Mycobacterial membrane protein Large 3‐like‐family proteins in bacteria, protozoa, fungi, plants, and animals: A bioinformatics and structural investigation

Abstract

Lipid transporters play an important role in most if not all organisms, ranging from bacteria to humans. For example, in Mycobacterium tuberculosis, the trehalose monomycolate transporter MmpL3 is involved in cell wall biosynthesis, while in humans, cholesterol transporters are involved in normal cell function as well as in disease.Here, using structural and bioinformatics information, we propose that there are proteins that also contain "MmpL3-like" (MMPL) transmembrane (TM) domains in many protozoa, including Trypanosoma cruzi, as well as in the bacterium Staphylococcus aureus, where the fatty acid transporter FarE has the same set of "active-site" residues as those found in the mycobacterial MmpL3s, and in T. cruzi. We also show that there are strong sequence and predicted structural similarities between the TM proton-translocation domain seen in the X-ray structures of mycobacterial MmpL3s and several human as well as fungal lipid transporters, leading to the proposal that there are similar proteins in apicomplexan parasites, and in plants. The animal, fungal, apicomplexan, and plant proteins have larger extra-membrane domains than are found in the bacterial MmpL3, but they have a similar TM domain architecture, with the introduction of a (catalytically essential) Phe > His residue change, and a Ser/Thr H-bond network, involved in H + -transport. Overall, the results are of interest since they show that MMPL-family proteins are present in essentially all life forms: archaea, bacteria, protozoa, fungi, plants and animals and, where known, they are involved in "lipid" (glycolipid, phospholipid, sphingolipid, fatty acid, cholesterol, ergosterol) transport, powered by transmembrane molecular pumps having similar structures.

In Vivo Efficacy of SQ109 against Leishmania donovani, Trypanosoma spp. and Toxoplasma gondii and In Vitro Activity of SQ109 Metabolites

“…In the mycobacteria, SQ109 is thought to target primarily the trehalose monomycolate transporter MmpL3 in addition to acting as a protonophore uncoupler [12]. Although there is an MmpL3-like protein in T. cruzi [34], its function is not known, and MmpL3 proteins are not present in T. brucei, L. donovani or in humans. The most likely reason for the strong correlation between the activity of SQ109 and the activity of the mono-oxygenated metabolites is, therefore, likely to be due to a more "physical" effect, for example, differences in cell membrane solubility between the metabolites, leading to differences in uncoupling activity.…”

New possibilities for chromoblastomycosis and phaeohyphomycosis treatment: identification of two compounds from the MMV Pathogen Box® that present synergism with itraconazole

“…Previous studies aiming to search for compounds with antifungal action found activity of the compound MMV687273 (SQ109) against Candida albicans biofilms 33 and Aspergillus fumigatus . 57 SQ109, in addition to exhibiting antibacterial activity against M. tuberculosis , 58 is also active against Trypanosoma cruzi 59 and was recently proposed as a new drug for the treatment of Chagas disease, 59 , 60 strongly suggesting its potential use for the treatment of different infectious diseases. This compound inhibits the trehalose monomycolate transporter MmpL3 in M. tuberculosis , which has homology with sphingolipid transporters found in fungi, 57 suggesting a mechanism of action for this compound distinct to that presented by currently used antifungal drugs.…”

Activity of (1-benzyl-4-triazolyl)-indole-2-carboxamides against Toxoplasma gondii and Cryptosporidium parvum

“…Rationale to prepare and test the triazole analogs of JS-2-02 against T. gondii and C. parvum stems from the fact that the small molecule SQ109, which was originally reported as an effective inhibitor of mycobacterial MmpL3 ( Tahlan et al, 2012 ) and is currently being investigated in clinical trials for tuberculosis, has shown potent efficacy against protozoan parasites including T. gondii ( Li et al, 2015 ; Baek et al, 2022 ). While bona fide MmpL3 transporter has not been identified in T. gondii or C. parvum , MmpL3-like proteins have been proposed to be present in many protozoa among other living organisms ( Malwal et al, 2021 ; Malwal and Oldfield, 2022 ).…”