Background

Many metabolites serve as important signalling molecules to adjust cellular activities and functions based on nutrient availability. Links between acetyl-CoA metabolism, histone lysine acetylation, and gene expression have been documented and studied over the past decade. In recent years, several additional acyl modifications to histone lysine residues have been identified, which depend on acyl-coenzyme A thioesters (acyl-CoAs) as acyl donors. Acyl-CoAs are intermediates of multiple distinct metabolic pathways, and substantial evidence has emerged that histone acylation is metabolically sensitive. Nevertheless, the metabolic sources of acyl-CoAs used for chromatin modification in most cases remain poorly understood. Elucidating how these diverse chemical modifications are coupled to and regulated by cellular metabolism is important in deciphering their functional significance.

Scope of review

In this article, we review the metabolic pathways that produce acyl-CoAs, as well as emerging evidence for functional roles of diverse acyl-CoAs in chromatin regulation. Because acetyl-CoA has been extensively reviewed elsewhere, we will focus on four other acyl-CoA metabolites integral to major metabolic pathways that are also known to modify histones: succinyl-CoA, propionyl-CoA, crotonoyl-CoA, and butyryl-CoA. We also briefly mention several other acyl-CoA species, which present opportunities for further research; malonyl-CoA, glutaryl-CoA, 3-hydroxybutyryl-CoA, 2-hydroxyisobutyryl-CoA, and lactyl-CoA. Each acyl-CoA species has distinct roles in metabolism, indicating the potential to report shifts in the metabolic status of the cell. For each metabolite, we consider the metabolic pathways in which it participates and the nutrient sources from which it is derived, the compartmentalisation of its metabolism, and the factors reported to influence its abundance and potential nuclear availability. We also highlight reported biological functions of these metabolically-linked acylation marks. Finally, we aim to illuminate key questions in acyl-CoA metabolism as they relate to the control of chromatin modification.

Major conclusions

A majority of acyl-CoA species are annotated to mitochondrial metabolic processes. Since acyl-CoAs are not known to be directly transported across mitochondrial membranes, they must be synthesized outside of mitochondria and potentially within the nucleus to participate in chromatin regulation. Thus, subcellular metabolic compartmentalisation likely plays a key role in the regulation of histone acylation. Metabolite tracing in combination with targeting of relevant enzymes and transporters will help to map the metabolic pathways that connect acyl-CoA metabolism to chromatin modification. The specific function of each acyl-CoA may be determined in part by biochemical properties that affect its propensity for enzymatic versus non-enzymatic protein modification, as well as the various enzymes that can add, remove and bind each modification. Further, competitive and inhibitory effects of different acyl-CoA species on these enzymes make determining the relative abundance of acyl-CoA species in specific contexts important to understand the regulation of chromatin acylation. An improved and more nuanced understanding of metabolic regulation of chromatin and its roles in physiological and disease-related processes will emerge as these questions are answered.

中文翻译：

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区室酰基辅酶 A 代谢及其在染色质调节中的作用。

背景

许多代谢物作为重要的信号分子，根据营养物质的可用性调节细胞活动和功能。在过去的十年中，乙酰辅酶A代谢、组蛋白赖氨酸乙酰化和基因表达之间的联系已被记录和研究。近年来，已鉴定出组蛋白赖氨酸残基的几种额外酰基修饰，这些修饰依赖于酰基辅酶 A 硫酯（酰基辅酶 A）作为酰基供体。酰基辅酶A是多种不同代谢途径的中间体，大量证据表明组蛋白酰化是代谢敏感的。然而，在大多数情况下，用于染色质修饰的酰基辅酶A的代谢来源仍然知之甚少。阐明这些不同的化学修饰如何与细胞代谢耦合并受细胞代谢调节对于破译它们的功能意义非常重要。

审查范围

在本文中，我们回顾了产生酰基辅酶A的代谢途径，以及不同酰基辅酶A在染色质调节中的功能作用的新证据。由于乙酰辅酶 A 已在其他地方进行了广泛的综述，因此我们将重点关注主要代谢途径中不可或缺的其他四种酰基辅酶 A 代谢物，这些代谢途径也已知可修饰组蛋白：琥珀酰辅酶 A、丙酰辅酶 A、巴豆酰辅酶 A 和丁酰辅酶 A。我们还简要提到了其他几种酰基 CoA 物种，它们为进一步研究提供了机会；丙二酰辅酶A、戊二酰辅酶A、3-羟基丁酰辅酶A、2-羟基异丁酰辅酶A和乳酰辅酶A。每个酰基辅酶 A 物种在代谢中具有不同的作用，表明有可能报告细胞代谢状态的变化。对于每种代谢物，我们考虑其参与的代谢途径和其来源的营养来源、其代谢的区室化以及据报道影响其丰度和潜在核可用性的因素。我们还强调了这些与代谢相关的酰化标记的生物学功能。最后，我们的目标是阐明酰基辅酶A代谢的关键问题，因为它们与染色质修饰的控制有关。

主要结论

大多数酰基辅酶A 物种都注释于线粒体代谢过程。由于尚不清楚酰基辅酶A是否直接跨线粒体膜转运，因此它们必须在线粒体外合成，并可能在细胞核内合成，以参与染色质调节。因此，亚细胞代谢区室化可能在组蛋白酰化的调节中发挥关键作用。代谢物追踪与相关酶和转运蛋白的靶向相结合将有助于绘制连接酰基辅酶A代谢与染色质修饰的代谢途径。每个酰基辅酶A的具体功能可能部分取决于影响其酶促与非酶促蛋白质修饰倾向的生化特性，以及可以添加、去除和结合每种修饰的各种酶。此外，不同酰基辅酶 A 种类对这些酶的竞争和抑制作用使得确定特定环境中酰基辅酶 A 种类的相对丰度对于理解染色质酰化的调节非常重要。随着这些问题的解答，我们将更好地、更细致地了解染色质的代谢调节及其在生理和疾病相关过程中的作用。