce of known ODC activity. The inhibitory activity could be removed b y a desalting column or by dialysis, allowing detection of P. carinii ODC. Indirect evidence indicates that the inhibition is only apparent and is caused by unlabeled ornithine in the extract of P. carinii whic h interferes with the radiolabel-based assay system. P. carinii and ho st ODCs respond differently to changes in pH. P. carinii ODC is much l ess susceptible to inhibition by eflornithine than host ODC. The prese nce of ODC in P. carinii suggests that P. carinii ODC is the target of eflornithine and that P. carinii ODC may have sufficiently specific p roperties that inhibitors with improved selectivity against P. carinii ODC could be identified.