Show simple item record

dc.contributor.authorMartin, JL
dc.contributor.authorBegun, J
dc.contributor.authorMcLeish, MJ
dc.contributor.authorCaine, JM
dc.contributor.authorGrunewald, GL
dc.date.accessioned2017-10-05T01:00:47Z
dc.date.available2017-10-05T01:00:47Z
dc.date.issued2001
dc.identifier.issn0969-2126
dc.identifier.doi10.1016/S0969-2126(01)00662-1
dc.identifier.urihttp://hdl.handle.net/10072/347874
dc.description.abstractBackground: Adrenaline is localized to specific regions of the central nervous system (CNS), but its role therein is unclear because of a lack of suitable pharmacologic agents. Ideally, a chemical is required that crosses the blood-brain barrier, potently inhibits the adrenaline-synthesizing enzyme PNMT, and does not affect other catecholamine processes. Currently available PNMT inhibitors do not meet these criteria. We aim to produce potent, selective, and CNS-active PNMT inhibitors by structure-based design methods. The first step is the structure determination of PNMT. Results: We have solved the crystal structure of human PNMT complexed with a cofactor product and a submicromolar inhibitor at a resolution of 2.4 Å. The structure reveals a highly decorated methyltransferase fold, with an active site protected from solvent by an extensive cover formed from several discrete structural motifs. The structure of PNMT shows that the inhibitor interacts with the enzyme in a different mode from the (modeled) substrate noradrenaline. Specifically, the position and orientation of the amines is not equivalent. Conclusions: An unexpected finding is that the structure of PNMT provides independent evidence of both backward evolution and fold recruitment in the evolution of a complex enzyme from a simple fold. The proposed evolutionary pathway implies that adrenaline, the product of PNMT catalysis, is a relative newcomer in the catecholamine family. The PNMT structure reported here enables the design of potent and selective inhibitors with which to characterize the role of adrenaline in the CNS. Such chemical probes could potentially be useful as novel therapeutics.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherCell Press
dc.relation.ispartofpagefrom977
dc.relation.ispartofpageto985
dc.relation.ispartofissue10
dc.relation.ispartofjournalStructure
dc.relation.ispartofvolume9
dc.subject.fieldofresearchChemical sciences
dc.subject.fieldofresearchBiological sciences
dc.subject.fieldofresearchBiochemistry and cell biology not elsewhere classified
dc.subject.fieldofresearchInformation and computing sciences
dc.subject.fieldofresearchcode34
dc.subject.fieldofresearchcode31
dc.subject.fieldofresearchcode310199
dc.subject.fieldofresearchcode46
dc.titleGetting the adrenaline going: Crystal structure of the adrenaline-synthesizing enzyme PNMT
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorMartin, Jennifer


Files in this item

FilesSizeFormatView

There are no files associated with this item.

This item appears in the following Collection(s)

  • Journal articles
    Contains articles published by Griffith authors in scholarly journals.

Show simple item record