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Selective Inhibition and Mechanistic Studies of the Human O2 Sensor, Prolyl Hydroxylase Domain 2 (PHD2)

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dc.contributor.advisorMichael J. Knapp
dc.contributor.advisorStephen Eyles
dc.contributor.advisorRobert M. Weis
dc.contributor.authorFlagg, Shannon Coates
dc.contributor.departmentUniversity of Massachusetts Amherst
dc.date2023-09-23T04:50:24.000
dc.date.accessioned2024-04-26T19:49:55Z
dc.date.available2024-04-26T19:49:55Z
dc.date.issued2011-09-01
dc.description.abstractProlyl Hydroxylase Domain 2 (PHD2) has been identified as a key oxygen sensor in humans along with Factor Inhibiting Hypoxia Inducible Factor (FIH). As such PHD2 and FIH play critical roles in myriad pathways of medical relevance by hydroxylation of their target substrate hypoxia inducible factor (HIF), a transcription factor responsible for the regulation of over 100+ genes. With such critical roles in human physiology the ability to selectively regulate these two enzymes could potentially lead the way for novel therapeutic treatments of a vast array of disease states from cancer to myocardial infarction. We report on three classes of iron chelators which show promise for independent regulation of the HIF hydroxylases. Compounds representing the pyrones/pyridinones, pyridines and catechols were tested and found to have differential impacts on PHD2 and FIH under the same experimental conditions. The mode of inhibition is the result of binding to the active site iron and is supported by UV-visible and electroparamagnetic resonance spectroscopy. PHD2 at the current time does not have a well resolved mechanistic understanding regarding its catalytic cycle and subsequent rate determining steps. We have employed pH, solvent isotope, and X-ray absorption studies in an effort to gain further understanding regarding PHD2's overall mechanism. Our data support that dissociation of an iron(II)-OH2 bond centered about the active site contributes to a portion of the overall rate determining steps in the catalytic reaction of PHD2 that activates oxygen and ends with the production of hydroxylated substrate.
dc.description.degreeDoctor of Philosophy (PhD)
dc.description.departmentChemistry
dc.identifier.doihttps://doi.org/10.7275/2389540
dc.identifier.urihttps://hdl.handle.net/20.500.14394/38908
dc.relation.urlhttps://scholarworks.umass.edu/cgi/viewcontent.cgi?article=1458&context=open_access_dissertations&unstamped=1
dc.source.statuspublished
dc.subjectHydroxylase
dc.subjectoxygenase
dc.subjectPHD2
dc.subjectProlyl
dc.subjectChemistry
dc.titleSelective Inhibition and Mechanistic Studies of the Human O2 Sensor, Prolyl Hydroxylase Domain 2 (PHD2)
dc.typedissertation
dc.typearticle
dc.typedissertation
digcom.contributor.authorisAuthorOfPublication|email:scf13@live.com|institution:University of Massachusetts Amherst|Flagg, Shannon Coates
digcom.identifieropen_access_dissertations/460
digcom.identifier.contextkey2389540
digcom.identifier.submissionpathopen_access_dissertations/460
dspace.entity.typePublication
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