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Publication Abstract from PubMed

Thiolases are essential CoA dependent enzymes in lipid metabolism. Here we report on crystal structures of trypanosomal and leishmanial SCP2-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 cysteines, functioning as a nucleophile and an acid/base, respectively. The latter cysteine is part of a CxG-motif. Interestingly, this cysteine is not conserved in SCP2-thiolases. The structural comparisons now show that in SCP2-thiolases the catalytic acid/base is provided by the cysteine of the HDCF-motif, which is unique for this thiolase subfamily. This HDCF-cysteine is spatially equivalent to the CxG-cysteine of classical thiolases. The HDCF-cysteine is activated for acid/base catalysis by two main chain NH-atoms, instead of two waters, as present in the CxG-active site. The structural results have been complemented with enzyme activity data, confirming the importance of the HDCF-cysteine 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.

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.,Harijan RK, Kiema TR, Karjalainen MP, Janardan N, Murthy MR, Weiss MS, Michels PA, Wierenga RK Biochem J. 2013 Aug 2. PMID:23909465^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.