TY - JOUR
T1 - Bioorganometallic chemistry with IspG and IspH
T2 - Structure, function, and inhibition of the [Fe4S4] proteins involved in isoprenoid biosynthesis
AU - Wang, Weixue
AU - Oldfield, Eric
PY - 2014/4/22
Y1 - 2014/4/22
N2 - Enzymes of the methylerythritol phosphate pathway of isoprenoid biosynthesis are attractive anti-infective drug targets. The last two enzymes of this pathway, IspG and IspH, are [Fe4S4] proteins that are not produced by humans and catalyze 2 H+/ 2 e- reductions with novel mechanisms. In this Review, we summarize recent advances in structural, mechanistic, and inhibitory studies of these two enzymes. In particular, mechanistic proposals involving bioorganometallic intermediates are presented, and compared with other mechanistic possibilities. In addition, inhibitors based on substrate analogues as well as developed by rational design and compound-library screening, are discussed. The results presented support bioorganometallic catalytic mechanisms for IspG and IspH, and open up new routes to anti-infective drug design targeting [Fe4S4] clusters in proteins. A mission based on inside information: The methylerythritol phosphate pathway is an attractive anti-infective drug target. The last two enzymes of this pathway, IspG and IspH, are [Fe4S4] proteins that catalyze 2 H+/2 e- dehydroxylation reactions. Recent progress in the elucidation of their biosynthetic mechanisms opens up new routes to the design of inhibitors that target these [Fe 4S4] enzymes.
AB - Enzymes of the methylerythritol phosphate pathway of isoprenoid biosynthesis are attractive anti-infective drug targets. The last two enzymes of this pathway, IspG and IspH, are [Fe4S4] proteins that are not produced by humans and catalyze 2 H+/ 2 e- reductions with novel mechanisms. In this Review, we summarize recent advances in structural, mechanistic, and inhibitory studies of these two enzymes. In particular, mechanistic proposals involving bioorganometallic intermediates are presented, and compared with other mechanistic possibilities. In addition, inhibitors based on substrate analogues as well as developed by rational design and compound-library screening, are discussed. The results presented support bioorganometallic catalytic mechanisms for IspG and IspH, and open up new routes to anti-infective drug design targeting [Fe4S4] clusters in proteins. A mission based on inside information: The methylerythritol phosphate pathway is an attractive anti-infective drug target. The last two enzymes of this pathway, IspG and IspH, are [Fe4S4] proteins that catalyze 2 H+/2 e- dehydroxylation reactions. Recent progress in the elucidation of their biosynthetic mechanisms opens up new routes to the design of inhibitors that target these [Fe 4S4] enzymes.
KW - EPR spectroscopy
KW - bioinorganic chemistry
KW - biophysics
KW - enzyme catalysis
KW - terpenoids
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U2 - 10.1002/anie.201306712
DO - 10.1002/anie.201306712
M3 - Review article
C2 - 24481599
AN - SCOPUS:84898969936
SN - 1433-7851
VL - 53
SP - 4294
EP - 4310
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 17
ER -