InhA, the primary target for the first line anti-tuberculosis drug isoniazid, is a key enzyme of the fatty-acid synthase II system involved in mycolic acid biosynthesis in Mycobacterium tuberculosis. In this study, we show that InhA is a substrate for mycobacterial serine/threonine protein kinases. Using a novel approach to validate phosphorylation of a substrate by multiple kinases in a surrog...

InhA, the primary target for the firstline anti-tuberculosis drug isoniazid, is a key enzyme of the Fatty Acid Synthase-II system involved in mycolic acid biosynthesis in Mycobacterium tuberculosis. In the present study, we show that InhA is a substrate for mycobacterial serine/threonine protein kinases. Using a novel approach to validate phosphorylation of a substrate by multiple kinases in a ...

Tuberculosis (TB) ranks second, next to AIDS making it most formidable disease if the present age. One of the crucial enzymes involved in cell wall synthesis of Mycobacterium tuberculosis, InhA (enoyl acyl carrier protein reductase) has been authenticated as an effective target for anti-mycobacterial drug development. In the current work, we have developed novel derivatives of 1,2,4-triazole-5-...

STUDIES ON BLOOD-BRAIN BARRIER DISRUPTION IN ANTHRAX MENINGITIS Dhritiman V. Mukherjee, Ph.D. George Mason University, 2009 Dissertation Director: Dr. Serguei G. Popov B. anthracis causes hemorrhagic meningitis. The pathogenesis and molecular mechanisms associated with blood-brain barrier (BBB) dysfunction in anthrax meningitis remain poorly understood. We reported previously that anthrax-secre...

Adrenocortical carcinoma (ACC) is a rare, but highly malignant tumor of unknown origin. Inhibin α-subunit (Inha) knockout mice develop ACCs following gonadectomy. In man, INHA expression varies widely within ACC tissues and its circulating peptide inhibin pro-αC has been described as a novel tumor marker for ACC. We investigated whether genetic and epigenetic changes of the INHA gene in human A...

OBJECTIVES Enoyl acyl-carrier-protein reductase (InhA), the primary endogenous target for isoniazid and ethionamide, is crucial to type-II fatty acid biosynthesis (FAS-II). The objectives of this study were first to generate InhA mutants of Mycobacterium aurum, secondly to characterize InhA-mediated isoniazid and ethionamide resistance mechanisms across those mutants and finally to investigate ...

The mechanism of action of isoniazid (INH), a first-line antituberculosis drug, is complex, as mutations in at least five different genes (katG, inhA, ahpC, kasA, and ndh) have been found to correlate with isoniazid resistance. 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 t...

A target of the anti-tuberculosis drugs isoniazid (INH) and ethionamide (ETH) has been shown to be an enoyl reductase, encoded by the inhA gene. The mabA (mycolic acid biosynthesis A) gene is located immediately upstream of inhA in Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium smegmatis. The MabA protein from M. tuberculosis was expressed in Escherichia coli and shown to hav...

InhA, the enoyl-ACP reductase in Mycobacterium tuberculosis is an attractive target for the development of novel drugs against tuberculosis, a disease that kills more than two million people each year. InhA is the target of the current first line drug isoniazid for the treatment of tuberculosis infections. Compounds that directly target InhA and do not require activation by the mycobacterial ca...

Isoniazid (INH), a frontline antitubercular drug, inhibits InhA, the enoyl reductase from Mycobacterium tuberculosis, by forming a covalent adduct with the NAD cofactor. Here, we report that the INH-NAD adduct is a slow, tight-binding competitive inhibitor of InhA. Demonstration that the adduct binds to WT InhA by a two-step enzyme inhibition mechanism, with initial, weak binding (K(-1) = 16 +/...