Structural highlights
Function
NMT_ASPFU Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins.
Publication Abstract from PubMed
Treatment of filamentous fungal infections relies on a limited repertoire of antifungal agents. Compounds possessing novel modes of action are urgently required. N-myristoylation is a ubiquitous modification of eukaryotic proteins. The enzyme N-myristoyltransferase (NMT) has been considered a potential therapeutic target in protozoa and yeasts. Here, we show that the filamentous fungal pathogen Aspergillus fumigatus possesses an active NMT enzyme that is essential for survival. Surprisingly, partial repression of the gene revealed downstream effects of N-myristoylation on cell wall morphology. Screening a library of inhibitors led to the discovery of a pyrazole sulphonamide compound that inhibits the enzyme and is fungicidal under partially repressive nmt conditions. Together with a crystallographic complex showing the inhibitor binding in the peptide substrate pocket, we provide evidence of NMT being a potential drug target in A. fumigatus.
N-myristoyltransferase is a cell wall target in Aspergillus fumigatus.,Fang W, Robinson DA, Raimi OG, Blair DE, Harrison JR, Lockhart DE, Torrie LS, Ruda GF, Wyatt PG, Gilbert IH, van Aalten DM ACS Chem Biol. 2015 Jun 19;10(6):1425-34. doi: 10.1021/cb5008647. Epub 2015 Feb, 27. PMID:25706802[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Fang W, Robinson DA, Raimi OG, Blair DE, Harrison JR, Lockhart DE, Torrie LS, Ruda GF, Wyatt PG, Gilbert IH, van Aalten DM. N-myristoyltransferase is a cell wall target in Aspergillus fumigatus. ACS Chem Biol. 2015 Jun 19;10(6):1425-34. doi: 10.1021/cb5008647. Epub 2015 Feb, 27. PMID:25706802 doi:http://dx.doi.org/10.1021/cb5008647
