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Progress towards a new type of β4GalT7 inhibitors

Malmquist, Hanna LU (2020) KEMR30 20201
Department of Chemistry
Abstract
Proteoglycans are important macromolecules located on the human cell surfaces. They have many different and important roles in communication between cells. These roles are especially important for cancer development and the survival of tumor cells and these proteoglycans are, therefore, interesting to study. The proteoglycans are made up of a protein core to which glycosaminoglycan chains are bound. These GAG-chains are long, linear, and negatively charged chains of carbohydrates that are constantly modified. There are different classes of GAG-chains and two of them, i.e. heparan sulfate (HS) and chondroitin/dermatan sulfate (CS/DS), are connected to the protein core by a xylose molecule and thus follow similar first steps in their... (More)
Proteoglycans are important macromolecules located on the human cell surfaces. They have many different and important roles in communication between cells. These roles are especially important for cancer development and the survival of tumor cells and these proteoglycans are, therefore, interesting to study. The proteoglycans are made up of a protein core to which glycosaminoglycan chains are bound. These GAG-chains are long, linear, and negatively charged chains of carbohydrates that are constantly modified. There are different classes of GAG-chains and two of them, i.e. heparan sulfate (HS) and chondroitin/dermatan sulfate (CS/DS), are connected to the protein core by a xylose molecule and thus follow similar first steps in their biosynthesis. One of the active enzymes in the synthesis of these chains is β4GalT7 which is responsible for the step where the first galactose is coupled to the xylose bound to the protein core. The aim of this project has been to synthesize a new type of inhibitors for β4GalT7. Previous studies have focused on modifying and testing different xylosides and have shown that XylNap is one of the active inhibitors. In this project, a new type of inhibitor was envisioned where the xylose was combined with a UDP-based residue since UDP-galactose normally is the second substrate for the enzyme and the idea was that by combining these two reach a much stronger inhibitor. The synthesis of this molecule turned out to be much more complicated than expected and many different reaction pathways have been investigated. In the end, the final product was not reached but progress had been made as well as new insights and solutions to the synthetic problems approaching the final goal. (Less)
Popular Abstract (Swedish)
Vår kropp är uppbyggd av biljontals celler, men utan kommunikation och samarbete dem emellan skulle kroppen och dess livsviktiga processer inte fungera. Denna kommunikation äger till stor del rum på cellernas yta, det så kallade cellmembranet, som alltså inte bara fungerar som en barriär mellan cellerna. Här finns nämligen flera olika molekyler och proteiner som sköter en stor del av kommunikationen mellan cellen och omgivningen. En av dessa viktiga familjer av meddelandemolekyler är proteoglykaner. Proteoglykanerna är uppbyggda av flera glykosaminoglykaner (GAG), långa kolhydratkedjor, bundna till ett kärnprotein, med en viktig roll i både celldelning, kontroll av inflammationer, angiogenes vilket är processen som sköter bildandet av nya... (More)
Vår kropp är uppbyggd av biljontals celler, men utan kommunikation och samarbete dem emellan skulle kroppen och dess livsviktiga processer inte fungera. Denna kommunikation äger till stor del rum på cellernas yta, det så kallade cellmembranet, som alltså inte bara fungerar som en barriär mellan cellerna. Här finns nämligen flera olika molekyler och proteiner som sköter en stor del av kommunikationen mellan cellen och omgivningen. En av dessa viktiga familjer av meddelandemolekyler är proteoglykaner. Proteoglykanerna är uppbyggda av flera glykosaminoglykaner (GAG), långa kolhydratkedjor, bundna till ett kärnprotein, med en viktig roll i både celldelning, kontroll av inflammationer, angiogenes vilket är processen som sköter bildandet av nya blodkärl, och i kommunikationen mellan celler. Allt detta sköts alltså av kolhydrater, ”sockermolekyler”, sammanlänkade till långa kedjor.

Dessa processer och denna kommunikation är också avgörande vid cancerutveckling och tumörtillväxt, och då cancerbehandling är en av dagens största utmaningar är bildandet av dessa långa kolhydratkedjor mycket intressant att studera. Bildandet av dessa GAG-kedjor är dock synnerligen komplicerat eftersom kolhydraterna byts ut och modifieras efter regler som vi ännu inte förstår. I detta projekt har ett specifikt enzym, β-1,4-Galaktosyltransferase 7 (β4GalT7), som ingår i ett av de första stegen i uppbyggandet av dessa kedjor studerats. Till detta enzym binder normalt en ovanlig kolhydrat som heter xylos och en UDP-galaktos, där xylosen och galaktosen kopplas ihop för att bygga upp kedjan. UDP-galaktosen består av en UDP vilket är en form av transportmolekyl för i detta fall kolhydraten galaktos. Tidigare studier har fokuserat på xylosen och modifieringar av denna med målet att hitta en ersättare som kan hindra enzymet från att fungera och på så viss stoppa uppbyggandet av dessa GAG-kedjor. I detta projekt har däremot en ny infallsvinkel påbörjats där målet var att kombinera xylosen med en del som efterliknar den UDP-molekyl som normalt binder till enzymet för att på det viset nå en mycket starkare hämmare till enzymet. (Less)
Please use this url to cite or link to this publication:
author
Malmquist, Hanna LU
supervisor
organization
course
KEMR30 20201
year
type
H2 - Master's Degree (Two Years)
subject
keywords
glycosaminoglycans, proteoglycans, β4GalT7, xylose, UDP-based, organic chemistry, organisk kemi
language
English
id
9022394
date added to LUP
2020-07-02 10:45:24
date last changed
2020-07-02 10:45:24
@misc{9022394,
  abstract     = {{Proteoglycans are important macromolecules located on the human cell surfaces. They have many different and important roles in communication between cells. These roles are especially important for cancer development and the survival of tumor cells and these proteoglycans are, therefore, interesting to study. The proteoglycans are made up of a protein core to which glycosaminoglycan chains are bound. These GAG-chains are long, linear, and negatively charged chains of carbohydrates that are constantly modified. There are different classes of GAG-chains and two of them, i.e. heparan sulfate (HS) and chondroitin/dermatan sulfate (CS/DS), are connected to the protein core by a xylose molecule and thus follow similar first steps in their biosynthesis. One of the active enzymes in the synthesis of these chains is β4GalT7 which is responsible for the step where the first galactose is coupled to the xylose bound to the protein core. The aim of this project has been to synthesize a new type of inhibitors for β4GalT7. Previous studies have focused on modifying and testing different xylosides and have shown that XylNap is one of the active inhibitors. In this project, a new type of inhibitor was envisioned where the xylose was combined with a UDP-based residue since UDP-galactose normally is the second substrate for the enzyme and the idea was that by combining these two reach a much stronger inhibitor. The synthesis of this molecule turned out to be much more complicated than expected and many different reaction pathways have been investigated. In the end, the final product was not reached but progress had been made as well as new insights and solutions to the synthetic problems approaching the final goal.}},
  author       = {{Malmquist, Hanna}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Progress towards a new type of β4GalT7 inhibitors}},
  year         = {{2020}},
}