The control of GAPDH on glycolytic flux in Lactococcus lactis and Plasmodium falciparum.

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dc.contributor.advisorVan Niekerk, David Douglasen_ZA
dc.contributor.advisorSnoep, Jacob Leenderten_ZA
dc.contributor.authorFrantz, Tagwin Claireen_ZA
dc.contributor.otherStellenbosch University. Faculty of Science. Dept. of Biochemistry.en_ZA
dc.date.accessioned2022-03-04T14:57:00Z
dc.date.accessioned2022-04-29T12:54:03Z
dc.date.available2022-09-04T03:00:14Z
dc.date.issued2022-03
dc.descriptionThesis (MSc)--Stellenbosch University, 2022. en_ZA
dc.description.abstractENGLISH ABSTRACT: The parasitic disease, malaria, has the highest prevalence in Africa, and Plasmodium fal- ciparum, the parasite responsible for severe malaria, has rapidly become resistant to cur- rent treatment options. There is a need for new drug targets, and the glycolytic pathway presents several possibilities since it is a source of energy and carbon for the parasite in certain stages of its life cycle. The malaria parasite utilizes host erythrocyte-derived glu- cose via glycolysis. The enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has emerged as a potential drug target in glycolysis, and several studies have associated glycolytic inhibition with organismal death. However, the overall glycolytic inhibition by an irreversible inhibitor, iodoacetic acid (IAA), acting on GAPDH activity has not been investigated in Plasmodium falciparum. The lactic acid bacterium, Lactococcus lactis, has a glycolytic pathway that is similar in structure to that of P. falciparum, and can serve as a model organism in the laboratory environment. It is also of significant industrial impor- tance. Previous studies have, however, found conflicting results for the glycolytic flux control of GAPDH in L. lactis. In this study we investigated GAPDH flux control by using experimental enzyme kinet- ics, mathematical modeling, and metabolic control analysis to analyze detailed models of glycolysis within L. lactis and P. falciparum, respectively, and to elucidate the flux control of GAPDH under titrations of IAA. We show that low flux control is exerted by GAPDH in both species, with the control in P. falciparum being marginally larger than in L. lactis, but when strongly inhibited, GAPDH obtained full control and was a good target to decrease the glycolytic flux. These results are in excellent agreement with independent simulations of detailed mathematical models that were previously constructed in our group.en_ZA
dc.description.abstractAFRIKAANSE OPSOMMING: Die parasitiese siekte, malaria, het die hoogste voorkoms in Afrika, en Plasmodium falci- parum, die parasiet wat verantwoordelik is vir ernstige malaria, het vinnig weerstandig geword teen huidige behandelingsopsies. Daar is ’n behoefte aan nuwe farmaseu- tiese teikens, en die glikolitiese pad bied verskeie moontlikhede, aangesien dit ’n bron van energie en koolstof vir die parasiet in sekere stadiums van sy lewensiklus is. Die malariaparasiet gebruik gasheer eritrosiet-afkomstige glukose via glikolise. Die ensiem gliseraldehied-3-fosfaat dehidrogenase (GAPDH) het na vore gekom as ’n potensiële teiken in glikolise, en verskeie studies het glikolitiese inhibisie met organisme dood geas- sosieer. Die algehele glikolitiese inhibisie deur ’n onomkeerbare inhibeerder, iodoasyn- suur (IAA), wat op GAPDH-aktiwiteit inwerk, is egter nog nie ondersoek in Plasmodium falciparum nie. Melksuurbakterieë, Lactococcus lactis, het ’n glikolitiese pad wat soortge- lyk is aan dié van P. falciparum, en kan dien as ’n modelorganisme in die laboratorium omgewing. Dit is ook van groot industriële belang. Vorige studies het egter teenstrydige resultate gevind vir die beheer van GAPDH op die glikolitiese fluksie in L. lactis. In hierdie studie het ons GAPDH-fluksiebeheer ondersoek deur onderskeidelik eksperi- mentele ensiemkinetika, wiskundige modellering en metaboliese kontrole-analise te ge- bruik om gedetailleerde modelle van glikolise binne L. lactis en P. falciparum te analiseer, en om die fluksiebeheer van GAPDH onder titrasies van IAA te belig. Ons toon aan dat lae fluksiebeheer deur GAPDH in beide spesies uitgeoefen word, met die beheer in P. falciparum marginaal groter as in L. lactis. Wanneer dit sterk geïnhibeer is, het GAPDH volle beheer verkry en was dit ’n goeie teiken om die glikolitiese fluk- sie te verminder. Hierdie resultate is in uitstekende ooreenstemming met onafhanklike simulasies van gedetailleerde wiskundige modelle wat voorheen in ons groep gebou is.af_ZA
dc.description.versionMastersen_ZA
dc.embargo.terms2022-09-04
dc.format.extentxiv, 83 pages : illustrationsen_ZA
dc.identifier.urihttp://hdl.handle.net/10019.1/125102
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subject.lcshMalaria -- Africaen_ZA
dc.subject.lcshPlasmodium falciparumen_ZA
dc.subject.lcshGlyceraldehyde-3-phosphate dehydrogenaseen_ZA
dc.subject.lcshEnzyme kinetics -- Mathematical modelsen_ZA
dc.subject.lcshLactic acid bacteriaen_ZA
dc.subject.lcshLactococcus lactisen_ZA
dc.subject.lcshGlycolysis -- Inhibitorsen_ZA
dc.subject.lcshGlycolytic fluxen_ZA
dc.subject.lcshUCTDen_ZA
dc.titleThe control of GAPDH on glycolytic flux in Lactococcus lactis and Plasmodium falciparum.en_ZA
dc.typeThesisen_ZA
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Masters Degrees (Biochemistry)