It is common for bacteriophages to encode proteins that are strongly inhibitory to growth of the bacterial host, and about 10% of mycobacteriophage-encoded proteins have this property. Adephagia is a Cluster K1 mycobacteriophage and prior cloning and expression of 66 Adephagia non-structural genes identified 14 that are toxic when expressed in Mycobacterium smegmatis. One of the expressed proteins, the 70-residue gp48, is highly toxic when expressed in both M. smegmatis and Mycobacterium abscessus and acts by binding to and inactivating the function of Msmeg_1828, a mannose-1-phosphate guanylyltransferase (Mpg). Mpg is an essential enzyme for biosynthesis of GDP-mannose, a precursor of several key cell wall constituents including lipoarabinomannan and phosphatidylinositol mannosides. The crystal structure of Adephagia gp48 shows that the N-terminal 43 residues form two alpha helices that strongly promote dimer formation; the C-terminal 27 residues are disordered but are predicted to bind Fe-S clusters via cysteine and histidine residues. Adephagia gp48 inhibits Mpg guanylyltransferase activity in vitro and is predicted to interrupt Mpg dimer formation. The C-terminal metal binding activity of gp48 is not required for toxicity, and non-toxic mutants have substitutions in the N-terminal alpha helices that are involved in dimerization. The selective advantage of Mpg inactivation for the phage is unclear, but it may protect from competing phages that require GDP-mannose derived molecules for efficient infection.
Lauer, M. J., Freeman, K. G., Jiang, D., Maneekul, J., VanDemark, A. P., Hatfull, G. F.
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