The First Identification of Lysine Malonylation Substrates and Its Regulatory Enzyme*

By Chao Peng, Zhike Lu, Zhongyu Xie, Zhongyi Cheng, Yue Chen, M. Tan, Hao Luo, Yi Zhang, W. He, Ke-Qian Yang and 9 more. Molecular & Cellular Proteomics, 2011

697 citations recorded by the source corpus.

Protein post-translational modifications (PTMs) at the lysine residue, such as lysine methylation, acetylation, and ubiquitination, are diverse, abundant, and dynamic. They play a key role in the regulation of diverse cellular physiology. Here we report discovery of a new type of lysine PTM, lysine malonylation (Kmal). Kmal was initially detected by mass spectrometry and protein sequence-database searching. The modification was comprehensively validated by Western blot, tandem MS, and high-performance liquid chromatography of synthetic peptides, isotopic labeling, and identification of multiple Kmal substrate proteins. Kmal is a dynamic and evolutionarily conserved PTM observed in mammalian cells and bacterial cells. In addition, we demonstrate that Sirt5, a member of the class III lysine deacetylases, can catalyze lysine demalonylation and lysine desuccinylation reactions both in vitro and in vivo. This result suggests the possibility of nondeacetylation activity of other class III lysine deacetylases, especially those without obvious acetylation protein substrates. Our results therefore reveal a new type of PTM pathway and identify the first enzyme that can regulate lysine malonylation and lysine succinylation status.

Subfields: Epidemiology, Geriatrics and Gerontology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/687974b9299c1723cbbae62221e7f064c6ad050b

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Citations in the corpus

Class I histone deacetylases (HDAC1–3) are histone lysine delactylases (2021, background): “demalonylase, desuccinylase, and deglutarylase but not deacetylase (25-28), and HDAC8, HDAC11, SIRT2, and SIRT6 harbor substantial activities against long chain acyl modifications (29-33).”
SIRT5-Mediated Lysine Desuccinylation Impacts Diverse Metabolic Pathways (2013, background): “Consistent with previous reports (Du et al., 2011; Peng et al., 2011), our data showed that Lys-succinylated proteins are significantly enriched in cellular metabolic process with specific enrichment in oxoacid metabolism (adjusted p = 1.”
Lysine Glutarylation Is a Protein Post-Translational Modification Regulated by SIRT5 (2014, methodology): “Succinate and malonate can be used by cells to generate lysine succinylation and malonylation, respectively, presumably by generating succinyl-CoA and malonyl-CoA intermediary metabolites (Peng et al., 2011; Zhang et al., 2011).”
Unraveling the Complex Interplay Between T Cell Metabolism and Function (2018, background): “In addition to the well-established phosphorylation (ATP) and acetylation of proteins (acetate), other TCA intermediates such as malate and succinate can be used to modify proteins through malonylation (43) and succinylation (44), respectively.”
Lysine succinylation is a frequently occurring modification in prokaryotes and eukaryotes and extensively overlaps with acetylation. (2013, background): “842 Cell Reports 4, 842–851, August 29, 2013 a2013 The Authors PTMs involving short-chain acyl-CoA metabolites are reported, such as malonylation (Peng et al., 2011; Xie et al., 2012), crotonylation (Montellier et al.”
SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks (2013, positive): “SIRT5, a mitochondrial sirtuin with very weak deacetylase activity, is a potent desuccinylase (Du et al., 2011; Peng et al., 2011).”
HAMAP in 2015: updates to the protein family classification and annotation system (2014, background): “Class III sirtuins, including the human SIR5 protein (UniProtKB/Swiss-Prot record Q9NXA8), were recently found to exhibit both protein demalonylase and protein desuccinylase activity (26,27).”