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

Published

Journal Article

Cryptococcus neoformans is a major cause of systemic fungal infection in immunocompromised patients. Myristoyl-CoA:protein N-myristoyltransferase (Nmt) catalyzes the transfer of myristate (C14:0) 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 degrees 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.

Full Text

Duke Authors

Cited Authors

  • Lodge, JK; Jackson-Machelski, E; Toffaletti, DL; Perfect, JR; Gordon, JI

Published Date

  • December 1994

Published In

Volume / Issue

  • 91 / 25

Start / End Page

  • 12008 - 12012

PubMed ID

  • 7991574

Pubmed Central ID

  • 7991574

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.91.25.12008

Language

  • eng