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Solution Structures and Models Describing the Thioredoxin System from Mycobacterium tuberculosis
Author(s) -
Neumann Terrence S,
Olson Andrew,
Cai Sheng,
Sem Daniel
Publication year - 2012
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.26.1_supplement.804.1
Subject(s) - thioredoxin reductase , thioredoxin , mycobacterium tuberculosis , chemistry , reductase , biochemistry , titration , enzyme , stereochemistry , tuberculosis , organic chemistry , medicine , pathology
Mycobacterium tuberculosis ( M. tb ) resists oxidative killing in part by using the thioredoxin (Trx) system. Trx's catalyzes thioldisulfide exchange reactions using redox active cysteine thiols to reduce disulfides of other essential proteins, including metabolically essential enzymes. Oxidized Trx is reduced by thioredoxin reductase (TrxR) in an NADPH dependant reaction. The M. tb Trx system consists of three Trx's (TrxA, TrxB, and TrxC) and one Trx reductase (TrxR). TrxB and TrxC are known substrates of TrxR, while TrxA has been reported to not bind to TrxR, and to possibly be “cryptic.” The M. tb Trx system is dissimilar to the human Trx system (25–35% identity) indicating inhibitor specificity for the M. tb Trx system is achievable. The M. tb Trx system appears to be a viable anti‐tuberculosis drug target. This study's objective was to calculate NMR solution structures of oxidized and reduced Trx's from M. tb . Structures were calculated using standard NMR methods and indicate that TrxA is wellfolded in oxidized and reduced states. Structures of the Trx's and binding models of the TrxN(N=A,B, or C)‐TrxR, constructed from NMR titrations of each 15 N enriched TrxN and TrxR, will be presented. These binding models show a pocket between the Trx and the TrxR which are being used to identify uncompetitive inhibitors that would be effective as drugs even at saturating substrate (Trx) levels. Supported by NIH GM085739.