Structure and biogenesis of high molecular weight lipids from. Thiolactomycin and related analogues as novel anti-mycobacterial agents targeting KasA and KasB condensing enzymes in. Mycolic acids, a homologous series of C60-C90 long-chain alpha-alkyl-&beta-hydroxy fatty acids, represent essential components of the mycobacterial cell wall. However, their mycolates are longer, on average, than the mycolates of other species (see Table I). of Molecular and Cell Biology, 229 Stanley Hall, University of California, Berkeley, CA 94720-3206. Conditional depletion of KasA, a key enzyme of mycolic acid biosynthesis, leads to mycobacterial cell lysis. The adjuvant activity of the mycobacterial lipid extract from. Targeting unique steps in MA pathway already inhibited by a current antibiotic, e.g., INH, is an effective strategy for anti-TB drug discovery by potentially bypassing existing resistance to current pathway inhibitors, especially in the context of MDR, XDR, and TDR TB. Image, Download Hi-res The M. chelonae strain has been described (7). Typical accumulation curves are shown in Fig. Studies on the virulence of tubercle bacilli; isolation and biological properties of a constituent of virulent organisms. The outer membrane contains an inner leaflet of very long chain mycolic acids… barrier by studying the physical organization of the cell wall lipids. Thermal transitions of MAMEs of various classes. Inhibition of mycolic acid transport across the, SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of. Until recently, the structures of MAs of genera other than that of mycobacteria were considered to be relatively simple in terms of chemical functions, being composed only of a homologous series with various numbers of double bonds, with up to six for some, Mycolic acid patterns of four vaccine strains of. NMR samples were analyzed in deuterochloroform on a Varian Unity Plus 500 MHz spectrometer. (ii) for isolation of intact wax ester mycolates, total mycolic acids were isolated using the milder 5% tetrabutylammonium Following esterification, the total mycolates were precipitated with toluene:acetonitrile and purified wax ester mycolates 6). Similarly, higher initial rates of accumulation for chenodeoxycholate were observed in M. avium A5 grown at lower temperatures (data not shown). The low fluidity of cell wall lipids was not limited to the previously studied M. chelonae and was indeed found in all of the mycobacterial species studied (Table I). have a phase transition temperature that was linearly related to the amount of trans-mycolate. described earlier (23), we confirmed that M. avium from each growth temperature released only tetracosanoic acid, suggesting that the length of the α-branch does not change we believe that the fraction of trans structure is likely to make a significant contribution. (9, 10). M. avium, where a lower growth temperature decreased the fraction of mycolates containing trans-cyclopropanes and was associated with a low melting temperature (Fig. [Structure of mycolic acids and an intermediate in the biosynthesis of dicarboxylic mycolic acids]. The rates of entry of norfloxacin and chenodeoxycholate by M. smegmatis indeed increased 2.5- and 3.8-fold, respectively, when assay temperature was raised by 10°C from those temperatures used Structure and mechanism. calorimeter. In the cell walls from organisms grown at 18, 30, 37 or 45°C, the highest thermal transitions A polyketide synthase catalyzes the last condensation step of mycolic acid biosynthesis in. (2). acids are composed of two aligned branches. In some species, the oxygen-containing group in the meromycolate branch is a carboxylic ester, producing wax ester mycolates. Dept. Apparently, during these cycles MAMEs become aligned spontaneously to form an and analyzed each of these mixed mycolate preparations by 1H NMR. Separation and analysis of novel polyunsaturated mycolic acids from a psychrophilic, acid-fast bacterium. range at 10°C/h; data were collected at 10-s intervals. Exposure of mycobacteria to cell wall-inhibitory drugs decreases production of arabinoglycerolipid related to mycolyl-arabinogalactan-peptidoglycan metabolism. phago-lysosome fusion and is often considered to be an indicator of The M. avium cell wall containing these trans-mycolates melted at a temperature higher by 3°C than the cell wall of M. tuberculosis H37Rv, which contained significantly lower fraction of such compounds (0, 0, and 17% trans in α-, methoxy-, and ketomycolates, respectively (Fig. Some problems concerning biological C-alkylation reactions and phytosterol biosynthesis. Thus, introduction of even a cis-cyclopropane in the proximal position of meromycolate actually increases the melting temperature. fluidity occurring in the innermost part.
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