scholarly journals MmpL3, the trehalose monomycolate transporter, is stable in solution in several detergents and can be reconstituted into peptidiscs

2021 ◽  
pp. 106014
Author(s):  
Kien Lam Ung ◽  
Husam Alsarraf ◽  
Laurent Kremer ◽  
Mickaël Blaise
Keyword(s):  
Trehalose Monomycolate

scholarly journals The crystal structure of the mycobacterial trehalose monomycolate transport factor A, TtfA, reveals an atypical fold

2019 ◽  
Vol 88 (6) ◽  
pp. 809-815 ◽  
Author(s):  
Kien Lam Ung ◽  
Husam M. A. B. Alsarraf ◽  
Laurent Kremer ◽  
Mickaël Blaise
Keyword(s):  
Crystal Structure ◽  
Transport Factor ◽  
Trehalose Monomycolate

scholarly journals MmpL3 is a lipid transporter that binds trehalose monomycolate and phosphatidylethanolamine

2019 ◽  
Vol 116 (23) ◽  
pp. 11241-11246 ◽  
Author(s):  
Chih-Chia Su ◽  
Philip A. Klenotic ◽  
Jani Reddy Bolla ◽  
Georgiana E. Purdy ◽  
Carol V. Robinson ◽  
...  
Keyword(s):  
Cell Wall ◽  
Cell Envelope ◽  
Native Mass Spectrometry ◽  
Mycolic Acids ◽  
Mycobacterial Cell ◽  
Exact Function ◽  
Species Specific ◽  
Mycobacterial Cell Wall ◽  
Trehalose Monomycolate ◽  
Lipid Transporter

The cell envelope ofMycobacterium tuberculosisis notable for the abundance of mycolic acids (MAs), essential to mycobacterial viability, and of other species-specific lipids. The mycobacterial cell envelope is extremely hydrophobic, which contributes to virulence and antibiotic resistance. However, exactly how fatty acids and lipidic elements are transported across the cell envelope for cell-wall biosynthesis is unclear. Mycobacterial membrane protein Large 3 (MmpL3) is essential and required for transport of trehalose monomycolates (TMMs), precursors of MA-containing trehalose dimycolates (TDM) and mycolyl arabinogalactan peptidoglycan, but the exact function of MmpL3 remains elusive. Here, we report a crystal structure ofMycobacterium smegmatisMmpL3 at a resolution of 2.59 Å, revealing a monomeric molecule that is structurally distinct from all known bacterial membrane proteins. A previously unknown MmpL3 ligand, phosphatidylethanolamine (PE), was discovered inside this transporter. We also show, via native mass spectrometry, that MmpL3 specifically binds both TMM and PE, but not TDM, in the micromolar range. These observations provide insight into the function of MmpL3 and suggest a possible role for this protein in shuttling a variety of lipids to strengthen the mycobacterial cell wall.

Syntheses of Trehalose Monomycolate and Related Compounds, and Their Lethal Toxicity and Adjuvant Activity

1986 ◽  
Vol 5 (1) ◽  
pp. 127-138 ◽  
Author(s):  
Fumio Numata ◽  
Hideharu Ishida ◽  
Keiko Nishimura ◽  
Isao Sekikawa ◽  
Ichiro Azuma
Keyword(s):  
Adjuvant Activity ◽  
Lethal Toxicity ◽  
Trehalose Monomycolate ◽  
Related Compounds

A chemical reporter strategy for detecting and identifying O-mycoloylated proteins in Corynebacterium

2016 ◽  
Vol 52 (95) ◽  
pp. 13795-13798 ◽  
Author(s):  
Herbert W. Kavunja ◽  
Brent F. Piligian ◽  
Taylor J. Fiolek ◽  
Hannah N. Foley ◽  
Temitope O. Nathan ◽  
...  
Keyword(s):  
Chemical Reporter ◽  
Trehalose Monomycolate

A trehalose monomycolate (TMM)-mimicking chemical reporter facilitated the investigation of a recently discovered class of lipidated proteins in the Corynebacterineae.

scholarly journals Pathway to Synthesis and Processing of Mycolic Acids in Mycobacterium tuberculosis

2005 ◽  
Vol 18 (1) ◽  
pp. 81-101 ◽  
Author(s):  
Kuni Takayama ◽  
Cindy Wang ◽  
Gurdyal S. Besra
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Fatty Acid ◽  
Candidate Genes ◽  
Abc Transporter ◽  
Polyketide Synthase ◽  
Acyl Carrier Protein ◽  
Fatty Acid Synthetase ◽  
Mycolic Acids ◽  
Trehalose Dimycolate ◽  
Trehalose Monomycolate

