Abstract
Sirtuins are pivotal regulators in various cellular processes, including transcription, DNA repair, genome stability, and energy metabolism. Their functions have been generally attributed to NAD-dependent deacetylase activity. However, human SIRT5 (sirtuin 5), which has been reported to exhibit little deacetylase activity, was recently identified as an NAD-dependent demalonylase and desuccinylase. Biochemical studies suggested that the mechanism of SIRT5-catalyzed demalonylation and desuccinylation is similar to that of deacetylation catalyzed by other sirtuins. Previously, we solved the crystal structure of a SIRT5-succinyl-lysine peptide-NAD complex. Here, we present two more structures: a binary complex of SIRT5 with an H3K9 succinyl peptide and a binary complex of SIRT5 with a bicyclic intermediate obtained by incubating SIRT5-H3K9 thiosuccinyl peptide co-crystals with NAD. To our knowledge, this represents the first bicyclic intermediate for a sirtuin-catalyzed deacylation reaction that has been captured in a crystal structure, thus providing unique insights into the reaction mechanism. The structural information should benefit the design of specific inhibitors for SIRT5 and help in exploring the therapeutic potential of targeting sirtuins for treating human diseases.
Highlights
Human SIRT5 was recently identified as an NAD-dependent demalonylase/desuccinylase
The structural alignment of the three SIRT5 structures SIRT5-ADP-ribose (ADPR) (27), SIRT5-thioacetylH3K9 (30), and SIRT5-sucH3K9 suggested that the interactions within the -sheet drive the zinc-binding
SIRT5 was recently identified as a novel desuccinylase and demalonylase (30), which is different from the widely known deacetylase activity of sirtuins
Summary
Human SIRT5 was recently identified as an NAD-dependent demalonylase/desuccinylase. Results: We have determined the crystal structures of SIRT5 with a succinyl peptide and with a bicyclic reaction intermediate. Sirtuins are pivotal regulators in various cellular processes, including transcription, DNA repair, genome stability, and energy metabolism Their functions have been generally attributed to NAD-dependent deacetylase activity. We present two more structures: a binary complex of SIRT5 with an H3K9 succinyl peptide and a binary complex of SIRT5 with a bicyclic intermediate obtained by incubating SIRT5-H3K9 thiosuccinyl peptide co-crystals with NAD To our knowledge, this represents the first bicyclic intermediate for a sirtuin-catalyzed deacylation reaction that has been captured in a crystal structure, providing unique insights into the reaction mechanism. Widely recognized as a family of NAD-dependent deacetylases that remove acetyl groups from protein lysine residues (1, 2), have been shown to play crucial roles in the regulation of numerous cellular processes, including DNA repair, cell survival, apoptosis, and energy metabolism
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