Lysine Acetylation Goes Global: From Epigenetics to Metabolism and Therapeutics

Abstract

Post-translational acetylation of lysine residues has emerged as a key regulatory mechanism in all eukaryotic organisms. Originally discovered in 1963 as a unique modification of histones, acetylation marks are now found on thousands of nonhistone proteins located in virtually every cellular compartment. Here we summarize key findings in the field of protein acetylation over the past 20 years with a focus on recent discoveries in nuclear, cytoplasmic, and mitochondrial compartments. Collectively, these findings have elevated protein acetylation as a major post-translational modification, underscoring its physiological relevance in gene regulation, cell signaling, metabolism, and disease.

Resveratrol modulates epigenetic regulators of promoter histone methylation and acetylation that restores BRCA1, p53, p21CIP1 in human breast cancer cell lines

“…The KATs catalyze the acetylation of ε‐N on many lysine residues in histones that disrupts the electrostatic interaction between DNA and histones expose DNA toward transcription machinery resulting in activation of gene expression, although the removal of the acetyl group by KDACs results in gene silencing. So far, several KATs (most notably, KAT2A/2B and KAT3A/3B) and 17 KDACs in mammals have been reported . Altered function or overexpression of PRMT5, EZH2, and KDACs is associated with many cancers .…”

“…So far, several KATs (most notably, KAT2A/2B and KAT3A/3B) and 17 KDACs in mammals have been reported. 8 Altered function or overexpression of PRMT5, EZH2, and KDACs is associated with many cancers. 6,9,10 Increasing quest for inhibitors of both PRMT5 and EZH2 in recent research as well as clinical trials indicates the immense possibilities of their therapeutic targeting in cancer.…”

Advancements in the Development of non‐BET Bromodomain Chemical Probes

“…CPI-637 (34), aC REBBP/EP300 inhibitor based around a benzo [1,4]-diazepin-2-one scaffold, has been reported by Genentech and Constellation Pharmaceuticals (Figure 7d). [58] A fragment screening of % 2000 compounds in at hermal shift assay was used to identify hit compound 33,c hosen for displaying potencya tC REBBP (pIC 50 = 4.5) and 7-fold selectivity over the BET subfamily.…”

“…[58] A fragment screening of % 2000 compounds in at hermal shift assay was used to identify hit compound 33,c hosen for displaying potencya tC REBBP (pIC 50 = 4.5) and 7-fold selectivity over the BET subfamily. X-ray crystallography identified the lactam portion of the benzo [1,4]-diazepin-2-one to be functioning as the KAc mimetic, with the expectedh ydrogen and water-mediated hydrogen bond interactions to the conserved Asn and Tyr, respectively observed. An additional hydrogen bond interaction was also observed between the lactam NH and the carbonyl group of the conserved Asn (Figure 7g), whilst the 4-methyl group was shown to occupy the hydrophobic binding pocket.…”

Dopamin, oxidativer Stress und Protein‐Chinonmodifikationen bei Parkinson und anderen neurodegenerativen Erkrankungen

“…Ursache ist der Verlust von Neuromelanin (NM), der dunklen Substanz, die in dopaminergen Neuronen infolge von oxidativen Vorgängen durch DA unter physiologischer Kontrolle akkumuliert wird. Solche Modifikationen kommen allerdings allgemein vor,u nd obwohl sie nicht in dem Maße voranschreiten, wie man es in NMs sieht, verursachen sie oft schwerere Proteinveränderungen als jene,die auf die üblichen ortsspezifischen Modifikationen, beispielsweise durch Phosphorylierung, [28] Acetylierung [29] oder Nitrierung [30] von Proteinresten, zurückgehen. [27] Wichtig ist, dass die NM-Bildung zumindest in den Anfangsstadien eine posttranslationale Proteinmodifikation darstellt, die durch von CA abgeleitete Chinone als Schutzmechanismus gegen chinonvermittelte Toxizität(als Folge von oxidativem Stress) induziert wird.…”