dc.contributor.author |
Huang, Amadeus |
en |
dc.contributor.author |
Burke, Julia |
en |
dc.contributor.author |
Bunker, Richard D |
en |
dc.contributor.author |
Mok, Yee-Foong |
en |
dc.contributor.author |
Griffin, Michael D |
en |
dc.contributor.author |
Baker, Edward |
en |
dc.contributor.author |
Loomes, Kerry |
en |
dc.date.accessioned |
2020-02-11T22:48:23Z |
en |
dc.date.issued |
2019-11 |
en |
dc.identifier.issn |
0264-6021 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/49919 |
en |
dc.description.abstract |
4-hydroxy-2-oxoglutarate aldolase (HOGA1) is a mitochondrial enzyme that plays a gatekeeper role in hydroxyproline metabolism. Its loss of function in humans causes primary hyperoxaluria type 3 (PH3), a rare condition characterised by excessive production of oxalate. In this study, we investigated the significance of the associated oxaloacetate decarboxylase activity which is also catalysed by HOGA1. Kinetic studies using the recombinant human enzyme (hHOGA1) and active site mutants showed both these dual activities utilise the same catalytic machinery with micromolar substrate affinities suggesting that both are operative in vivo. Biophysical and structural studies showed that pyruvate was a competitive inhibitor with an inhibition constant in the micromolar range. By comparison α-ketoglutarate was a weak inhibitor with an inhibition constant in the millimolar range and could only be isolated as an adduct with the active site Lys196 in the presence of sodium borohydride. These studies suggest that pyruvate inhibits HOGA1 activity during gluconeogenesis. We also propose that loss of HOGA1 function could increase oxalate production in PH3 by decreasing pyruvate availability and metabolic flux through the Krebs cycle. |
en |
dc.format.medium |
Print |
en |
dc.language |
eng |
en |
dc.relation.ispartofseries |
The Biochemical journal |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
Humans |
en |
dc.subject |
Hyperoxaluria, Primary |
en |
dc.subject |
Ketoglutaric Acids |
en |
dc.subject |
Pyruvic Acid |
en |
dc.subject |
Oxo-Acid-Lyases |
en |
dc.subject |
Enzyme Inhibitors |
en |
dc.subject |
Catalytic Domain |
en |
dc.subject |
Kinetics |
en |
dc.title |
Regulation of human 4-hydroxy-2-oxoglutarate aldolase by pyruvate and α-ketoglutarate: implications for primary hyperoxaluria type-3. |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1042/bcj20190548 |
en |
pubs.issue |
21 |
en |
pubs.begin-page |
3369 |
en |
pubs.volume |
476 |
en |
dc.rights.holder |
Copyright: The author |
en |
pubs.end-page |
3383 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
en |
pubs.subtype |
Journal Article |
en |
pubs.elements-id |
788442 |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Biological Sciences |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
dc.identifier.eissn |
1470-8728 |
en |
pubs.record-created-at-source-date |
2019-11-08 |
en |
pubs.dimensions-id |
31696211 |
en |