2014
DOI: 10.1002/anie.201306712
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Bioorganometallic Chemistry with IspG and IspH: Structure, Function, and Inhibition of the [Fe4S4] Proteins Involved in Isoprenoid Biosynthesis

Abstract: The methylerythritol phosphate pathway of isoprenoid biosynthesis is an attractive anti-infective drug target. The last two enzymes of this pathway, IspG and IspH, are [Fe4S4] proteins not produced by humans that catalyze 2H+/2e− 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 possi… Show more

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Cited by 54 publications
(87 citation statements)
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References 114 publications
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“…When taken together, the results shown above together with other reported work [1] , show that there are several ways that ligands can bind to IspH, and suggest a potential route to finding new inhibitors. First , most ligands bind with η 1 coordination with O, N and S binding via σ-interactions with the 4 th Fe.…”
Section: Resultssupporting
confidence: 61%
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“…When taken together, the results shown above together with other reported work [1] , show that there are several ways that ligands can bind to IspH, and suggest a potential route to finding new inhibitors. First , most ligands bind with η 1 coordination with O, N and S binding via σ-interactions with the 4 th Fe.…”
Section: Resultssupporting
confidence: 61%
“…The enzymes IspG (( E )-1-hydroxy-2-methyl-but-2-enyl 4-diphosphate synthase, also known as GcpE) and IspH (( E )-1-hydroxy-2-methyl-but-2-enyl 4-diphosphate reductase, also known as LytB) are the last two enzymes of the 2- C -methyl-D-erythritol 4-phosphate (MEP) pathway of isoprenoid biosynthesis in many bacteria, as well as in some protozoa, and in plants [1] . They are both 4Fe-4S cluster-containing proteins that are involved in 2H + /2e reductions: IspG converts 2- C -methyl-D-erythritol-2,4- cyclo -diphosphate (MEcPP, 1 , Scheme 1) to ( E )-1-hydroxy-2-methyl-but-2-enyl 4-diphosphate (HMBPP; 2 ), and IspH converts 2 to dimethylallyl diphosphate ( 3 ) and isopentenyl diphosphate ( 4 ), the building blocks of isoprenoid biosynthesis.…”
Section: Introductionmentioning
confidence: 99%
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“…IspH is used by malaria parasites and by bacteria containing the non-mevalonate pathway, and is a drug target. [82] Inhibiting IspH will inhibit bacterial cell wall biosynthesis (as well as diverse other processes) and will result in accumulation of high levels of the HMBPP substrate. The interesting point here is that HMBPP and related compounds[83] are exceptionally potent “phosphoantigens” that stimulate the expansion of γδ T cells (containing the Vγ2Vδ2 T cell receptor) which can then differentiate into multi-functional effector sub-populations capable of producing cytokines, INFγ and perforin/granulysin[83].…”
Section: Targeting Virulence and The Innate Immune System Are Under-ementioning
confidence: 99%
“…7, 8 Both experimental and computational studies now generally agree on a reaction mechanism involving two consecutive one-electron transfer steps with a HIPIP (high-potential iron protein)-like [Fe 4 S 4 ] 3+ -allyl anion intermediate. 7, 9-12 The X-ray structures of IspH from E. coli 13 , Aquifex aeolicus 14 as well as an N-terminal truncation mutant of Plasmodium falciparum 15 have been obtained and show a similar "trefoil" arrangement of α/β domains with the Fe-S cluster bound at the center of the structure. However, both E. coli IspH (EcIspH) and P. falciparum IspH (PfIspH) also contain a C-terminal extension that is missing in A. aeolicus IspH (AaIspH), raising the question as to the role of this domain.…”
mentioning
confidence: 81%