Regulation of human 4-hydroxy-2-oxoglutarate aldolase by pyruvate and α-ketoglutarate: implications for primary hyperoxaluria type-3.

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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


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