Biological Channeling of a Reactive Intermediate in the Bifunctional Enzyme DmpFG

Natalie Smith, Alice Vrielink, Paul Attwood, Ben Corry

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

It has been hypothesized that the bifunctional enzyme DmpFG channels its intermediate, acetaldehyde, from one active site to the next using a buried intermolecular channel identified in the crystal structure. This channel appears to switch between an open and a closed conformation depending on whether the coenzyme NAD(+) is present or absent. Here, we applied molecular dynamics and metadynamics to investigate channeling within DmpFG in both the presence and absence of NAD(+). We found that substrate channeling within this enzyme is energetically feasible in the presence of NAD(+) but was less likely in its absence. Tyr-291, a proposed control point at the channel's entry, does not appear to function as a molecular gate. Instead, it is thought to orientate the substrate 4-hydroxy-2-ketovalerate in DmpG before reaction occurs, and may function as a proton shuttle for the DmpG reaction. Three hydrophobic residues at the channel's exit appear to have an important role in controlling the entry of acetaldehyde into the DmpF active site.
Original languageEnglish
Pages (from-to)868-877
JournalBiophysical Journal
Volume102
DOIs
Publication statusPublished - 2012

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