通过酶解逆转蛋白质化学老化
Reversal of protein chemical aging by enzymatic deglycation.
摘要(中文译文)
晚期糖基化终产物（AGEs）在长寿命蛋白中的积累是哺乳动物衰老的标志，并被认为是代谢功能障碍的驱动因素。在这些加合物中，N-羧甲基赖氨酸（CML）在衰老组织中尤为丰富，其修饰蛋白质并作为晚期糖基化终产物受体（RAGE）的配体，从而持续引发慢性炎症和氧化应激。尽管针对反应性前体存在内源性解毒系统，但稳定的CML加合物历来被认为不可逆。在此，我们报道了CMLase的开发——一种通过对超过5亿个变体进行定向进化而工程化的酶，可特异性氧化CML并恢复天然赖氨酸残基。我们证明CMLase在体外模型蛋白以及来自老年供者的人体组织样本中有效逆转CML修饰，提供了概念验证，即此前被认为不可逆的蛋白质损伤可通过酶促修复。总体而言，我们的方法建立了一个平台，用于开发逆转年龄相关分子损伤的酶，并最终修复因衰老和疾病而受损的组织蛋白。
Abstract
The accumulation of advanced glycation end products (AGEs) in long-lived proteins is a hallmark of mammalian aging and implicated as a driver of metabolic dysfunction. Among these adducts, N-carboxymethyl-lysine (CML) is particularly abundant in aging tissues, where it modifies proteins and acts as a ligand for the receptor for advanced glycation end products (RAGE), thereby perpetuating chronic inflammation and oxidative stress. While endogenous detoxification systems exist for reactive precursors, the stable CML adduct has historically been considered irreversible. Here, we report the development of CMLase - an enzyme engineered through the directed evolution of over 500 million variants to specifically oxidize CML and restore the native lysine residue. We demonstrate that CMLase effectively reverses CML modifications in model proteins in vitro and in human tissue samples from elderly donors, providing proof-of-concept that protein damage previously deemed irreversible is amenable to enzymatic repair. Collectively, our approach establishes a platform for developing enzymes to reverse age-related molecular damage and ultimately repair tissue proteins compromised by aging and disease.
如何引用
AMA
Narisa Trabosh, Jason Smith, Maggie Yun-Hsuan Hsu, Sudipta Panja, Ram Nagaraj, Niclas Olsson, et al. Reversal of protein chemical aging by enzymatic deglycation.. Nature communications. 2026; doi:10.1038/s41467-026-75141-2.
APA
Narisa Trabosh, Jason Smith, Maggie Yun-Hsuan Hsu, Sudipta Panja, Ram Nagaraj, Niclas Olsson, et al (2026). Reversal of protein chemical aging by enzymatic deglycation.. Nature communications. https://doi.org/10.1038/s41467-026-75141-2
GB/T 7714
Narisa Trabosh, Jason Smith, Maggie Yun-Hsuan Hsu, Sudipta Panja, Ram Nagaraj, Niclas Olsson, et al. Reversal of protein chemical aging by enzymatic deglycation.[J]. Nature communications, 2026 doi:10.1038/s41467-026-75141-2.
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