| dc.description.abstract | Sedert die eerste beskrywing van 'n pasient met Maple Syrup-uriendefek in 1954, is
verskeie ander pasiente met dieselfde defek van die vertakteketting-2-ketosuur
dehidrogenase-ensiem beskryf. Tot nou is hoofsaaklik van dieet gebruik gemaak om
hierdie pasiente te behandel. Dit het aanleiding gegee tot hierdie studie wat ten doel
het om die moontlike toksiese metaboliete en metaboliese wee, betrokke by die
vorming van die metaboliete te identifiseer en om 'n beter klinies-biochemiese beeld
te verkry. Hierdie kennis kan moontlik tot 'n verbeterde behandeling vir hierdie
pasiente lei.
Om in die doel te slaag, is gebruik gemaak van 'n analities-biocherniese benadering
om die rnetaboliete te voorspel wat rnoontlik gevorm kan word as gevolg van 'n defek
van die vertakteketting-2-ketosuur dehidrogenase-ensiem. Hierdie benadering behels
dat potensieel geYnduseerde metaboliete op grond van die kennis van rneganismes van
bestaande metaboliese wee voorspel word. Hierdie rnetaboliete is dan chemies
gesintetiseer, of indien moontlik, in die handel verkry. Spektra is dan verkry van die
standaarde met behulp van elektronionisasie-rnassaspektrometrie, cherniese-ionisasiemassaspektrornetrie
en v loeistofchromatografie-elektrosproei-tandernmassaspektrometrie
die teenwoordigheid van die moontlike metaboliete in die urine
van pasiente is dan met die verkrygde spektra ondersoek.
Op hierdie wyse is meer as sewentig metaboliete ge1dentifiseer by pasiente met Maple
Syrup-uriendefek, waarvan ongeveer sestig nuwe metaboliete is. Die oorblywende
metaboliete is 6f reeds in die literatuur bekend 6f is nie positief geYdentifiseer in
hierdie studie nie. Hoewel sommige van die metaboliete in lae konsentrasies in die
urine van hierdie pasiente voorkom, is die intrasellulere konsentrasies moontlik hoog
genoeg om 'n invloed op ensiemreaksies te he, hetsy deur middel van inhibisie van die ensiem( e ), of deur middel van kompetisie van die geYnduseerde metaboliet met die
normale substraat van die ensiem.
Dit wil ook voorkom uit die resultate verkry uit hierdie studie, dat die tempo van
reaksies by individuele persone in 'n groot mate kan bydra tot die prognose van 'n
bepaalde pasient. Verder blyk dit uit die resultate dat die konsentrasies of
beskikbaarheid van ko-faktore soos tiamienpirofosfaat 'n belangrike rol by Maple
Syrup-uriendefek-pasiente kan speel. The first description of a patient with Maple Syrup Urine Disease was done in 1954.
Since then several other patients with the same deficiency of the branched chain 2-
keto-acid dehydrogenase enzyme have been described. To date, diet has mainly been
used as a treatment for these patients. This has resulted in this study which aims at
identifying the possible toxic metabolites and metabolic pathways involved in the
formation of these metabolites and, in doing so, to try and obtain a better clinicalbiochemical
relationship. This information could possibly lead to the improvement of
the treatment of these patients.
To achieve this goal, an analytical-biochemical approach was used to predict the
formation of possible metabolites that can be formed as a result of a deficiency of the
branched chain 2-keto-acid dehydrogenase enzyme. This approach entails that the
possible induced metabolites are predicted based on a knowledge of the mechanisms
of existing metabolic pathways. These metabolites are then synthesized, or if possible,
commercially obtained. The mass spectrum of the compound is then obtained by
using standard techniques such as electron impact ionization mass spectrometry,
chemical ionization mass spectrometry and liquid chromatography electrospray
tandem mass spectrometry. The existence of these metabolites in the urine of MSUD
patients are subsequently investigated by using the obtained mass spectra.
In this manner more than seventy metabolites have been identified in the urine of
patients with Maple Syrup Urine Disease of which approximately sixty are new
metabolites. The remainder of the metabolites have been discussed previously in the
literature or could not be identified positively during this study. Although some of the
metabolites are _ present in low concentrations in the urine, the intracellular
concentrations might be high enough to influence enzyme reactions, either by inhibition of the enzyme or by means of competition of the induced metabolite with
the normal substrate of the enzyme.
It also appears from the results obtained during this study that the rate of the enzyme
reactions in individual patients can to a large extent contribute to the prognosis of the
individual patient. It also appears from the results that the concentrations or
availability of co-factors such as thiamin pyrophosphate could play an important role
in patients suffering from Maple Syrup Urine Disease | en_US |
