Research Perspective|Volume 3, Issue 6|pp 635—642

SIRT1 and SIRT3 Deacetylate Homologous Substrates: AceCS1,2 and HMGCS1,2

Matthew D. Hirschey¹, Tadahiro Shimazu¹, John A. Capra², Katherine S. Pollard^2,³, Eric Verdin^1,⁴

¹Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94158
²Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158
³Division of Biostatistics & Institute for Human Genetics, University of California, San Francisco, CA 94107
⁴Department of Medicine, University of California, San Francisco, CA 94143

* * Equal contribution

Received: June 12, 2011Accepted: June 18, 2011Published: June 19, 2011

Copyright: © 2011 Hirschey et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

SIRT1 and SIRT3 are NAD+-dependent protein deacetylases that are evolutionarily conserved across mammals. These proteins are located in the cytoplasm/nucleus and mitochondria, respectively. Previous reports demonstrated that human SIRT1 deacetylates Acetyl-CoA Synthase 1 (AceCS1) in the cytoplasm, whereas SIRT3 deacetylates the homologous Acetyl-CoA Synthase 2 (AceCS2) in the mitochondria. We recently showed that 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2) is deacetylated by SIRT3 in mitochondria, and we demonstrate here that SIRT1 deacetylates the homologous 3-hydroxy-3-methylglutaryl CoA synthase 1 (HMGCS1) in the cytoplasm. This novel pattern of substrate homology between cytoplasmic SIRT1 and mitochondrial SIRT3 suggests that considering evolutionary relationships between the sirtuins and their substrates may help to identify and understand the functions and interactions of this gene family. In this perspective, we take a first step by characterizing the evolutionary history of the sirtuins and these substrate families.