"When proteins become hypersuccinylated we see a disruption of metabolic pathways, including a buildup of fatty acids in the liver and a decrease in ketone body production," says Rardin. The researchers showed, for example, that HMGCS2 a rate-limiting enzyme in ketone body production important for energy production during fasting has at least 15 sites of succinlyation. Moreover, they demonstrated that succinylation of specific lysine residues near the substrate binding pocket on HMGCS2 abolishes enzyme activity. Therefore, the role of SIRT5 appears to be the removal of these succinyl modifications and restoration of enzyme activity at HMGCS2 as well as other mitochondrial enzymes. "While we still don't know all the implications that lysine succinylation has for mitochondrial function, we have assembled a large list of proteins whose succinylation state appears to be highly regulated by SIRT5," said Gibson. "This list of proteins and sites will be an extremely valuable resource for scientists to examine how these structural alterations are affecting many critical metabolic pathways in normal and pathological conditions."
This work was part of a larger continuing investigation by this same group to better understand the role of sirtuins in mitochondrial biology and metabolism. In work published earlier this year (Rardin et al., Proc Natl Acad Sci, 2013), these scientists examined the activity of the related sirtuin, SIRT3, which regulates lysine acetylation in mitochondria. In contrast to succinylation, which carries a negative charge, acetylation of lysine residues only neutralizes the positive state of the lys
|Contact: Kris Rebillot|
Buck Institute for Age Research