Details

Autor(en) / Beteiligte

• Moreth, Kristin
• Riester, Daniel
• Hildmann, Christian
• Hempel, René
• Wegener, Dennis
• Schober, Andreas
• Schwienhorst, Andreas

Titel

Active site tyrosine is essential for amidohydrolase but not for esterase activity of a class 2 histone deacetylase-like bacterial enzyme

Ist Teil von

• Biochemical journal, 2006-10, Vol.401 (3), p.659-665

Ort / Verlag

Portland Press

Erscheinungsjahr

2006

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Histone deacetylases (HDACs) are considered to be among the most important enzymes that regulate gene expression in eukaryotic cells acting through deacetylation of {epsilon}-acetyl-lysine residues within the N-terminal tail of core histones. In addition, both eukaryotic HDACs as well as their bacterial counterparts were reported to also act on nonhistone targets. However, we are still far from comprehensive understanding of the biological activities of this ancient class of enzymes. Here, we studied in more detail the esterase activity of HDACs focussing on the histone deacetylase-like amidohydrolase (HDAH) from Bordetella/Alcaligenes strain FB188. This enzyme was classified as a class 2 HDAC based on sequence comparison as well as functional data. Using chromogenic and fluorogenic ester substrates we show that histone deacetylases such as FB188 HDAH have indeed esterase activity that is comparable to those of known esterases. Similar results were obtained for human HDAC1, 3 and 8. Standard HDAC inhibitors were able to block both activities with similar IC50 values. Interestingly, HDAC inhibitors such as SAHA or MS275 also showed inhibitory activity against porcine liver esterase and Pseudomonas fluorescens lipase. Both, the esterase- and the amidohydrolase activity of FB188 HDAH appear to have the same substrate specificity concerning the acyl moiety. Interestingly, a Y312F mutation in the active site of HDAH obstructed amidohydrolase activity but significantly improved esterase activity indicating subtle differences in the mechanism of both catalytic activities. Our results suggest that HDACs, in principle, may have other biological roles besides acting as protein deacetylases. Furthermore, data on HDAC inhibitors affecting known esterases indicate that these molecules which are currently among the most promising drug candidates in cancer therapy may have a broader target profile that needs further exploration.