癌症的高死亡率和侵袭性所面临的紧迫挑战需要改进的治疗方法。针对癌细胞内的营养依赖性已成为一种有前途的方法。这项研究致力于证明精氨酸消耗在癌症治疗中的潜力。值得注意的是，重点集中在精氨酸脱羧酶（RDC）上，这是一种 pH 依赖性酶，有望在肿瘤微酸性微环境中增强活性。为了研究单位点突变对 RDC 催化功效的影响，研究人员对多种氨基酸（包括甘氨酸、丙氨酸、苯丙氨酸、酪氨酸、色氨酸、对叠氮基苯丙氨酸和氢取代四嗪的苯丙氨酸类似物）进行了研究。在多聚体形成界面的关键苏氨酸位点（位置 39）引入。值得注意的是，在 39 位引入天然或非天然芳香族氨基酸显着增强了酶活性，而具有较小侧链的氨基酸则没有表现出相同的效果。这种增强的酶活性可能归因于通过引入的芳香族氨基酸和邻近亚基之间的有利相互作用增强了多聚体结构的形成。值得注意的是，在弱酸性 pH 条件下，与野生型 RDC 相比，第 39 位具有色氨酸的 RDC 变体表现出增强的针对肿瘤细胞的细胞毒性。这一属性与肿瘤微环境相一致，并将这些变异定位为靶向癌症治疗的潜在候选者。本文受版权保护。保留所有权利。本文受版权保护。版权所有。

The pressing challenge of cancer's high mortality and invasiveness demands improved therapeutic approaches. Targeting the nutrient dependencies within cancer cells has emerged as a promising approach. This study is dedicated to demonstrating the potential of arginine depletion for cancer treatment. Notably, the focus centers on arginine decarboxylase (RDC), a pH-dependent enzyme expecting enhanced activity within the slightly acidic microenvironments of tumors. To investigate the effect of a single-site mutation on the catalytic efficacy of RDC, diverse amino acids, including glycine, alanine, phenylalanine, tyrosine, tryptophan, p-azido-phenylalanine, and a phenylalanine analog with a hydrogen-substituted tetrazine, were introduced at the crucial threonine site (position 39) in the multimer-forming interface. Remarkably, the introduction of either a natural or a non-natural aromatic amino acid at position 39 substantially boosted enzymatic activity, while amino acids with smaller sidechains did not show the same effect. This enhanced enzymatic activity is likely attributed to the reinforced formation of multimer structures through favorable interactions between the introduced aromatic amino acid and the neighboring subunit. Noteworthy, at slightly acidic pH, the RDC variant featuring tryptophan at position 39 demonstrated augmented cytotoxicity against tumor cells compared to the wild-type RDC. This attribute aligns with the tumor microenvironment and positions these variants as potential candidates for targeted cancer therapy. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.