uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
X-ray structure of peptidyl-prolyl cis-trans isomerase A from Mycobacterium tuberculosis
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
2004 In: Eur. J. Biochem., ISSN 1742-464X, Vol. 271, 4107-4113 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2004. Vol. 271, 4107-4113 p.
Identifiers
URN: urn:nbn:se:uu:diva-96291OAI: oai:DiVA.org:uu-96291DiVA: diva2:170816
Available from: 2007-10-19 Created: 2007-10-19Bibliographically approved
In thesis
1. Structural and Functional Studies of Peptidyl-prolyl cis-trans isomerase A and 1-deoxy-D-xylulose- 5-phosphate reductoisomerase from Mycobacterium tuberculosis
Open this publication in new window or tab >>Structural and Functional Studies of Peptidyl-prolyl cis-trans isomerase A and 1-deoxy-D-xylulose- 5-phosphate reductoisomerase from Mycobacterium tuberculosis
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mycobacterium tuberculosis, the causative pathogen of tuberculosis, currently infects one-third of the world’s population, resulting in two million deaths annually. This clearly shows that tuberculosis is one of the most serious diseases of our times. The often unpleasant side effects from the current drugs, combined with the difficulty of ensuring patient compliance, and the emergence of drug-resistant and multidrug-resistant strains, makes the need for new and better drugs urgent.

In this thesis, all the steps, from cloning, purification, crystallization, to activity determination, and structure determination are presented for two different M. tuberculosis enzymes. The structures, which were modeled from X-ray crystallographic data, provide the framework for structure-based drug design. Here, new potential inhibitors can be tailor-made based on the specific interactions in the enzyme’s active site.

The bacteria have two different peptidyl-prolyl cis-trans isomerases that catalyze the isomerization of peptide bonds preceding proline residues, a process of high importance for correct folding. Here we present the structure of peptidyl-prolyl cis-trans isomerase A, an enzyme present inside the bacteria, and distinguish it from the B form of the enzyme, which is membrane bound, placing its active site outside the bacteria.

The enzyme 1-deoxy-D-xylulose-5-phosphate reductoisomerase catalyzes the second step within the non-mevalonate pathway, which leads to the production of isopentenyl diphosphate. This compound is the precursor of various isoprenoids, vital to all living organisms. In humans, isopentenyl diphosphate is produced via a different pathway, indicating that all the enzymes within the non-mevalonate pathway may be suitable drug targets in M. tuberculosis. Several structures of both wild type and mutant 1-deoxy-D-xylulose-5-phosphate reductoisomerase in complex with different substrates, and also with the known inhibitor fosmidomycin, provide valuable information not only to the field of drug design, but also, in this case, into the catalysis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 103 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 351
Keyword
Molecular biology, Mycobacterium tuberculosis, Rv0009, peptidyl-prolyl cis-trans isomerase, Rv2870c, 1-deoxy-D-xylulose-5-phosphate reductoisomerase, non-mevalonate pathway, DOXP/MEP pathway, X-ray crystallography, Molekylärbiologi
Identifiers
urn:nbn:se:uu:diva-8253 (URN)978-91-554-6985-6 (ISBN)
Public defence
2007-11-09, B41, BMC, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2007-10-19 Created: 2007-10-19 Last updated: 2009-11-29Bibliographically approved

Open Access in DiVA

No full text

By organisation
Department of Cell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 460 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf