Enzymatic assembly of the salinosporamide γ-lactam-β-lactone anticancer warhead
作者:Bauman, Katherine D., Shende, Vikram V., Chen, Percival Yang-Ting, Trivella, Daniela B. B., Gulder, Tobias A. M., Vellalath, Sreekumar, Romo, Daniel, Moore, Bradley S.
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期刊:Nature Chemical Biology
发表时间:2022/03/21
The marine microbial natural product salinosporamide A (marizomib) is a potent proteasome inhibitor currently in clinical trials for the treatment of brain cancer. Salinosporamide A is characterized by a complex and densely functionalized γ-lactam-β-lactone bicyclic warhead, the assembly of which has long remained a biosynthetic mystery. Here, we report an enzymatic route to the salinosporamide core catalyzed by a standalone ketosynthase (KS), SalC. Chemoenzymatic synthesis of carrier protein-tethered substrates, as well as intact proteomics, allowed us to probe the reactivity of SalC and understand its role as an intramolecular aldolase/β-lactone synthase with roles in both transacylation and bond-forming reactions. Additionally, we present the 2.85-Å SalC crystal structure that, combined with site-directed mutagenesis, allowed us to propose a bicyclization reaction mechanism. This work challenges our current understanding of the role of KS enzymes and establishes a basis for future efforts toward streamlined production of a clinically relevant chemotherapeutic.
Salinosporamide A是海洋盐孢菌制造的一种蛋白酶体抑制剂,发现于1990年。这种化合物可以帮助盐孢菌抵御捕食者,但科学家发现其具有抗癌作用,目前已进入治疗胶质母细胞瘤的3期临床试验。这种化合物结构中存在特殊的双环结构,对其活性具有重要作用,但其酶促生物合成机制尚不明确。3月21日发表在《自然·化学生物学》的一项研究揭示了这一机制。
研究者发现,一种称为SalC的酮基合成酶催化了Salinosporamide A的双环结构装配反应。这种酶催化了转酰基和成键反应,充当了分子内醛缩酶和β-内酰合成酶的角色,合成出具有活性双环结构的Salinosporamide A分子。研究者表示,SalC的发现为基于Salinosporamide A的化疗药物开发奠定了基础,未来研究人员或可以通过修改该化合物的分子结构,将其用于治疗多种类型的疾病,例如自身免疫病。
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