Efficient demyristoylase activity of SIRT2 revealed by kinetic and structural studies.

Yan-Bin Teng,Jing Hu,Hui Jing,Bin He,Pornpun Aramsangtienchai,Saba Khan,Quan Hao,Hening Lin

doi:10.1038/srep08529

Yan-Bin Teng, Jing Hu + Show 6 more

Open Access

https://doi.org/10.1038/srep08529

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Journal: Scientific Reports	Publication Date: Feb 23, 2015
Citations: 151	License type: CC BY 4.0

Affiliation: Cornell University, University of Hong Kong

Abstract

Sirtuins are a class of enzymes originally identified as nicotinamide adenine dinucleotide (NAD)-dependent protein lysine deacetylases. Among the seven mammalian sirtuins, SIRT1-7, only SIRT1-3 possess efficient deacetylase activity in vitro, whereas SIRT4-7 possess very weak in vitro deacetylase activity. Several sirtuins that exhibit weak deacetylase activity have recently been shown to possess more efficient activity for the removal other acyl lysine modifications, such as succinyl lysine and palmitoyl lysine. Here, we demonstrate that even the well-known deacetylase SIRT2 possesses efficient activity for the removal of long-chain fatty acyl groups. The catalytic efficiency (kcat/Km) for the removal of a myristoyl group is slightly higher than that for the removal of an acetyl group. The crystal structure of SIRT2 in complex with a thiomyristoyl peptide reveals that SIRT2 possesses a large hydrophobic pocket that can accommodate the myristoyl group. Comparison of the SIRT2 acyl pocket to those of SIRT1, SIRT3, and SIRT6 reveals that the acyl pockets of SIRT1-3 are highly similar, and to a lesser degree, similar to that of SIRT6. The efficient in vitro demyristoylase activity of SIRT2 suggests that this activity may be physiologically relevant and warrants future investigative studies.

Highlights

Sirtuins are a class of enzymes originally identified as nicotinamide adenine dinucleotide (NAD)-dependent protein lysine deacetylases
We have demonstrated that SIRT2 is an efficient demyristoylase in vitro
The crystal structure of SIRT2 in complex with a thiomyristoyl peptide, BHJH-TM1, reveals a larger hydrophobic pocket that is responsible for binding the long-chain fatty acyl groups

Summary

Introduction

Sirtuins are a class of enzymes originally identified as nicotinamide adenine dinucleotide (NAD)-dependent protein lysine deacetylases. We demonstrate that even the well-known deacetylase SIRT2 possesses efficient activity for the removal of long-chain fatty acyl groups. We have demonstrated that SIRT6, which is a class IV sirtuin that exhibits weak deacetylase activity, can remove long-chain fatty acyl groups more efficiently[13]. These studies have established that sirtuins are NAD-dependent protein lysine deacylases and that different sirtuins may exhibit different acyl group preferences. A crystal structure of SIRT2 in complex with a thiomyristoyl peptide reveals a hydrophobic pocket responsible for the recognition of long-chain www.nature.com/scientificreports fatty acyl groups. Our studies demonstrate that the defatty-acylase activity of SIRT2 is highly efficient and provide compelling rationale for future studies on the physiological relevance of this activity

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