Background

The abundance of energy metabolites is intimately interconnected with the activity of chromatin-modifying enzymes in order to guarantee the finely tuned modulation of gene expression in response to cellular energetic status. Metabolism-induced epigenetic gene regulation is a key molecular axis for the maintenance of cellular homeostasis, and its deregulation is associated with several pathological conditions. Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme that catalyzes the methylation of nicotinamide (NAM) using the universal methyl donor S-adenosyl methionine (SAM), directly linking one-carbon metabolism with a cell's methylation balance and nicotinamide adenine dinucleotide (NAD⁺) levels. NNMT expression and activity are regulated in a tissue-specific-manner, and the protein can act either physiologically or pathologically depending on its distribution. While NNMT exerts a beneficial effect by regulating lipid parameters in the liver, its expression in adipose tissue correlates with obesity and insulin resistance. NNMT upregulation has been observed in a variety of cancers, and increased NNMT expression has been associated with tumor progression, metastasis and worse clinical outcomes. Accordingly, NNMT represents an appealing druggable target for metabolic disorders as well as oncological and other diseases in which the protein is improperly activated.

Scope of review

This review examines emerging findings concerning the complex NNMT regulatory network and the role of NNMT in both NAD metabolism and cell methylation balance. We extensively describe recent findings concerning the physiological and pathological regulation of NNMT with a specific focus on the function of NNMT in obesity, insulin resistance and other associated metabolic disorders along with its well-accepted role as a cancer-associated metabolic enzyme. Advances in strategies targeting NNMT pathways are also reported, together with current limitations of NNMT inhibitor drugs in clinical use.

Major conclusions

NNMT is emerging as a key point of intersection between cellular metabolism and epigenetic gene regulation, and growing evidence supports its central role in several pathologies. The use of molecules that target NNMT represents a current pharmaceutical challenge for the treatment of several metabolic-related disease as well as in cancer.

中文翻译：

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烟酰胺 N-甲基转移酶：处于细胞代谢和表观遗传调控之间的十字路口

背景

能量代谢物的丰度与染色质修饰酶的活性密切相关，以保证对细胞能量状态作出响应的基因表达的精细调节。代谢诱导的表观遗传基因调控是维持细胞稳态的关键分子轴，其失调与多种病理状况有关。烟酰胺 N-甲基转移酶 (NNMT) 是一种代谢酶，它使用通用甲基供体 S-腺苷甲硫氨酸 (SAM) 催化烟酰胺 (NAM) 的甲基化，直接将单碳代谢与细胞的甲基化平衡和烟酰胺腺嘌呤二核苷酸 (NAD ⁺) 水平。NNMT 的表达和活性以组织特异性方式进行调节，并且蛋白质可以根据其分布在生理或病理上起作用。虽然 NNMT 通过调节肝脏中的脂质参数发挥有益作用，但其在脂肪组织中的表达与肥胖和胰岛素抵抗相关。已在多种癌症中观察到 NNMT 上调，并且 NNMT 表达增加与肿瘤进展、转移和更差的临床结果相关。因此，NNMT 代表了一个有吸引力的药物靶点，用于代谢紊乱以及肿瘤和其他蛋白质被不正确激活的疾病。

审查范围

本综述审查了有关复杂 NNMT 调节网络的新发现以及 NNMT 在 NAD 代谢和细胞甲基化平衡中的作用。我们广泛描述了关于 NNMT 生理和病理调节的最新发现，特别关注 NNMT 在肥胖、胰岛素抵抗和其他相关代谢紊乱中的功能，以及其作为癌症相关代谢酶的公认作用。还报告了针对 NNMT 通路的策略的进展，以及目前临床使用 NNMT 抑制剂药物的局限性。

主要结论

NNMT 正在成为细胞代谢和表观遗传基因调控之间的关键交叉点，越来越多的证据支持其在多种病理中的核心作用。使用靶向 NNMT 的分子代表了当前治疗多种代谢相关疾病和癌症的药物挑战。