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Identification and characterization of a thiamine pyrophosphate riboswitch in Mycobacterium tuberculosis: A new drug target in tuberculosis drug design
Author(s) -
Mitra Sunayana,
Aboulela Fareed
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.496.1
Subject(s) - riboswitch , thiamine pyrophosphate , thiamine , mycobacterium tuberculosis , biochemistry , computational biology , biology , drug discovery , chemistry , rna , tuberculosis , cofactor , gene , medicine , non coding rna , enzyme , pathology
Riboswitches are cis‐acting mRNA regulatory elements which control the gene activity by binding to small ligands such as nucleotides, amino acids etc. This also makes them an attractive drug target. The thiamine pyrophosphate (TPP) binding riboswitch is involved in the control of the thiamine biosynthetic pathway in E.coli which is essential for its survival. Similar regions were identified in Mycobacterium tuberculosis, the causative organism of the disease tuberculosis, through sequence alignment studies. However, these putative riboswitches remain to be structurally and biochemically characterized. Analysis of one such candidate, the ThiC riboswitch by in‐vitro structure probing processes such as NMR and selective 2′‐hydroxyl acylation analyzed by primer extension (SHAPE) combined with computational biology methods reveal a probable riboswitch which is tested for its binding ability to thiamine and drug‐like thiamine analogs in‐vitro by above schemes. It is also tested in‐vivo by GFP tagging and cloning into E.coli, where fluorescence is used as an indicator for riboswitch activity. This two pronged approach gives insights into its mechanism of action, opening new horizons in drug design and development. This research is funded by NIH/NCRR(P20RR020159)