The center of attention: IscS cysteine desulfurases and IscU scaffolds are involved in biological iron–sulfur cluster assembly. The X‐ray structure of an anaerobically produced, mutated (Fe2S2‐(IscS‐IscUD35A))2 complex reveals a cluster coordinated by three IscU cysteines and the IscS active cysteine (see picture). In air‐exposed crystals the cluster is oxidized to an Fe2S–S center; D35 is essential for complex dissociation.
Tuberculosis made a resurgence in the mid-1980s and now kills approximately 3 million people a year. The re-emergence of tuberculosis as a public health threat, the high susceptibility of HIV-infected persons and the proliferation of multi-drug-resistant strains have created a need to develop new drugs. Shikimate kinase and other enzymes in the shikimate pathway are attractive targets for development of non-toxic antimicrobial agents, herbicides and anti-parasitic drugs, because the pathway is essential in these species whereas it is absent from mammals. The crystal structure of shikimate kinase from Mycobacterium tuberculosis (MtSK) complexed with MgADP and shikimic acid (shikimate) has been determined at 2.3 A resolution, clearly revealing the amino-acid residues involved in shikimate binding. This is the first three-dimensional structure of shikimate kinase complexed with shikimate. In MtSK, the Glu61 residue that is strictly conserved in shikimate kinases forms a hydrogen bond and salt bridge with Arg58 and assists in positioning the guanidinium group of Arg58 for shikimate binding. The carboxyl group of shikimate interacts with Arg58, Gly81 and Arg136 and the hydroxyl groups interact with Asp34 and Gly80. The crystal structure of MtSK-MgADP-shikimate will provide crucial information for the elucidation of the mechanism of the shikimate kinase-catalyzed reaction and for the development of a new generation of drugs against tuberculosis.
Tuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis. The reemergence of tuberculosis as a potential public health threat, the high susceptibility of human immunodeficiency virus-infected persons to the disease, and the proliferation of multi-drug-resistant strains have created a need for the development of new antimycobacterial agents. Mycolic acids, the hallmark of mycobacteria, are high-molecular-weight alpha-alkyl, beta-hydroxy fatty acids, which appear mostly as bound esters in the mycobacterial cell wall. The product of the M. tuberculosis inhA structural gene (InhA) has been shown to be the primary target for isoniazid (INH), the most prescribed drug for active TB and prophylaxis. InhA was identified as an NADH-dependent enoyl-ACP reductase specific for long-chain enoyl thioesters. InhA is a member of the mycobacterial Type II fatty acid biosynthesis system, which elongates acyl fatty acid precursors of mycolic acids. Although the history of chemotherapeutic agent development demonstrates the remarkably successful tinkering of a few structural scaffolds, it also emphasizes the ongoing, cyclical need for innovation. The main focus of our contribution is on new data describing the rationale for the design of a pentacyano(isoniazid)ferrateII compound that requires no KatG-activation, its chemical characterization, in vitro activity studies against WT and INH-resistant I21V M. tuberculosis enoyl reductases, the slow-onset inhibition mechanism of WT InhA by the inorganic complex, and molecular modeling of its interaction with WT InhA. This inorganic complex represents a new class of lead compounds to the development of anti-tubercular agents aiming at inhibition of a validated target.
The in vitro kinetics of inactivation of both wild-type and I21V InhA enzymes by [FeII(CN)5(INH)]3- indicate that this process requires no activation by KatG, and no need for the presence of NADH. This inorganic complex may represent a new class of lead compounds to the development of anti-tubercular agents aiming at inhibition of a validated target.
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