SUMMARY Mycobacterium tuberculosis is known to synthesize α-, methoxy-, and keto-mycolic acids. We propose a detailed pathway to the biosynthesis of all mycolic acids in M. tuberculosis. Fatty acid synthetase I provides C20-S-coenzyme A to the fatty acid synthetase II system (FAS-IIA). Modules of FAS-IIA and FAS-IIB introduce cis unsaturation at two locations on a growing meroacid chain to yield three different forms of cis,cis-diunsaturated fatty acids (intermediates to α-, methoxy-, and keto-meroacids). These are methylated, and the mature meroacids and carboxylated C26-S-acyl carrier protein enter into the final Claisen-type condensation with polyketide synthase-13 (Pks13) to yield mycolyl-S-Pks13. We list candidate genes in the genome encoding the proposed dehydrase and isomerase in the FAS-IIA and FAS-IIB modules. We propose that the processing of mycolic acids begins by transfer of mycolic acids from mycolyl-S-Pks13 to d-mannopyranosyl-1-phosphoheptaprenol to yield 6-O-mycolyl-β-d-mannopyranosyl-1-phosphoheptaprenol and then to trehalose 6-phosphate to yield phosphorylated trehalose monomycolate (TMM-P). Phosphatase releases the phosphate group to yield TMM, which is immediately transported outside the cell by the ABC transporter. Antigen 85 then catalyzes the transfer of a mycolyl group from TMM to the cell wall arabinogalactan and to other TMMs to produce arabinogalactan-mycolate and trehalose dimycolate, respectively. We list candidate genes in the genome that encode the proposed mycolyltransferases I and II, phosphatase, and ABC transporter. The enzymes within this total pathway are targets for new drug discovery.

First access to a mycolic acid-based bioorthogonal reporter for the study of the mycomembrane and mycoloyltransferases in Corynebacteria

2019 ◽  
Vol 55 (87) ◽  
pp. 13074-13077
Author(s):  
Emilie Lesur ◽  
Aurélie Baron ◽  
Christiane Dietrich ◽  
Marie Buchotte ◽  
Gilles Doisneau ◽  
...  
Keyword(s):  
Mycolic Acid ◽  
Complex Pattern ◽  
Mycolic Acids ◽  
Trehalose Monomycolate

In this study we describe the first synthesis of an alkyne-based trehalose monomycolate probe closely mimicking the complex pattern of mycolic acids and its utility for the study of mycomembrane and mycoloyltransferases in Corynebacteria.

scholarly journals Differences in serological responses to specific glycopeptidolipid-core and common lipid antigens in patients with pulmonary disease due to Mycobacterium tuberculosis and Mycobacterium avium complex

2006 ◽  
Vol 55 (2) ◽  
pp. 189-199 ◽  
Author(s):  
Yukiko Fujita ◽  
Takeshi Doi ◽  
Ryoji Maekura ◽  
Masami Ito ◽  
Ikuya Yano
Keyword(s):  
Pulmonary Disease ◽  
Mycobacterium Avium ◽  
Control Level ◽  
Specific Antigen ◽  
Healthy Controls ◽  
Igg Antibody ◽  
Lipid Antigens ◽  
Antigen Elisa ◽  
Multiple Antigen ◽  
Trehalose Monomycolate

Disease due to the Mycobacterium avium complex (MAC) is one of the most important opportunistic pulmonary infections. Since the clinical features of MAC pulmonary disease and tuberculosis (TB) resemble each other, and the former is often difficult to treat with chemotherapy, early differential diagnosis is desirable. The humoral immune responses to both diseases were compared by a unique multiple-antigen ELISA using mycobacterial species-common and species-specific lipid antigens, including glycopeptidolipid (GPL)-core. The results were assessed for two patient groups hospitalized and diagnosed clinically as having TB or MAC pulmonary disease. Diverse IgG antibody responsiveness was demonstrated against five lipid antigens: (1) monoacyl phosphatidylinositol dimannoside (Ac-PIM2), (2) cord factor (trehalose 6,6′-dimycolate) (TDM-T) and (3) trehalose monomycolate from Mycobacterium bovis Bacillus Calmette-Guérin (BCG) (TMM-T), and (4) trehalose monomycolate (TMM-M) and (5) GPL-core from MAC. Anti-GPL-core IgG antibody was critical, and detected only in the primary and the secondary MAC diseases with high positivity, up to 88·4 %. However, IgG antibodies against Ac-PIM2, TDM-T and TMM-T were elevated in both TB and MAC patients. Anti-TMM-M IgG antibody was also elevated in MAC disease preferentially, with a positive rate of 89·9 %, and therefore, it was also useful for the diagnosis of the disease. IgG antibody levels were increased at the early stages of the disease and declined in parallel to the decrease of bacterial burden to near the normal healthy control level, when the anti-mycobacterial chemotherapy was completed successfully. Unexpectedly, about 25 % of hospitalized TB patient sera were anti-GPL-core IgG antibody positive, although the specificity of GPL-core was sufficiently high (95·8 % negative in healthy controls), suggesting that a considerable number of cases of latent co-infection with MAC may exist in TB patients. Taken together, the combination of multiple-antigen ELISA using mycobacterial lipids, including GPL-core and TMM-M, gives good discrimination between healthy controls and sera from patients with TB or MAC disease, although for accurate diagnosis of TB more specific antigen(s) are needed.

