Thiolases are essential CoA-dependent enzymes in lipid metabolism. In the present study we report the crystal structures of trypanosomal and leishmanial SCP2 (sterol carrier protein, type-2)-thiolases. Trypanosomatidae cause various widespread devastating (sub)-tropical diseases, for which adequate treatment is lacking. The structures reveal the unique geometry of the active site of this poorly characterized subfamily of thiolases. The key catalytic residues of the classical thiolases are two cysteine residues, functioning as a nucleophile and an acid/base respectively. The latter cysteine residue is part of a CxG motif. Interestingly, this cysteine residue is not conserved in SCP2-thiolases. The structural comparisons now show that in SCP2-thiolases the catalytic acid/base is provided by the cysteine residue of the HDCF motif, which is unique for this thiolase subfamily. This HDCF cysteine residue is spatially equivalent to the CxG cysteine residue of classical thiolases. The HDCF cysteine residue is activated for acid/base catalysis by two main chain NH-atoms, instead of two water molecules, as present in the CxG active site. The structural results have been complemented with enzyme activity data, confirming the importance of the HDCF cysteine residue for catalysis. The data obtained suggest that these trypanosomatid SCP2-thiolases are biosynthetic thiolases. These findings provide promise for drug discovery as biosynthetic thiolases catalyse the first step of the sterol biosynthesis pathway that is essential in several of these parasites.
Skip Nav Destination
Article navigation
October 2013
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
September 13 2013
Crystal structures of SCP2-thiolases of Trypanosomatidae, human pathogens causing widespread tropical diseases: the importance for catalysis of the cysteine of the unique HDCF loop
Rajesh K. Harijan;
Rajesh K. Harijan
*Department of Biochemistry, Biocenter Oulu, University of Oulu, Oulu FIN-90014, Finland
Search for other works by this author on:
Tiila R. Kiema;
Tiila R. Kiema
*Department of Biochemistry, Biocenter Oulu, University of Oulu, Oulu FIN-90014, Finland
Search for other works by this author on:
Mikael P. Karjalainen;
Mikael P. Karjalainen
*Department of Biochemistry, Biocenter Oulu, University of Oulu, Oulu FIN-90014, Finland
Search for other works by this author on:
Neelanjana Janardan;
Neelanjana Janardan
†Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India
Search for other works by this author on:
M. R. N. Murthy;
M. R. N. Murthy
†Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India
Search for other works by this author on:
Manfred S. Weiss;
Manfred S. Weiss
‡Helmholtz-Zentrum Berlin, Macromolecular Crystallography (HZB-MX), Albert-Einstein-Str. 15, D-12489 Berlin, Germany
Search for other works by this author on:
Paul A. M. Michels;
Paul A. M. Michels
1
§Research Unit for Tropical Diseases, de Duve Institute and Laboratory of Biochemistry, Université Catholique de Louvain, Avenue Hippocrate 74, P.O. Box B1.74.01, B-1200 Brussels, Belgium
Search for other works by this author on:
Rik K. Wierenga
Rik K. Wierenga
2
*Department of Biochemistry, Biocenter Oulu, University of Oulu, Oulu FIN-90014, Finland
2To whom correspondence should be addressed (email rik.wierenga@oulu.fi).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
May 16 2013
Revision Received:
August 01 2013
Accepted:
August 02 2013
Accepted Manuscript online:
August 02 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 455 (1): 119–130.
Article history
Received:
May 16 2013
Revision Received:
August 01 2013
Accepted:
August 02 2013
Accepted Manuscript online:
August 02 2013
Citation
Rajesh K. Harijan, Tiila R. Kiema, Mikael P. Karjalainen, Neelanjana Janardan, M. R. N. Murthy, Manfred S. Weiss, Paul A. M. Michels, Rik K. Wierenga; Crystal structures of SCP2-thiolases of Trypanosomatidae, human pathogens causing widespread tropical diseases: the importance for catalysis of the cysteine of the unique HDCF loop. Biochem J 1 October 2013; 455 (1): 119–130. doi: https://doi.org/10.1042/BJ20130669
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Captcha Validation Error. Please try again.