Structural highlights
Publication Abstract from PubMed
The cytochrome P450 (CYP) AspB is involved in the biosynthesis of the diketopiperazine (DKP) aspergilazine A. Tryptophan-linked dimeric DKP alkaloids are a large family of natural products that are found in numerous species and exhibit broad and often potent bioactivity. The proposed mechanisms for C-N bond formation by AspB, and similar C-C bond formations by related CYPs, have invoked the use of a ferryl-intermediate as an oxidant to promote substrate dimerization. Here, the parallel application of steady-state and transient kinetic approaches reveals a very different mechanism that involves a ferric-superoxide species as a primary oxidant to initiate DKP-assembly. Single turnover kinetic isotope effects and a substrate analog suggest the probable nature and site for abstraction. The direct observation of CYP-superoxide reactivity rationalizes the atypical outcome of AspB and reveals a new reaction manifold in heme enzymes.
A Ferric-Superoxide Intermediate Initiates P450-Catalyzed Cyclic Dipeptide Dimerization.,Gering HE, Li X, Tang H, Swartz PD, Chang WC, Makris TM J Am Chem Soc. 2023 Sep 6;145(35):19256-19264. doi: 10.1021/jacs.3c04542. Epub , 2023 Aug 23. PMID:37611404[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Gering HE, Li X, Tang H, Swartz PD, Chang WC, Makris TM. A Ferric-Superoxide Intermediate Initiates P450-Catalyzed Cyclic Dipeptide Dimerization. J Am Chem Soc. 2023 Sep 6;145(35):19256-19264. PMID:37611404 doi:10.1021/jacs.3c04542