scholarly journals SQ109 Targets MmpL3, a Membrane Transporter of Trehalose Monomycolate Involved in Mycolic Acid Donation to the Cell Wall Core of Mycobacterium tuberculosis

2012 ◽  
Vol 56 (4) ◽  
pp. 1797-1809 ◽  
Author(s):  
Kapil Tahlan ◽  
Regina Wilson ◽  
David B. Kastrinsky ◽  
Kriti Arora ◽  
Vinod Nair ◽  
...  
Keyword(s):  
Cell Wall ◽  
Mycobacterium Tuberculosis ◽  
Mycolic Acid ◽  
Spontaneous Generation ◽  
Content Type ◽  
Mycolic Acids ◽  
Cell Wall Assembly ◽  
Resistant Mutants ◽  
Trehalose Monomycolate

ABSTRACTSQ109, a 1,2-diamine related to ethambutol, is currently in clinical trials for the treatment of tuberculosis, but its mode of action remains unclear. Here, we demonstrate that SQ109 disrupts cell wall assembly, as evidenced by macromolecular incorporation assays and ultrastructural analyses. SQ109 interferes with the assembly of mycolic acids into the cell wall core ofMycobacterium tuberculosis, as bacilli exposed to SQ109 show immediate inhibition of trehalose dimycolate (TDM) production and fail to attach mycolates to the cell wall arabinogalactan. These effects were not due to inhibition of mycolate synthesis, since total mycolate levels were unaffected, but instead resulted in the accumulation of trehalose monomycolate (TMM), the precursor of TDM and cell wall mycolates.In vitroassays using purified enzymes showed that this was not due to inhibition of the secreted Ag85 mycolyltransferases. We were unable to achieve spontaneous generation of SQ109-resistant mutants; however, analogs of this compound that resulted in similar shutdown of TDM synthesis with concomitant TMM accumulation were used to spontaneously generate resistant mutants that were also cross-resistant to SQ109. Whole-genome sequencing of these mutants showed that these all had mutations in the essentialmmpL3gene, which encodes a transmembrane transporter. Our results suggest that MmpL3 is the target of SQ109 and that MmpL3 is a transporter of mycobacterial TMM.

scholarly journals Detection of live mycobacteria with a solvatochromic trehalose probe for point-of-care tuberculosis diagnosis

2017 ◽  
Author(s):  
M. Kamariza ◽  
P. Shieh ◽  
F. P. Rodriguez-Rivera ◽  
C. S. Ealand ◽  
B. Chu ◽  
...  
Keyword(s):  
Point Of Care ◽  
Patient Treatment ◽  
Diagnostic Tools ◽  
Bacterial Disease ◽  
Simple Method ◽  
Tb Control ◽  
Control Programs ◽  
Tuberculosis Diagnosis ◽  
Trehalose Monomycolate ◽  
Affect Patient Care

Abstract:Tuberculosis (TB) is the leading cause of death from an infectious bacterial disease. Poor diagnostic tools to detect active disease plague TB control programs and affect patient care. Accurate detection of live Mycobacterium tuberculosis (Mtb), the causative agent of TB, will improve TB diagnosis and patient treatment. We report that live mycobacteria can be specifically detected with a fluorogenic trehalose analog. We designed a 4-N,N-dimethylamino-1,8- naphthalimide-trehalose (DMN-Tre) conjugate that undergoes >700-fold fluorescence increase when transitioned from aqueous to hydrophobic environments. This enhancement occurs upon metabolic conversion of DMN-Tre to trehalose monomycolate and incorporation into the outer membrane. DMN-Tre labeling enabled the rapid, no-wash visualization of mycobacterial and corynebacterial species without nonspecific labeling of Gram-positive or –negative bacteria. DMN-Tre labeling was selective for live mycobacteria and was reduced by treatment with TB drugs. Lastly, DMN-Tre labeled Mtb in TB-positive sputum samples suggesting this operationally simple method may be deployable for TB diagnosis.

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