Diarylcoumarins inhibit mycolic acid biosynthesis and …

Tuberculosis (TB) is one of the world's deadliest diseases (). The Centers for Disease Control and Prevention has reported that each year, eight million people around the world become sick with TB and there are over two million TB-related deaths worldwide. Moreover, one-third of the world's population is infected with TB. Thus, Mycobacterium tuberculosis (the causative agent of TB) is clearly the most predominant global human pathogen. Two decades ago, it was thought that TB was under control and that it was a matter of time before it would be eradicated. Today, this disease has reestablished itself due to several factors. The lack of drug compliance, the appearance of multiple-drug-resistant strains, and the AIDS epidemic are a few factors that have led to the resurgence in TB. Drug resistance arises following inadequate compliance, and AIDS patients with weakened immune system are very susceptible to M. tuberculosis and the usual cause of death.

LanéelleThe biosynthesis of mycolic acids by ..

These effects may be a strategy developed bymycobacteria for repressing the host innate immunity.

Mycolic acid; Mycobacterium tuberculosis ..

(iii) Mycolic acid synthesis is the target of well-known antituberculosis drugs, i.e., isoniazid, ethionamide, and thiocarlide (). This suggests that all reactions on the pathway to synthesis and processing of mycolic acids are viable targets for new drug discovery (target validation).

Mycolic acid biosynthesis and ..

(ii) Deletion of the proximal cyclopropane ring of α-mycolate or deletion of the methoxy- and keto-mycolates leads to a significant attenuation of growth of the two mutants in the mouse model of infection. Deletion of keto-mycolates in M. tuberculosis leads to restricted growth of this mutant in macrophages. Thus, the distribution and fine structure of mycolic acids determine the virulence of M. tuberculosis. It can be concluded that mycolic acids are very important components of the pathogenic M. tuberculosis.

the Mycobacterium tuberculosis fatty acid ..

These fatty acids may be of value for the knowledge of biomass and of the metabolic status of the viable microbial community.
A novel dimethylated fatty acid, 12,17-dimethyloctadecanoic acid, has been described in high concentration (16.3 % of total fatty acids) in an extremophile bacteria, sp (Vyssotski M et al., Lipids 2012, 47, 601).
Multimethyl branched acids are abundant in cell wall lipids of Mycobacteria, each methyl group being on even carbon atoms (2,4,6,8...from the methyl end). Thus, forming and glycolipids (), several multibranched fatty acids are commonly found :
- mycolipanolic acid (2,4,6-trimethyltetracosanoic acid).

There are five forms of mycolic acids in M

We wish to identify the gene that encodes the TMM-6-phosphate phosphatase. Two possible trehalose 6-phosphate phosphatase genes (otsB1 and otsB2) were identified in M. tuberculosis (). A recent study demonstrated that recombinant OtsB2 exhibited highly specific trehalose 6-P phosphatase activity, while OtsB1 had no detectable phosphatase activity (). Our analysis of the M. tuberculosis genomic sequence revealed that a probable hydrolase gene (Rv3400) and the N-terminal hydrolase domain of otsB1 (Rv2006) share significant sequence homology with otsB1 and otsB2 (46 to 48% identity and 58 to 59% similarity) (C. Wang and K. Takayama, unpublished results). This is shown in Fig. . An NCBI BLAST search of mycobacterial genomes revealed that otsB1 is unique to the M. tuberculosis and M. bovis genomes, while homologous genes of Rv3400 were found in M. bovis, M. smegmatis, M. marinum, M. leprae, and M. avium. Rv3400 encodes a 262-amino-acid acidic protein that is predicted to be an intracellular protein. This enzyme belongs to a subgroup of phosphatases that use aspartate residues as the active-site nucleophile. A characteristic N-terminal Asp-X1-Asp-X2-Thr/Val motif is conserved in Rv3400 (, ). Variations in the C-terminal motif have been reported for this class of phosphatases (). Computational analysis revealed that Rv3400 is functionally linked with otsB1 (). The gene products of otsB1 and Rv3400 are potential candidates for TMM-P phosphatase (Fig. , reaction 3).

Regulation of Cell Wall Mycolic Acid Biosynthesis in Acid ..

Further analysis of the M. tuberculosis genomic sequence revealed two conserved proteins encoded by Rv0519c and Rv0774c that shared low sequence homology with the protein encoded by Rv1288 (11.0% identity and 30.4% similarity) (C. Wang and K. Takayama, unpublished results). The protein encoded by Rv0774c shares 27% sequence identity and 43% similarity with Rv1288 in a 66-amino-acid overlap, with an E value of 1.3. The protein encoded by Rv0519c shares 29% sequence identity and 48% similarity with Rv1288 in a 114-amino-acid overlap, with an E value of 2.1. The highly homologous proteins encoded by Rv0519c and Rv0774c share 58% sequence identity in a 299-amino-acid overlap, which indicates that these two proteins may have similar cellular functions. Like in Rv1288, the proteins encoded by Rv0519c and Rv0774c belong to the esterase D family (). An NCBI BLAST search of mycobacterial genomes revealed that Rv0519c and Rv0774c have homologous genes in M. bovis, M. smegmatis, M. marinum, and M. avium. A catalytic triad (Ser, His, and Arg) was identified by sequence alignment of proteins encoded by Rv0519c and Rv0774c with mycolyltransferases (FbpA, FbpB, and FbpC) (Fig. ). Rv0519c is predicted to encode a 300-amino-acid basic membrane protein, whereas Rv0774c encodes a 312-amino-acid exported protein. The potential cellular localization of these enzymes is consistent with the proposed functions of transferring mycolic acid from Myc-PL to trehalose 6-phosphate on or close to the inner membrane surface. These two proteins are additional candidates for mycolyltransferase II (Fig. , reaction 2).