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Originally published In Press as doi:10.1074/jbc.M002103200 on September 29, 2000

J. Biol. Chem., Vol. 275, Issue 51, 40628-40634, December 22, 2000
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Cell Wall Assembly by Pneumocystis carinii
EVIDENCE FOR A UNIQUE Gsc-1 SUBUNIT MEDIATING beta -1,3-GLUCAN DEPOSITION*

Theodore J. Kottom and Andrew H. LimperDagger

From the Thoracic Diseases Research Unit, Departments of Medicine and Biochemistry, Mayo Clinic, Rochester, Minnesota 55905

Pneumocystis carinii remains a persistent cause of severe pneumonia in immune compromised patients. Recent studies indicate that P. carinii is a fungal species possessing a glucan-rich cyst wall. Pneumocandin antagonists of beta -1,3-glucan synthesis rapidly suppress infection in animal models of P. carinii pneumonia. We, therefore, sought to define the molecular mechanisms of beta -glucan cell wall assembly by P. carinii. Membrane extracts derived from freshly purified P. carinii incorporate uridine 5'-diphosphoglucose into insoluble carbohydrate, in a manner that was completely inhibited by the pneumocandin L733-560, an antagonist of Gsc-1-type beta -glucan synthetases. Using degenerative polymerase chain reaction and library screening, the P. carinii Gsc-1 catalytic subunit of beta -1,3-glucan synthetase was cloned and characterized. P. carinii gsc1 exhibited homology to phylogenetically related fungal beta -1,3-glucan synthetases, encoding a predicted 214-kDa integral membrane protein with 12 transmembrane domain structure. Immunoprecipitation of P. carinii extracts, with a synthetic peptide anti-Gsc-1 antibody, specifically yielded a protein of 219.4 kDa, which was also capable of incorporating 5'-diphosphoglucose into insoluble glucan carbohydrate. As opposed to other fungi, the expression of gsc-1 mRNA is uniquely regulated over P. carinii's life cycle, having minimal expression in trophic forms, but substantial expression in the thick-walled cystic form of the organism. These results indicate that P. carinii contains a unique catalytic subunit of beta -1,3-glucan synthetase utilized in cyst wall formation. Because synthesis of beta -1,3-glucan is absent in mammalian cells, inhibition of the P. carinii Gsc-1 represents an attractive molecular target for therapeutic exploitation.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF191096 and AF291999.

Dagger To whom correspondence should be addressed: 601C Guggenheim Bldg., Mayo Clinic, Rochester, MN 55905. Tel.: 507-284-2964; Fax: 507-284-4521; E-mail: limper.andrew@mayo.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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