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- Roos, Annette K.,1978-Uppsala universitet,Institutionen för cell- och molekylärbiologi (author)
Structural and Functional Studies of Ribose-5-phosphate isomerase B
- BookEnglish2007
Publisher, publication year, extent ...
- Uppsala :Acta Universitatis Upsaliensis,2007
- iv, 73 s.
- electronicrdacarrier
Numbers
- LIBRIS-ID:oai:DiVA.org:uu-8182
- ISBN:9789155469528
- https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8182URI
Supplementary language notes
- Language:English
- Summary in:English
Part of subdatabase
- SwePubSwePub
Classification
Series
- Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology,1651-6214 ;332
Notes
- Ribose 5-phosphate isomerase (Rpi) is one of the major enzymes of the pentose phosphate pathway, where it catalyses the inter-conversion of ribose 5-phosphate (R5P) and ribulose 5-phosphate. Two forms of this isomerase with no significant amino acid sequence similarity exist, RpiA and RpiB. This thesis describes RpiB from the organisms Mycobacterium tuberculosis (Mt) and Escherichia coli (Ec) from a structural and functional point of view.Since the E. coli genome encodes both an RpiA and an RpiB, which generally is not expressed, it has been proposed that EcRpiB has a different role as an allose-6-phosphate isomerase. Activity measurements presented here show that EcRpiB does have this second activity. In the M. tuberculosis genome there is only a gene for RpiB. The crystal structure of MtRpiB was solved in complex with several different inhibitors designed to mimic the reaction intermediate as well as with the substrate, R5P. The organisation of the active site in these structures could be used to derive the reaction mechanism for MtRpiB and for other RpiBs in general. Activity measurements of MtRpiB showed that it can catalyse the R5P isomerisation, but not the allose 6-phosphate reaction. Differences observed in the active site between EcRpiB and MtRpiB explain these kinetic results. Activity measurements and a structure of an EcRpiB mutant, where histidine99 was changed to asparagine, implies that RpiB catalyses the first step of the reaction in which the sugar ring must be opened, and gives a possible explanation for how this could occur. Inhibition studies have uncovered a compound that selectively inhibits MtRpiB over RpiA from spinach, which is homologous to the human RpiA. Differences in the inhibition patterns and active site residues of these two species’ Rpi may provide information for future virtual screening approaches, with the aim of discovering new anti-tuberculosis agents.
Subject headings and genre
- Molecular biology
- Mycobacterium tuberculosis
- reaction mechanism
- cis-enediolate high energy intermediate
- allose-6-phosphate isomerase
- rare sugar
- pentose phosphate pathway
- Rv2465c
- X-ray crystallography
- Molekylärbiologi
Added entries (persons, corporate bodies, meetings, titles ...)
- Mowbray, Sherry L. (thesis advisor)
- Unge, Torsten (thesis advisor)
- Jeffery, Constance,ProfessorUniversity of Illinois at Chicago, Chicago (opponent)
- Uppsala universitetInstitutionen för cell- och molekylärbiologi (creator_code:org_t)
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