3DM from data to medicine

Research output: Thesisinternal PhD, WU

Abstract

A powerful method to gain biological insights in the functioning of a protein is to use data available for the protein (super) family and transfer this data to the protein of interest. Systematically correlating the sheer amount of data available is difficult and time consuming. Therefore protein superfamily-specific databases are needed. It is shown that such systems can help to predict protein interaction sites, active site residues, residues important in enzyme specificity, protein stabilizing residues, etc. These systems are therefore powerful tools in drug design and protein engineering studies, but building and keeping such systems op to date is time consuming. This thesis is on 3DM, a system that can automatically build such protein superfamily databases. The system starts with building a large accurate structure based multiple sequence alignment of a class of proteins (superfamily). Secondly, it collects and stores amino acid associated data, such as mutational information, ligand- and substrate contacts, etc. together with data derived form the alignment such as correlated mutations and conservation information. These information types are linked to the alignment making it possible to easily transfer information from well studied members of the family to the protein of interest. Navigating between the alignment and associated data is done via interactive HTML pages. Chapter 1 of this thesis is a general introduction on how 3DM databases can be used for protein engineering and drug design processes. Chapter 2 (3DM: A new generation of molecular-class-specific information systems applied to four protein super-families) describes 3DM as a method which is tested on four superfamilies. Chapter 3 (Identification of fungal oxaloacetate hydrolyase within the isocitrate lyase/PEP mutase enzyme superfamily using a sequence marker based method) describes how 3DM was used to classify a new fungal protein family (the OAH-like protein class) and how it was used to distinguish true OAH proteins from very similar paralogues proteins. In this chapter it is shown that the OAH route is the only route used by fungi to produce oxalate, which important since it was shown that oxalate production is a virulent factor used by pathogen fungi. Chapter 4 (Oxaloacetate hydrolase: The C-C bond lyase of oxalate secreting fungi) focuses on OAH. This chapter describes how the 3DM results were used to find the reaction mechanism of OAH en how this resulted in the synthesis of a compound that strongly inhibits OAH. Since oxalate production is a virulent factor used by fungi, this compound can be considered as a potential new drug. This thesis comprises all steps between data collection and the final synthesis and testing of the inhibitor. Therefore, this thesis is called: 3DM, from Data to Medicine.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Wageningen University
Supervisors/Advisors
  • van den Berg, J.A., Promotor
  • Schaap, Peter, Co-promotor
  • Vervoort, Jacques, Co-promotor
Award date7 Dec 2007
Place of Publication[S.l.]
Print ISBNs9789085046950
Publication statusPublished - 2007

Keywords

  • hydrolases
  • new drugs
  • biochemical receptors
  • nucleotide sequences

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