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      Lessons Learnt and the Way Forward for Drug Development Against Isocitrate Lyase from Mycobacterium tuberculosis.

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          Abstract

          Isocitrate lyase (ICL), an enzyme of the glyoxylate shunt pathway, is essential for the virulence and persistence of dreaded Mycobacterium tuberculosis (Mtb) in its host. This pathway, along with the methylcitrate cycle, facilitates the utilization of fatty acids as a carbon source inside hostile host environments such as in granulomas, and hence enzymes of this pathway are novel antitubercular targets. The genome sequence of pathogenic Mtb H37Rv presents three ICLs annotated as Rv0467 (prokaryotic homologue), Rv1915 and Rv1916. The latter two, Rv1915 and Rv1916, together constitute the longer version of ICL2, a eukaryotic counterpart. Despite being a well-known drug target, no Mtb ICL inhibitor has reached clinical trials due to challenges associated with targeting all the 3 orthologs. This gap is the result of uncharacterized Rv1915 and Rv1916. This review aims to appreciate chronologically the key studies that have built our comprehension of Mtb ICLs. Recently characterized Mtb Rv1915 and Rv1916, which further open venues for developing effective inhibitors against the persistent and drug-resistant Mtb, are discussed separately.

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          Author and article information

          Journal
          Protein Pept Lett
          Protein and peptide letters
          Bentham Science Publishers Ltd.
          1875-5305
          0929-8665
          2022
          : 29
          : 12
          Affiliations
          [1 ] Department of Biotechnology, Jaypee Institute of Information Technology, Noida - 201309, India.
          Article
          PPL-EPUB-126817
          10.2174/0929866529666221006121831
          36201276
          63c112c1-81ff-4ed7-a3e8-b994e53dd92c
          History

          drug development,Mycobacterium tuberculosis,Glyoxylate shunt pathway,proteogenomics,phylogenetic analysis,isocitrate lyase

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