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).
This family belongs to the Actinobacterial Outer Membrane Porin (A-OMP) Superfamily.
References:
Ates, L.S., R. Ummels, S. Commandeur, R. van de Weerd, R. van der Weerd, M. Sparrius, E. Weerdenburg, M. Alber, R. Kalscheuer, S.R. Piersma, A.M. Abdallah, M. Abd El Ghany, A.M. Abdel-Haleem, A. Pain, C.R. Jiménez, W. Bitter, and E.N. Houben. (2015). Essential Role of the ESX-5 Secretion System in Outer Membrane Permeability of Pathogenic Mycobacteria. PLoS Genet 11: e1005190.
Ehtram, A., M. Shariq, S. Ali, N. Quadir, J.A. Sheikh, F. Ahmad, T. Sharma, N.Z. Ehtesham, and S.E. Hasnain. (2021). Teleological cooption of Mycobacterium tuberculosis PE/PPE proteins as porins: Role in molecular immigration and emigration. Int. J. Med. Microbiol. 311: 151495.
Pajón, R., D. Yero, A. Lage, A. Llanes, and C.J. Borroto. (2006). Computational identification of β-barrel outer-membrane proteins in Mycobacterium tuberculosis predicted proteomes as putative vaccine candidates. Tuberculosis (Edinb) 86: 290-302.
Sankey, N., H. Merrick, P. Singh, J. Rogers, A. Reddi, S.D. Hartson, and A. Mitra. (2023). Role of the Mycobacterium tuberculosis ESX-4 Secretion System in Heme Iron Utilization and Pore Formation by PPE Proteins. mSphere 8: e0057322.
Wang, Q., H.I.M. Boshoff, J.R. Harrison, P.C. Ray, S.R. Green, P.G. Wyatt, and C.E. Barry, 3rd. (2020). PE/PPE proteins mediate nutrient transport across the outer membrane of. Science 367: 1147-1151.
Examples:
TC#	Name	Organismal Type	Example
1.B.94.1.1	Mycobacterial outer membrane porin PPE51 of 380 aas and about 8 TMSs. It is associated with the PE19 protein of 99 aas. The complex probably transports a large range of nutrients and other solutes including propionamide, glucose and glycerol (Wang et al. 2020).		PPE51 of Mycobacterium tuberculosis

1.B.94.1.2	*Mg²⁺-transporting outer membrane porin, PPE31 (399 aas)/PE20 complex (99 aas) (Wang et al.* 2020). The PPE31 protein probably has about 8 TMSs**		Mg2+ porin, PPE31/PE20, of Mycobacterium tuberculosis

1.B.94.1.3	*Heterodimeric outer membrane porin specific for inorganic phosphate, consisting of PPE25 of 365 aas and probably ~ 8 TMSs. The PE19 associated protein is of 99 aas (Wang et al.* 2020).**		PPE25/PE19 of Mycobacterium tuberculosis

1.B.94.1.4	*Heterodimeric outer membrane porin consisting of two proteins, PPE65 of 413 aas and 8 probable TMSs, as well as PE32 of 99 aas. This porin transports inorganic phosphate (Wang et al.* 2020).**		PPE65/PE32 phosphate porin of Mycobacterium tuberculosis

1.B.94.1.5	Uncharacterized protein of 615 aas and ~ 12 TMSs, with applorimately 7 TMSs at the N-terminus in adomain that is similar to other members of the 1.B.94 family, and another domain of 5 TMSs at the C-terminus that resembles the proteins with TC# 8.A.128.2.4 and 3.		UP of Mycobacterium shinjukuense

1.B.94.1.6	PPE domain-containing protein of 626 aas and ~ 10 TMSs.		PPE protein of Mycobacterium tuberculosis

1.B.94.1.7	PPE20 of 539 aas and ~ 8 TMSs.		PPE20 of Mycobacterium canettii

1.B.94.1.8	*Outer membrane porin PPE family protein, MT0318, of 3,186 aas and many (> 8) repeat units (Pajón et al.* 2006).**		MT0318 of Mycobacterium tuberculosis

1.B.94.1.9	*The Proline-Proline-Glutamate (PPE) Family protein, PPE64, of 552 aas. It is a heme-binding protein and forms pores in the outer membrane of Mycobacterium tuberculosis* (Sankey et al. 2023).**		PPE64 of Mycobacterium tuberculosis