Browsing by Author "Tan, Lin"

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    KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase
    (Springer Nature, 2017) Wang, Yugang; Guo, Yusong R.; Liu, Ke; Yin, Zheng; Liu, Rui; Xia, Yan; Tan, Lin; Yang, Peiying; Lee, Jong-Ho; Li, Xin-jian; Hawke, David; Zheng, Yanhua; Qian, Xu; Lyu, Jianxin; He, Jie; Xing, Dongming; Tao, Yizhi Jane; Lu, Zhimin
    Histone modifications, such as the frequently occurring lysine succinylation1,2, are central to the regulation of chromatin-based processes. However, the mechanism and functional consequences of histone succinylation are unknown. Here we show that the α-ketoglutarate dehydrogenase (α-KGDH) complex is localized in the nucleus in human cell lines and binds to lysine acetyltransferase 2A (KAT2A, also known as GCN5) in the promoter regions of genes. We show that succinyl-coenzyme A (succinyl-CoA) binds to KAT2A. The crystal structure of the catalytic domain of KAT2A in complex with succinyl-CoA at 2.3 Å resolution shows that succinyl-CoA binds to a deep cleft of KAT2A with the succinyl moiety pointing towards the end of a flexible loop 3, which adopts different structural conformations in succinyl-CoA-bound and acetyl-CoA-bound forms. Site-directed mutagenesis indicates that tyrosine 645 in this loop has an important role in the selective binding of succinyl-CoA over acetyl-CoA. KAT2A acts as a succinyltransferase and succinylates histone H3 on lysine 79, with a maximum frequency around the transcription start sites of genes. Preventing the α-KGDH complex from entering the nucleus, or expression of KAT2A(Tyr645Ala), reduces gene expression and inhibits tumour cell proliferation and tumour growth. These findings reveal an important mechanism of histone modification and demonstrate that local generation of succinyl-CoA by the nuclear α-KGDH complex coupled with the succinyltransferase activity of KAT2A is instrumental in histone succinylation, tumour cell proliferation, and tumour development.
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    Pleozymes: Pleiotropic Oxidized Carbon Nanozymes Enhance Cellular Metabolic Flexibility
    (MDPI, 2024) Vo, Anh T. T.; Mouli, Karthik; Liopo, Anton V.; Lorenzi, Philip; Tan, Lin; Wei, Bo; Martinez, Sara A.; McHugh, Emily A.; Tour, James M.; Khan, Uffaf; Derry, Paul J.; Kent, Thomas A.; Smalley-Curl Institute;Rice Advanced Materials Institute;The NanoCarbon Center
    Our group has synthesized a pleiotropic synthetic nanozyme redox mediator we term a “pleozyme” that displays multiple enzymatic characteristics, including acting as a superoxide dismutase mimetic, oxidizing NADH to NAD+, and oxidizing H2S to polysulfides and thiosulfate. Benefits have been seen in acute and chronic neurological disease models. The molecule is sourced from coconut-derived activated charcoal that has undergone harsh oxidization with fuming nitric acid, which alters the structure and chemical characteristics, yielding 3–8 nm discs with broad redox potential. Prior work showed pleozymes localize to mitochondria and increase oxidative phosphorylation and glycolysis. Here, we measured cellular NAD+ and NADH levels after pleozyme treatment and observed increased total cellular NADH levels but not total NAD+ levels. A 13C-glucose metabolic flux analysis suggested pleozymes stimulate the generation of pyruvate and lactate glycolytically and from the tricarboxylic acid (TCA) cycle, pointing to malate decarboxylation. Analysis of intracellular fatty acid abundances suggests pleozymes increased fatty acid β-oxidation, with a concomitant increase in succinyl- and acetyl-CoA. Pleozymes increased total ATP, potentially via flexible enhancement of NAD+-dependent catabolic pathways such as glycolysis, fatty acid β-oxidation, and metabolic flux through the TCA cycle. These effects may be favorable for pathologies that compromise metabolism such as brain injury.