Visualizing the enzyme mechanism of mevalonate diphosphate decarboxylase

Chen, Chun-Liang; Paul, Lake N.; Mermoud, James C.; Steussy, Calvin Nicklaus; Stauffacher, Cynthia V.

doi:10.1038/s41467-020-17733-0

Visualizing the enzyme mechanism of mevalonate diphosphate decarboxylase

Journal Article · Fri Aug 07 00:00:00 EDT 2020 · Nature Communications

DOI:https://doi.org/10.1038/s41467-020-17733-0· OSTI ID:1659311

^[1]; Paul, Lake N. ^[2]; Mermoud, James C. ^[1]; Steussy, Calvin Nicklaus ^[1]; ^[1]

Purdue Univ., West Lafayette, IN (United States)
Purdue Univ., West Lafayette, IN (United States); BioAnalysis, LLC, Philadelphia, PA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

OSTI ID:: 1659311

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 11; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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