Identification of SIRT3 as an eraser of H4K16la

SIRT3 Activation a Promise in Drug Development? New Insights into SIRT3 Biology and Its Implications on the Drug Discovery Process

“…Very recently, Hao et al found that SIRT3 is able to remove the lactoyl group at H4K16, and they confirmed this with crystal structural analysis, also applying several chemical probes. As for the histone lysine acetylation, the lactylation stimulates gene transcription by maintaining open the chromatin .…”

“…48 Notably, deacetylated FOXO3α seems to protect cells from apoptosis via activating a range of autophagy-related genes, such as ULK1, ATG5, and ATG7. 49 Very recently, Hao et al 50 found that SIRT3 is able to remove the lactoyl group at H4K16, and they confirmed this with crystal structural analysis, also applying several chemical probes. As for the histone lysine acetylation, the lactylation stimulates gene transcription by maintaining open the chromatin.…”

“…The same authors have also demonstrated that SIRT3 prefers to delactylate N -lactyl- d -lysine rather than N -lactyl- l -lysine. Particularly, crystal analysis reveals that the lysine hydrocarbon chain is located in a hydrophobic pocket of SIRT3, while the hydroxyl group of lactyl-lysine is stabilized by a hydrogen bond network, including some water molecules …”

Histone lactylation: from tumor lactate metabolism to epigenetic regulation

“…These assertions were further validated through analogous experiments conducted by other researchers, which yielded congruent outcomes 9 , 69 . Regarding the fourth sequential stage, a recent report revealed that SIRT3 can act as an "eraser" of Kla at the H4K16 site 70 , which can also prevent the proliferation of cancer cells by reducing the activity of cyclin E2, a famous proliferation-related molecule 71 . A study pertaining to Kla provides promising insights.…”

The (patho)physiological roles of the individual deacylase activities of a sirtuin

“…One major discovery in the sirtuin field has been that many sirtuins each possesses multiple deacylase activities acting on N ε ‐acyl‐lysine substrates with different acyl groups (Figure 1) (Abmayr & Workman, 2019; Anderson et al., 2017; Bheda et al., 2016; Chen et al., 2015; Chio et al., 2023; Colak et al., 2013; Delaney et al., 2021; Dong et al., 2022; Fan et al., 2023; Feldman et al., 2013; Gil et al., 2013; Huang, Zhang, et al., 2018; Ji et al., 2021; Jin et al., 2016, 2023; Li & Zheng, 2018; Liu et al., 2020; Mikulik et al., 2012; Olesen et al., 2018; Rajabi et al., 2018; Ringel et al., 2014; Seidel et al., 2016; Sun et al., 2022; Tan et al., 2022; Teng et al., 2015; Wang et al., 2023; Zhang et al., 2023; Zhang, Cao, et al., 2019; Zhang, Li, et al., 2019; Zhu et al., 2012; Zu et al., 2022). Specifically, SIRT1/2/3 are all able to catalyze efficiently the deacetylation and defatty‐acylation (e.g., demyristoylation) reactions; CobB from certain bacterial strains is able to catalyze the deacetylation and desuccinylation reactions with comparable catalytic efficiency; CobB from Escherichia coli was further found to catalyze the delactylation reaction with comparable catalytic efficiency to its deacetylase activity; SIRT1 is also able to catalyze deformylation reaction albeit being ~6.6‐fold less proficient than its deacetylase activity; SIRT1 was further found to be an in vivo debenzoylase and delactylase; SIRT2 is also able to catalyze debenzoylation, demethacrylation, and de‐4‐oxononanoylation (de‐4‐ONylation) reactions with more or less comparable catalytic proficiency to that of deacetylation; SIRT2 and SIRT3 were also found to possess an in vivo delactylase activity; SIRT3 is also capable of catalyzing proficiently the decrotonylation and de‐β‐hydroxybutyrylation reactions; SIRT4 is able to catalyze proficiently the deglutarylation and de‐3‐methyl‐glutarylation reactions; SIRT5 is able to catalyze proficiently the demalonylation, desuccinylation, and deglutarylation reactions; SIRT6 was found to catalyze both deacetylation and defattyl‐acylation (e.g., demyristoylation) reactions, with the former activity being weaker than the latter activity on isolated protein substrates; however, the former activity can be enhanced when the substrates are core histone proteins present in a nucleosome unit together with double‐stranded DNA (dsDNA), which has been rationalized very recen...…”