The Structural and Functional Characterization of Mammalian ADP-dependent Glucokinase.

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dc.citation.issue8
dc.citation.volume291
dc.contributor.authorRichter JP
dc.contributor.authorGoroncy AK
dc.contributor.authorRonimus RS
dc.contributor.authorSutherland-Smith AJ
dc.date.available2016-02-19
dc.date.issued2016-02-19
dc.description.abstractThe enzyme-catalyzed phosphorylation of glucose to glucose-6-phosphate is a reaction central to the metabolism of all life. ADP-dependent glucokinase (ADPGK) catalyzes glucose-6-phosphate production, utilizing ADP as a phosphoryl donor in contrast to the more well characterized ATP-requiring hexokinases. ADPGK is found in Archaea and metazoa; in Archaea, ADPGK participates in a glycolytic role, but a function in most eukaryotic cell types remains unknown. We have determined structures of the eukaryotic ADPGK revealing a ribokinase-like tertiary fold similar to archaeal orthologues but with significant differences in some secondary structural elements. Both the unliganded and the AMP-bound ADPGK structures are in the "open" conformation. The structures reveal the presence of a disulfide bond between conserved cysteines that is positioned at the nucleotide-binding loop of eukaryotic ADPGK. The AMP-bound ADPGK structure defines the nucleotide-binding site with one of the disulfide bond cysteines coordinating the AMP with its main chain atoms, a nucleotide-binding motif that appears unique to eukaryotic ADPGKs. Key amino acids at the active site are structurally conserved between mammalian and archaeal ADPGK, and site-directed mutagenesis has confirmed residues essential for enzymatic activity. ADPGK is substrate inhibited by high glucose concentration and shows high specificity for glucose, with no activity for other sugars, as determined by NMR spectroscopy, including 2-deoxyglucose, the glucose analogue used for tumor detection by positron emission tomography.
dc.description.publication-statusPublished
dc.format.extent3694 - 3704
dc.identifierhttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000371338400002&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=c5bb3b2499afac691c2e3c1a83ef6fef
dc.identifier.citationJOURNAL OF BIOLOGICAL CHEMISTRY, 2016, 291 (8), pp. 3694 - 3704
dc.identifier.doi10.1074/jbc.M115.679902
dc.identifier.eissn1083-351X
dc.identifier.elements-id259180
dc.identifier.harvestedMassey_Dark
dc.relation.isPartOfJOURNAL OF BIOLOGICAL CHEMISTRY
dc.rights(c) The author/s CC BY
dc.subjectADP
dc.subjectAMP
dc.subjectenzyme structure
dc.subjectglucokinase
dc.subjectglucose metabolism
dc.subjectx-ray crystallography
dc.subjectADP-dependent glucokinase
dc.subjectNMR spectroscopy
dc.subjectglucose-6-phosphate
dc.subjectribokinase
dc.subject.anzsrc03 Chemical Sciences
dc.subject.anzsrc06 Biological Sciences
dc.subject.anzsrc11 Medical and Health Sciences
dc.titleThe Structural and Functional Characterization of Mammalian ADP-dependent Glucokinase.
dc.typeJournal article
pubs.notesNot known
pubs.organisational-group/Massey University
pubs.organisational-group/Massey University/College of Sciences
pubs.organisational-group/Massey University/College of Sciences/School of Natural Sciences
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