bims-meprid 2024-07-21 papers

Nat Commun. 2024 Jul 17. 15(1): 6002

Acetyl-CoA synthetase activity is enzymatically regulated by lysine acetylation using acetyl-CoA or acetyl-phosphate as donor molecule.

Chuan Qin, Leonie G Graf, Kilian Striska, Markus Janetzky, Norman Geist, Robin Specht, Sabrina Schulze, Gottfried J Palm, Britta Girbardt, Babett Dörre, Leona Berndt, Stefan Kemnitz, Mark Doerr, Uwe T Bornscheuer, Mihaela Delcea, Michael Lammers.

The AMP-forming acetyl-CoA synthetase is regulated by lysine acetylation both in bacteria and eukaryotes. However, the underlying mechanism is poorly understood. The Bacillus subtilis acetyltransferase AcuA and the AMP-forming acetyl-CoA synthetase AcsA form an AcuA•AcsA complex, dissociating upon lysine acetylation of AcsA by AcuA. Crystal structures of AcsA from Chloroflexota bacterium in the apo form and in complex with acetyl-adenosine-5'-monophosphate (acetyl-AMP) support the flexible C-terminal domain adopting different conformations. AlphaFold2 predictions suggest binding of AcuA stabilizes AcsA in an undescribed conformation. We show the AcuA•AcsA complex dissociates upon acetyl-coenzyme A (acetyl-CoA) dependent acetylation of AcsA by AcuA. We discover an intrinsic phosphotransacetylase activity enabling AcuA•AcsA generating acetyl-CoA from acetyl-phosphate (AcP) and coenzyme A (CoA) used by AcuA to acetylate and inactivate AcsA. Here, we provide mechanistic insights into the regulation of AMP-forming acetyl-CoA synthetases by lysine acetylation and discover an intrinsic phosphotransacetylase allowing modulation of its activity based on AcP and CoA levels.

DOI: https://doi.org/10.1038/s41467-024-49952-0

bioRxiv. 2024 Jul 02. pii: 2024.07.02.600738. [Epub ahead of print]

Polyamines regulate cell fate by altering the activity of histone-modifying enzymes.

Maya Emmons-Bell, Grace Forsyth, Abby Sundquist, Sylvie Oldeman, Angeliki Gardikioti, Roshni de Souza, Jonathan Coene, Maryam H Kamel, Shine Ayyapan, Harrison A Fuchs, Steven Verhelst, Joanna Smeeton, Catherine A Musselman, Juan-Manuel Schvartzman.

Polyamines are polycationic alkyl-amines abundant in proliferating stem and cancer cells. How these metabolites influence numerous cellular functions remains unclear. Here we show that polyamine levels decrease during differentiation and that inhibiting polyamine synthesis leads to a differentiated-like cell state. Polyamines concentrate in the nucleus and are further enriched in the nucleoli of cells in culture and in vivo . Loss of polyamines drives changes in chromatin accessibility that correlate with altered histone post-translational modifications. Polyamines interact electrostatically with DNA on the nucleosome core, stabilizing histone tails in conformations accessible to modifying enzymes. These data reveal a mechanism by which an abundant metabolite influences chromatin structure and function in a non-sequence specific manner, facilitating chromatin remodeling during reprogramming and limiting it during fate commitment.

DOI: https://doi.org/10.1101/2024.07.02.600738

Nat Chem Biol. 2024 Jul 19.

Lysine L-lactylation is the dominant lactylation isomer induced by glycolysis.

Di Zhang, Jinjun Gao, Zhijun Zhu, Qianying Mao, Zhiqiang Xu, Pankaj K Singh, Cornelius C Rimayi, Carlos Moreno-Yruela, Shuling Xu, Gongyu Li, Yi-Cheng Sin, Yue Chen, Christian A Olsen, Nathaniel W Snyder, Lunzhi Dai, Lingjun Li, Yingming Zhao.

Lysine L-lactylation (Kl-la) is a novel protein posttranslational modification (PTM) driven by L-lactate. This PTM has three isomers: Kl-la, N-ε-(carboxyethyl)-lysine (Kce) and D-lactyl-lysine (Kd-la), which are often confused in the context of the Warburg effect and nuclear presence. Here we introduce two methods to differentiate these isomers: a chemical derivatization and high-performance liquid chromatography analysis for efficient separation, and isomer-specific antibodies for high-selectivity identification. We demonstrated that Kl-la is the primary lactylation isomer on histones and dynamically regulated by glycolysis, not Kd-la or Kce, which are observed when the glyoxalase system was incomplete. The study also reveals that lactyl-coenzyme A, a precursor in L-lactylation, correlates positively with Kl-la levels. This work not only provides a methodology for distinguishing other PTM isomers, but also highlights Kl-la as the primary responder to glycolysis and the Warburg effect.

DOI: https://doi.org/10.1038/s41589-024-01680-8

bioRxiv. 2024 Jul 14. pii: 2024.07.12.603313. [Epub ahead of print]

Acetate drives ovarian cancer quiescence via ACSS2-mediated acetyl-CoA production.

Allison C Sharrow, Emily Megill, Amanda J Chen, Afifa Farooqi, Stacy McGonigal, Nadine Hempel, Nathaniel W Snyder, Ronald J Buckanovich, Katherine M Aird.

Quiescence is a reversible cell cycle exit traditionally thought to be associated with a metabolically inactive state. Recent work in muscle cells indicates that metabolic reprogramming is associated with quiescence. Whether metabolic changes occur in cancer to drive quiescence is unclear. Using a multi-omics approach, we found that the metabolic enzyme ACSS2, which converts acetate into acetyl-CoA, is both highly upregulated in quiescent ovarian cancer cells and required for their survival. Indeed, quiescent ovarian cancer cells have increased levels of acetate-derived acetyl-CoA, confirming increased ACSS2 activity in these cells. Furthermore, either inducing ACSS2 expression or supplementing cells with acetate was sufficient to induce a reversible quiescent cell cycle exit. RNA-Seq of acetate treated cells confirmed negative enrichment in multiple cell cycle pathways as well as enrichment of genes in a published G0 gene signature. Finally, analysis of patient data showed that ACSS2 expression is upregulated in tumor cells from ascites, which are thought to be more quiescent, compared to matched primary tumors. Additionally, high ACSS2 expression is associated with platinum resistance and worse outcomes. Together, this study points to a previously unrecognized ACSS2-mediated metabolic reprogramming that drives quiescence in ovarian cancer. As chemotherapies to treat ovarian cancer, such as platinum, have increased efficacy in highly proliferative cells, our data give rise to the intriguing question that metabolically-driven quiescence may affect therapeutic response.

DOI: https://doi.org/10.1101/2024.07.12.603313