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A new member of the 4-methylideneimidazole-5-one–containing aminomutase family from the enediyne kedarcidin biosynthetic pathway

Huang, Sheng-Xiong, Lohman, Jeremy R., Huang, Tingting, Shen, Ben
Proceedings of the National Academy of Sciences of the United States of America 2013 v.110 no.20 pp. 8069-8074
acids, antibiotics, biochemical pathways, biosynthesis, enantiomers, multigene family, stereochemistry, substrate specificity
4-Methylideneimidazole-5-one (MIO)-containing aminomutases catalyze the conversion of l -α-amino acids to β-amino acids with either an (R) or an (S) configuration. l -Phenylalanine and l -tyrosine are the only two natural substrates identified to date. The enediyne chromophore of the chromoprotein antitumor antibiotic kedarcidin (KED) harbors an (R)-2-aza-3-chloro-β-tyrosine moiety reminiscent of the (S)-3-chloro-5-hydroxy-β-tyrosine moiety of the C-1027 enediyne chromophore, the biosynthesis of which uncovered the first known MIO-containing aminomutase, SgcC4. Comparative analysis of the KED and C-1027 biosynthetic gene clusters inspired the proposal for (R)-2-aza-3-chloro-β-tyrosine biosynthesis starting from 2-aza- l -tyrosine, featuring KedY4 as a putative MIO-containing aminomutase. Here we report the biochemical characterization of KedY4, confirming its proposed role in KED biosynthesis. KedY4 is an MIO-containing aminomutase that stereospecifically catalyzes the conversion of 2-aza- l -tyrosine to (R)-2-aza-β-tyrosine, exhibiting no detectable activity toward 2-aza- l -phenylalanine or l -tyrosine as an alternative substrate. In contrast, SgcC4, which stereospecifically catalyzes the conversion of l -tyrosine to (S)-β-tyrosine in C-1027 biosynthesis, exhibits minimal activity with 2-aza- l -tyrosine as an alternative substrate but generating (S)-2-aza-β-tyrosine, a product with the opposite stereochemistry of KedY4. This report of KedY4 broadens the scope of known substrates for the MIO-containing aminomutase family, and comparative studies of KedY4 and SgcC4 provide an outstanding opportunity to examine how MIO-containing aminomutases control substrate specificity and product enantioselectivity.