Aspartate aminotransferase Rv3722c governs aspartate-dependent nitrogen metabolism in Mycobacterium tuberculosis

Abstract

Gene rv3722c of Mycobacterium tuberculosis is essential for in vitro growth, and encodes a putative pyridoxal phosphate-binding protein of unknown function. Here we use metabolomic, genetic and structural approaches to show that Rv3722c is the primary aspartate aminotransferase of M. tuberculosis, and mediates an essential but underrecognized role in metabolism: nitrogen distribution. Rv3722c deficiency leads to virulence attenuation in macrophages and mice. Our results identify aspartate biosynthesis and nitrogen distribution as potential species-selective drug targets in M. tuberculosis.

Rv3722c Promotes Mycobacterium tuberculosis Survival in Macrophages by Interacting With TRAF3

“…It has been shown that aspartate aminotransferase R3722c mediates an essential role in metabolism and is required for virulence of M.tb ( Jansen et al., 2020 ). Previously, we constructed a filtered PPI network with 441 PPIs between M.tb membrane and secreted proteins and host immunity-related proteins ( Yang et al., 2018 ).…”

“…As Rv3722c is essential for M.tb growth in vitro and interacts with host proteins such as TRAF3 (Yang et al, 2018;Jansen et al, 2020), we hypothesized this protein might play an important role Verification of the protein-protein interaction by Y2H assay. Rv3722c in the pmBD destination vector was used as bait.…”

“…MPT53, an M.tb secreted disulfide-bond-forming-like protein, interacts with TAK1 in a TLR2- or MyD88-independent manner, and induces the host inflammatory responses ( Wang et al., 2019 ). Rv3722c, an M.tb secreted antigen, is annotated as an aspartate aminotransferase, which is a transcription factor that belongs to the GntR family ( Grishin et al., 1995 ; Bramucci et al., 2011 ; Ortega et al., 2016 ; Penn et al., 2018 ; El-Gebali et al., 2019 ; Yang et al., 2019 ; Jansen et al., 2020 ). Proteomics analysis revealed that Rv3722c belongs to the top 10–25% of the most abundant proteins in M.tb ( Wang M, et al., 2015 ).…”

“…Proteomics analysis revealed that Rv3722c belongs to the top 10–25% of the most abundant proteins in M.tb ( Wang M, et al., 2015 ). Rv3722c was identified to be essential for bacillus growth in vitro and infection ( Griffin et al., 2011 ; Jansen et al., 2020 ). Previously, we identified that Rv3722c can interact with host immune-related proteins in different pathways ( Yang et al., 2018 ), suggesting that Rv3722c may play an important role in disturbing host immune clearance.…”

Who Is Metabolizing What? Discovering Novel Biomolecules in the Microbiome and the Organisms Who Make Them

“…ABPP can help address this challenge, as ABP-labeling directly signifies protein function (Adam et al, 2004 ; Kamat et al, 2015 ; Xu et al, 2015 ; Martell et al, 2016 ; Ortega et al, 2018 ; Elahi et al, 2019 ). This is especially true when accompanying metabolomics data can provide added confidence (Jansen et al, 2020 ). ABPP can also identify viable whole cells in complex samples based on a certain function without needing any information beforehand, which may aid in the study of un-culturable microbes with poorly characterized genomes.…”