1.B.94.  The Pro-Pro-Glu Actinobacterial Outer Membrane Porin (PPE) Family

Mycobacterium tuberculosis and other bacteria belonging to the Gram + Actinobacterial phylum have  unusual outer membranes that lacks canonical porin proteins typical of Gram negative bacteria for the transport of small solutes to the periplasm. However they do have β-barrel proteins, 40 of which have the PPE motif (Pajón et al. 2006). Wang et al. 2020 discovered that 3,3-bis-di(methylsulfonyl)propionamide (3bMP1) inhibits the growth of M. tuberculosis, and resistance to this compound is conferred by mutation within a member of the proline-proline-glutamate (PPE) family, PPE51 (TC# 1.B.94.1.1). Deletion of PPE51 rendered M. tuberculosis cells unable to replicate on propionamide, glucose, or glycerol. Growth was restored upon loss of the mycobacterial cell wall component phthiocerol dimycocerosate. Mutants in other proline-glutamate (PE)/PPE clusters, responsive to magnesium and phosphate, also showed a phthiocerol dimycocerosate-dependent growth compromise upon limitation of the corresponding substrate. Phthiocerol dimycocerosate determined the low permeability of the mycobacterial outer membrane, and the PE/PPE proteins apparently act as solute-specific channels (Wang et al. 2020). PE/PPEs probably play roles as nutrient-specific outer membrane 'porins' for selective uptake of small molecular nutrients and as possible molecular export transporters (Ehtram et al. 2021). Proteomic analyses were used to identify crucial ESX-5 substrates, confirming that all detectable PE and PPE proteins in the cell surface and cell envelope fractions were routed through ESX-5 (Ates et al. 2015).