Disease relevance of MT2600

• The Condensing Activities of the Mycobacterium tuberculosis Type II Fatty Acid Synthase Are Differentially Regulated by Phosphorylation [1].
• Cloning, sequencing and characterization of a fatty acid synthase-encoding gene from Mycobacterium tuberculosis var. bovis BCG [2].

High impact information on MT2600

• One enzyme, AcpS, activates the two fatty acid synthase systems of mycobacteria, whereas the other PPTase, PptT, acts on type-I polyketide synthases and nonribosomal peptide synthases, both of which are involved in the biosynthesis of virulence factors [3].
• Here we show that isoniazid induced several genes that encode proteins physiologically relevant to the drug's mode of action, including an operonic cluster of five genes encoding type II fatty acid synthase enzymes and fbpC, which encodes trehalose dimycolyl transferase [4].
• In mycobacteria, long chain acyl-CoA products (C(14)-C(26)) generated by a type I fatty-acid synthase can be used directly for the alpha-branch of mycolic acid or can be extended by a type II fatty-acid synthase to make the meromycolic acid (C(50)-C(56)))-derived component [5].
• The long-chain alpha-alkyl-beta-hydroxy fatty acids, termed mycolic acids, which are characteristic components of the mycobacterial cell wall are produced by successive rounds of elongation catalyzed by a multifunctional (type I) fatty acid synthase complex followed by a dissociated (type II) fatty acid synthase [6].
• This fatty acid synthase elongated long-chain fatty acyl-CoA primers using methylmalonyl-CoA and NADPH to produce multimethyl-branched mycocerosic acids [7].

Chemical compound and disease context of MT2600

• Fatty acid biosynthesis in Mycobacterium tuberculosis var. bovis Bacillus Calmette-Guérin. Purification and characterization of a novel fatty acid synthase, mycocerosic acid synthase, which elongates n-fatty acyl-CoA with methylmalonyl-CoA [7].
• Isoniazid affects multiple components of the type II fatty acid synthase system of Mycobacterium tuberculosis [8].
• The Mycobacterium tuberculosis acyl-coenzyme A (CoA) carboxylases provide the building blocks for de novo fatty acid biosynthesis by fatty acid synthase I (FAS I) and for the elongation of FAS I end products by the FAS II complex to produce meromycolic acids [9].

Biological context of MT2600

• By comparing the Fas aa sequence with the sequences in the active site regions of known fas and polyketide synthase-encoding genes, the functional catalytic domains in Fas were identified [2].
• Domain Analysis of Fatty Acid Synthase Protein (NP_217040) from Mycobacterium tuberculosis H37Rv -- A Bioinformatics Study [10].
• The results showed that the resistant strain did not exhibit the characteristic gene-expression signature of type II fatty acid synthase (FAS-II) inhibition when exposed to low-level INH, but it responded with that specific pattern under high-level INH, although the response profile was somewhat shrunken relative to that for a susceptible strain [11].

Anatomical context of MT2600

• Cerulenin is a potent inhibitor of fatty acid synthase (FAS) in a variety of prokaryotic and eukaryotic cells [12].

Associations of MT2600 with chemical compounds

• Genetic and biochemical evidence has implicated two different target enzymes for isoniazid (INH) within the unique type II fatty acid synthase (FAS) system involved in the production of mycolic acids [8].
• Pyrazinoic Acid and Its n-Propyl Ester Inhibit Fatty Acid Synthase Type I in Replicating Tubercle Bacilli [13].
• In addition, the BCG-specific reduction in phospholipids and mycolic acids suggests the presence of a unique cerulenin-sensitive FAS system in tuberculous mycobacteria [12].
• Effects of pyrazinamide on fatty acid synthesis by whole mycobacterial cells and purified fatty acid synthase I [14].
• Fatty acid synthase required both NADH (Km, 11 microM) and NADPH (Km, 14 microM) [15].

Other interactions of MT2600

• Despite this complexity, a preponderance of evidence implicates inhA, which codes for an enoyl-acyl carrier protein reductase of the fatty acid synthase II (FASII), as the primary target of INH [16].

References