Chemistry and structure elucidation of the kedarcidin chromophore

Leet, John E.; Schroeder, Daniel R.; Langley, David R.; Colson, Kimberly L.; Huang, Stella; Klohr, Steven E.; Lee, Mike S.; Golik, Jerzy; Hofstead, Sandra J.

doi:10.1021/ja00071a062

Cited by 110 publications

(69 citation statements)

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“…These molecules also possess a recognition Scheme 1. Structure of kedarcidin chromophore as α-amino acid derivative (1) proposed by Leet in 1993. unit responsible for delivering and establishing their position to the biological target, i.e. DNA.…”

Section: Introductionmentioning

confidence: 99%

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DFT/NMR integrated approach: a valid support to the total synthesis of chiral molecules

Chini¹,

Riccio²,

Bifulco³

2008

Magnetic Reson in Chemistry

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Section: Introductionmentioning

confidence: 99%

“…A first-structure elucidation of kedarcidin chromophore was proposed in 1992 by Leet and coworkers. It is here displayed as 1 [9] (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

DFT/NMR integrated approach: a valid support to the total synthesis of chiral molecules

Chini¹,

Riccio²,

Bifulco³

2008

Magnetic Reson in Chemistry

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“…1). 2 The major difficulty in synthesising the kedarcidin chromophore 1 pertains to surmounting the high enthalpic and entropic barriers during the construction of the nine-membered, bicyclic core. This difficulty is typically heightened by the short bench-lives of the strained diyne products, whose CMC-C bond-angles are distorted to around 160u.…”

mentioning

confidence: 99%

Synthesis of the entire carbon framework of the kedarcidin chromophore aglycon

et al. 2007

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“…JX679499). and to exploit their utility for natural product structural diversity by combinatorial biosynthesis strategies, we were intrigued by the enediyne chromophore of the chromoprotein antitumor antibiotic kedarcidin (KED) (22)(23)(24). The KED chromophore harbors a (R)-2-aza-3-chloro-β-tyrosine moiety, which can be envisioned to derive from 2-aza-L-phenylalanine or 2-aza-L-tyrosine via an MIOcontaining aminomutase in a mechanism analogous to that of the PAMs and TAMs.…”

Section: Streptomyces Globisporusmentioning

confidence: 99%

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

Huang¹,

Lohman²,

Huang³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Chemistry and structure elucidation of the kedarcidin chromophore

Cited by 110 publications

References 0 publications

DFT/NMR integrated approach: a valid support to the total synthesis of chiral molecules

DFT/NMR integrated approach: a valid support to the total synthesis of chiral molecules

Synthesis of the entire carbon framework of the kedarcidin chromophore aglycon

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

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