Targeted gene replacement demonstrates that myristoyl-CoA:protein N- myristoyltransferase is essential for viability of Cryptococcus neoformans

J. K. Lodge, E. Jackson-Machelski, D. L. Toffaletti, J. R. Perfect, J. I. Gordon

Research output: Contribution to journalArticlepeer-review

162 Scopus citations

Abstract

Cryptococcus neoformans is a major cause of systemic fungal infection in immunocompromised patients. Myristoyl-CoA:protein N-myristoyltransferase (Nmt) catalyzes the transfer of myristate (C(14:0)) from myristoyl-CoA to the N-terminal glycine of a subset of cellular proteins produced during vegetative growth of C. neoformans. A Gly487 → Asp mutation was introduced into C. neoformans NMT by targeted gene replacement. The resulting strains are temperature-sensitive myristic acid auxotrophs. They are killed at 37°C when placed in medium lacking myristate and, in an immunosuppressed animal model of cryptococcal meningitis, are completely eliminated from the subarachnoid space within 12 days of initial infection. C. neoformans and human Nmts exhibit differences in their peptide substrate specificities. These differences can be exploited to develop a new class of fungicidal drugs.

Original languageEnglish
Pages (from-to)12008-12012
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number25
DOIs
StatePublished - Dec 16 1994

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