SUMO fused Trehalose Synthase (TreS) of Mycobacterium tuberculosis
Components
SUMO fused Trehalose Synthase (TreS),Trehalose synthase/amylase TreS
Keywords
SUGAR BINDING PROTEIN / TreS / Trehalose Synthase / Mycobacterium tuberculosis / CYTOSOLIC PROTEIN
Function / homology
Function and homology information
maltose alpha-D-glucosyltransferase / maltose alpha-D-glucosyltransferase activity / SUMO is conjugated to E1 (UBA2:SAE1) / SUMOylation of nuclear envelope proteins / SUMO is transferred from E1 to E2 (UBE2I, UBC9) / SUMO is proteolytically processed / SUMOylation of transcription factors / Postmitotic nuclear pore complex (NPC) reformation / capsule polysaccharide biosynthetic process / SUMOylation of transcription cofactors ...maltose alpha-D-glucosyltransferase / maltose alpha-D-glucosyltransferase activity / SUMO is conjugated to E1 (UBA2:SAE1) / SUMOylation of nuclear envelope proteins / SUMO is transferred from E1 to E2 (UBE2I, UBC9) / SUMO is proteolytically processed / SUMOylation of transcription factors / Postmitotic nuclear pore complex (NPC) reformation / capsule polysaccharide biosynthetic process / SUMOylation of transcription cofactors / SUMOylation of DNA damage response and repair proteins / SUMOylation of DNA replication proteins / septin ring / alpha-amylase / SUMOylation of SUMOylation proteins / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / SUMOylation of RNA binding proteins / glycogen biosynthetic process / SUMOylation of chromatin organization proteins / alpha-amylase activity / ubiquitin-like protein ligase binding / protein sumoylation / polysaccharide catabolic process / condensed nuclear chromosome / PML body / protein tag activity / identical protein binding / nucleus / metal ion binding Similarity search - Function
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
AI105084
United States
Citation
Journal: ACS Infect Dis / Year: 2024 Title: Targeting Persistence through Inhibition of the Trehalose Catalytic Shift. Authors: Karishma Kalera / Rachel Liu / Juhyeon Lim / Rasangi Pathirage / Daniel H Swanson / Ulysses G Johnson / Alicyn I Stothard / Jae Jin Lee / Anne W Poston / Peter J Woodruff / Donald R Ronning ...Authors: Karishma Kalera / Rachel Liu / Juhyeon Lim / Rasangi Pathirage / Daniel H Swanson / Ulysses G Johnson / Alicyn I Stothard / Jae Jin Lee / Anne W Poston / Peter J Woodruff / Donald R Ronning / Hyungjin Eoh / Benjamin M Swarts / Abstract: Tuberculosis (TB), caused by (Mtb), is the leading cause of death worldwide by infectious disease. Treatment of Mtb infection requires a six-month course of multiple antibiotics, an extremely ...Tuberculosis (TB), caused by (Mtb), is the leading cause of death worldwide by infectious disease. Treatment of Mtb infection requires a six-month course of multiple antibiotics, an extremely challenging regimen necessitated by Mtb's ability to form drug-tolerant persister cells. Mtb persister formation is dependent on the trehalose catalytic shift, a stress-responsive metabolic remodeling mechanism in which the disaccharide trehalose is liberated from cell surface glycolipids and repurposed as an internal carbon source to meet energy and redox demands. Here, using a biofilm-persister model, metabolomics, and cryo-electron microscopy (EM), we found that azidodeoxy- and aminodeoxy-d-trehalose analogues block the Mtb trehalose catalytic shift through inhibition of trehalose synthase TreS (Rv0126), which catalyzes the isomerization of trehalose to maltose. Out of a focused eight-member compound panel constructed by chemoenzymatic synthesis, the natural product 2-trehalosamine exhibited the highest potency and significantly potentiated first- and second-line TB drugs in broth culture and macrophage infection assays. We also report the first structure of TreS bound to a substrate analogue inhibitor, obtained via cryo-EM, which revealed conformational changes likely essential for catalysis and inhibitor binding that can potentially be exploited for future therapeutic development. Our results demonstrate that inhibition of the trehalose catalytic shift is a viable strategy to target Mtb persisters and advance trehalose analogues as tools and potential adjunctive therapeutics for investigating and targeting mycobacterial persistence.
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