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Drug resistance to almost all antibiotics of Shigella flexneri, a major cause of shigellosis in developing countries, necessitates continuous discovery of novel therapeutics. This study reports a structure-function analysis of a potential drug target serine acetyltransferase (CysE), an enzyme of de novo cysteine biosynthesis pathway that is absent in humans. Analysis of CysE sequences of S. flexneri species and serotypes displayed only two variants that differed by a single amino acid substitution at position 241. Structural inspection of the available crystal structure disclosed this site to be distinct from the substrate/cofactor binding pockets or dimer/trimer interfaces. This study discovers that V241 variant of S. flexneri CysE has nearly null enzymatic activity. The observation is explained by molecular dynamic studies which reveal that the disorder generated by A241V substitution is the basis of dissociation of the quaternary assembly of S. flexneri CysE leading to loss of enzymatic activity and stability. The study provides the first evidence that position 241 of CysE, affects the catalytic efficiency of enzyme and suggests this locus as a 'hot spot' for the propagation of conformational changes. It may be postulated that transient quaternary structure of CysE maybe another mechanism for regulating the intracellular level of cysteine., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The antimicrobial resistant strains of several pathogens are major culprits of hospital-acquired nosocomial infections. An active and urgent action is necessary against these pathogens for the development of unique therapeutics. The cysteine biosynthetic pathway or genes (that are absent in humans) involved in the production of L-cysteine appear to be an attractive target for developing novel antibiotics. CysE, a Serine Acetyltransferase (SAT), catalyzes the first step of cysteine synthesis and is reported to be essential for the survival of persistence in several microbes including Mycobacterium tuberculosis. Structure determination provides fundamental insight into structure and function of protein and aid in drug design/discovery efforts. This review focuses on the overview of current knowledge of structure function, regulatory mechanism, and potential inhibitors (active site as well as allosteric site) of CysE. Despite having conserved structure, slight modification in CysE structure lead to altered the regulatory mechanism and hence affects the cysteine production. Due to its possible role in virulence and vital metabolism of pathogens makes it a potential target in the quest to develop novel therapeutics to treat multi-drug-resistant bacteria. [ABSTRACT FROM AUTHOR]