期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 129, 期 41, 页码 12432-12438出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja072311g
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资金
- NCI NIH HHS [F32 CA105984, U19 CA113297, R01 CA078747-08, R01 CA078747, U19 CA113297-03, CA78747, CA1059845, CA113297] Funding Source: Medline
C-1027 is a potent antitumor antibiotic composed of an apo-protein and a reactive enediyne chromophore. The chromophore consists of four different chemical subunits including an (S)-3-chloro-4,5dihydroxy-beta-phenylalanine moiety, the biosynthesis of which from L-a-tyrosine is catalyzed by six proteins, SgcC, SgcC1, SgcC2, SgcC3, SgcC4, and SgcC5. Biochemical characterization of SgcC3 unveiled the following: (i) SgcC3 is a flavin adenine dinucleoticle (FAD)-dependent halogenase; (ii) SgcC3 acts only on the SgcC2 pepticlyl carrier protein-tethered substrates; (iii) SgcC3-catalyzed halogenation requires 02 and reduced FAD and either the C-1027 pathway-specific flavin reductase SgcE6 or E. coli flavin reductase (Fre) can support the SgcC3 activity; (iv) SgcC3 also efficiently catalyzes bronnination but not fluorination or iodination; (v) SgcC3 can utilize both (S)- and (R)-beta-tyrosyl-S-SgcC2 but not 3-hydroxy-beta-tyrosyl-SSgcC2 as a substrate. These results establish that SgcC3 catalyzes the third enzymatic transformation during the biosynthesis of the (S)-3-chloro-4,5-dihydroxy- beta-phenylalanine moiety of C-1027 from L-alpha-tyrosine. SgcC3 now represents the second biochemically characterized flavin-dependent halogenase that acts on a carrier protein-tethered substrate. These findings will facilitate the engineering of new C-1027 analogs by combinatorial biosynthesis methods.
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