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The SCP2-thiolase-like protein (SLP) of Trypanosoma brucei is an enzyme involved in lipid metabolism

DOI: 10.1002/prot.25054 DOI Help

Authors: Rajesh Harijan (University of Oulu) , Muriel Mazet (UMR5234, Université De Bordeaux) , Tiila-Riikka Kiema (University of Oulu) , Guillaume Bouyssou (UMR-5200, Université De Bordeaux) , Stefan E. H. Alexson (Karolinska Institutet; Karolinska University Hospital) , Ulrich Bergmann (University of Oulu) , Patrick Moreau (UMR-5200, Université De Bordeaux) , Paul A. M. Michels (University of Edinburgh) , Frédéric Bringaud (UMR5234 CNRS, UMR5536, Université de Bordeaux) , Rik K. Wierenga (University of Oulu)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proteins: Structure, Function, And Bioinformatics , VOL 84 , PAGES 1075 - 1096

State: Published (Approved)
Published: August 2016

Abstract: Bioinformatics studies have shown that the genomes of trypanosomatid species each encode one SCP2-thiolase-like protein (SLP), which is characterized by having the YDCF thiolase sequence fingerprint of the Cβ2-Cα2 loop. SLPs are only encoded by the genomes of these parasitic protists and not by those of mammals, including human. Deletion of the Trypanosoma brucei SLP gene (TbSLP) increases the doubling time of procyclic T. brucei and causes a 5-fold reduction of de novo sterol biosynthesis from glucose- and acetate-derived acetyl-CoA. Fluorescence analyses of EGFP-tagged TbSLP expressed in the parasite located the TbSLP in the mitochondrion. The crystal structure of TbSLP (refined at 1.75 Å resolution) confirms that TbSLP has the canonical dimeric thiolase fold. In addition, the structures of the TbSLP-acetoacetyl-CoA (1.90 Å) and TbSLP-malonyl-CoA (2.30 Å) complexes reveal that the two oxyanion holes of the thiolase active site are preserved. TbSLP binds malonyl-CoA tightly (Kd 90 µM), acetoacetyl-CoA moderately (Kd 0.9 mM) and acetyl-CoA and CoA very weakly. TbSLP possesses low malonyl-CoA decarboxylase activity. Altogether, the data show that TbSLP is a mitochondrial enzyme involved in lipid metabolism.

Journal Keywords: Trypanosoma brucei; SCP2-thiolase; SCP2-thiolase-like protein; malonyl-CoA decarboxylase; malonyl-CoA:ACP transacylase; gene knockout; crystal structure; mitochondrial lipid metabolism

Diamond Keywords: Sleeping Sickness; Enzymes

Subject Areas: Chemistry, Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 05/09/2016 16:18

Discipline Tags:

Infectious Diseases Disease in the Developing World Health & Wellbeing Biochemistry Genetics Chemistry Structural biology Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)