Abstract
Mevalonate diphosphate decarboxylases (MDDs) catalyze the ATP-dependent-Mg2+-decarboxylation of mevalonate-5-diphosphate (MVAPP) to produce isopentenyl diphosphate (IPP), which is essential in both eukaryotes and prokaryotes for polyisoprenoid synthesis. The substrates, MVAPP and ATP, have been shown to bind sequentially to MDD. Here we report crystals in which the enzyme remains active, allowing the visualization of conformational changes in Enterococcus faecalis MDD that describe sequential steps in an induced fit enzymatic reaction. Initial binding of MVAPP modulates the ATP binding pocket with a large loop movement. Upon ATP binding, a phosphate binding loop bends over the active site to recognize ATP and bring the molecules to their catalytically favored configuration. Positioned substrates then can chelate two Mg2+ ions for the two steps of the reaction. Closure of the active site entrance brings a conserved lysine to trigger dissociative phosphoryl transfer of γ-phosphate from ATP to MVAPP, followed by the production of IPP.
Highlights
Mevalonate diphosphate decarboxylases (MDDs) catalyze the ATP-dependent-Mg2+decarboxylation of mevalonate-5-diphosphate (MVAPP) to produce isopentenyl diphosphate (IPP), which is essential in both eukaryotes and prokaryotes for polyisoprenoid synthesis
Enzymes in the mevalonate pathway have been suggested as therapeutic targets for treatment of infectious diseases caused by these Gram(+) bacterial pathogens, especially for those bearing multidrug-resistance genes such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE)[4,5,6], which cause a range of clinical infections[4,5,6,7,8]
An in vitro study had shown feedback regulation by mevalonate-5-diphosphate (MVAPP) of the mevalonate kinase (MK) from Streptococcus pneumonia[16]. This implies that accumulation of MVAPP caused by inhibition of MDD can down-regulate the upstream MK enzymes, indicating that the mevalonate pathway can be effectively inhibited by targeting the MDD enzyme
Summary
Mevalonate diphosphate decarboxylases (MDDs) catalyze the ATP-dependent-Mg2+decarboxylation of mevalonate-5-diphosphate (MVAPP) to produce isopentenyl diphosphate (IPP), which is essential in both eukaryotes and prokaryotes for polyisoprenoid synthesis. An in vitro study had shown feedback regulation by mevalonate-5-diphosphate (MVAPP) of the mevalonate kinase (MK) from Streptococcus pneumonia[16] This implies that accumulation of MVAPP caused by inhibition of MDD can down-regulate the upstream MK enzymes, indicating that the mevalonate pathway can be effectively inhibited by targeting the MDD enzyme. Β10-α4 loop of MDD, 6-fluoromevalonate diphosphate (FMVAPP), has been identified This inhibitor, binds to the highly conserved MVAPP-binding site in the MDD family of proteins (MDDs)[17,18,19,20,21,22], including human MDD. To avoid side effects on humans when treating bacterial infections, structure-based drug development toward an MDD with both sensitivity and specificity is needed[23]
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