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

Rajesh K. Harijan, Muriel Mazet, Tiila R. Kiema, Guillaume Bouyssou, Stefan E.H. Alexson, Ulrich Bergmann, Patrick Moreau, Paul A.M. Michels, Frédéric Bringaud, Rik K. Wierenga

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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. Proteins 2016; 84:1075–1096.

Original languageEnglish (US)
Pages (from-to)1075-1096
Number of pages22
JournalProteins: Structure, Function and Bioinformatics
Volume84
Issue number8
DOIs
StatePublished - Aug 1 2016

Keywords

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

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology

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