Jiang Ziran, Chen Aochiu, Chen Jeffrey, Sekhon Arman, Louie Gordon V, Noel Joseph P, La Clair James J, Burkart Michael D
Department of Chemistry and Biochemistry, University of California San Diego La Jolla CA 92093-0358 USA
The Salk Institute for Biological Studies, Jack H. Skirball Center for Chemical Biology and Proteomics La Jolla CA 92037 USA.
Chem Sci. 2023 Sep 8;14(39):10925-10933. doi: 10.1039/d3sc02864j. eCollection 2023 Oct 11.
Protein-reactive natural products such as the fungal metabolite cerulenin are recognized for their value as therapeutic candidates, due to their ability to selectively react with catalytic residues within a protein active site or a complex of protein domains. Here, we explore the development of fatty-acid and polyketide-synthase probes by synthetically modulating cerulenin's functional moieties. Using a mechanism-based approach, we reveal unique reactivity within cerulenin and adapt it for fluorescent labeling and crosslinking of fatty-acid and iterative type-I polyketide synthases. We also describe two new classes of silylcyanohydrin and silylhemiaminal masked crosslinking probes that serve as new tools for activity and structure studies of these biosynthetic pathways.
蛋白质反应性天然产物，如真菌代谢物浅蓝菌素，因其能够与蛋白质活性位点或蛋白质结构域复合物中的催化残基选择性反应，而被视为具有治疗潜力的候选物。在此，我们通过合成调节浅蓝菌素的功能基团，探索脂肪酸和聚酮合酶探针的开发。采用基于机制的方法，我们揭示了浅蓝菌素内部独特的反应性，并将其应用于脂肪酸和迭代型I聚酮合酶的荧光标记和交联。我们还描述了两类新型的硅氰醇和硅半缩醛掩蔽交联探针，它们可作为研究这些生物合成途径的活性和结构的新工具。
