Enediyne Biosynthesis and Self-Resistance: A Progress Report

Thorson, Jon S.; Shen, Ben; Whitwam, Ross E.; Liu, Wen; Li, Yuan; Ahlert, Joachim

doi:10.1006/bioo.1998.1122

Cited by 49 publications

(70 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1) is characterized structurally by an enediyne core unit consisting of two acetylenic groups conjugated to a double bond or incipient double bond within a 9-or 10-membered ring (1)(2)(3). To date, five unique 9-membered enediynes (1)(2)(3)(4)(5) (Fig. 1), also often designated as the chromoprotein enediynes, and five additional distinct naturally occurring 10-membered enediynes (6)(7)(8)(9)(10) (Fig.…”

mentioning

confidence: 99%

“…1), also often designated as the chromoprotein enediynes, and five additional distinct naturally occurring 10-membered enediynes (6)(7)(8)(9)(10) (Fig. 1) have been elucidated structurally (4)(5)(6). In general, these enediynes contain three distinct structural elements: a DNArecognition unit, which serves to deliver the metabolite to its target DNA; an activation component, which sets the stage for cycloaromatization; and the enediyne ''warhead,'' which cycloaromatizes to a highly reactive diradical species and, in the presence of DNA, results in oxidative strand scission of the targeted sequence (7)(8)(9)(10).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Rapid PCR amplification of minimal enediyne polyketide synthase cassettes leads to a predictive familial classification model

Ahlert

Gao

et al. 2003

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

Self Cite

129

View full text Add to dashboard Cite

A universal PCR method for the rapid amplification of minimal enediyne polyketide synthase (PKS) genes and the application of this methodology to clone remaining prototypical genes from producers of structurally determined enediynes in both family types are presented. A phylogenetic analysis of the new pool of bona fide enediyne PKS genes, consisting of three from 9-membered producers (neocarzinostatin, C1027, and maduropeptin) and three from 10-membered producers (calicheamicin, dynemicin, and esperamicin), reveals a clear genotypic distinction between the two structural families from which to form a predictive model. The results from this study support the postulation that the minimal enediyne PKS helps define the structural divergence of the enediyne core and provides the key tools for generating enediyne hybrid genes͞molecular scaffolds; by using the model, a classification is also provided for the unknown enediyne PKS genes previously identified via genome scanning.

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

Rapid PCR amplification of minimal enediyne polyketide synthase cassettes leads to a predictive familial classification model

Ahlert

Gao

et al. 2003

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

Self Cite

129

View full text Add to dashboard Cite

show abstract

“…The enediyne antibiotics are the focus of intense research activity in the fields of chemistry, biology, and medical sciences because of their unique molecular architectures, biological activities, and modes of action (7,49). Since the unveiling of the structure of neocarzinostatin chromophore (8) in 1985, the enediyne family has grown steadily.…”

mentioning

confidence: 99%

“…The last group includes neocarzinostatin, kedarcidin, C-1027 ( Fig. 1), and maduropeptin, whose enediyne chromophore structures have been established, as well as several others whose enediyne chromophore structures are yet to be determined due to their instabilities (49). N1999A2, in contrast to the other chromoproteins, exists as an enediyne chromophore alone, even though its structure is very similar to those of the other chromoprotein chromophores (49).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Genes for Production of the Enediyne Antitumor Antibiotic C-1027 in Streptomyces globisporus Are Clustered with the cagA Gene That Encodes the C-1027 Apoprotein

Liu

Shen

2000

Antimicrob Agents Chemother

Self Cite

108

View full text Add to dashboard Cite

C-1027, the most potent member of the enediyne antitumor antibiotic family, is produced by Streptomyces globisporus C-1027 and consists of an apoprotein (encoded by the cagA gene) and a nonpeptidic chromophore. The C-1027 chromophore could be viewed as being derived biosynthetically from a benzoxazolinate, a deoxyamino hexose, a ␤-amino acid, and an enediyne core. By adopting a strategy for cloning of the C-1027 biosynthesis gene cluster by mapping a putative dNDP-glucose 4,6-dehydratase (NGDH) gene to cagA, we have localized 75 kb of contiguous DNA from S. globisporus. DNA sequence analysis of two regions of the cloned gene cluster revealed two genes, sgcA and sgcB, that encode an NGDH enzyme and a transmembrane efflux protein, respectively, and confirmed that the cagA gene resides approximately 14 kb upstream of the sgcAB locus. The involvement of the cloned gene cluster in C-1027 biosynthesis was demonstrated by disrupting the sgcA gene to generate C-1027-nonproducing mutants and by complementing the sgcA mutants in vivo to restore C-1027 production. These results represent the first cloning of a gene cluster for enediyne antitumor antibiotic biosynthesis and provide a starting point for future genetic and biochemical investigations of C-1027 biosynthesis.

show abstract

Thepara-didehydropyridine,para-didehydropyridinium, and related biradicals?a contribution to the chemistry of enediyne antitumor drugs

Kraka

2000

J. Comput. Chem.

View full text Add to dashboard Cite

Structure and stability of seven singlet (S) biradicals formed byBergman cyclization from enediynes are investigated with unrestricted DFT using B3LYP/6-31G(d,p) and B3LYP/6-311+G(3df,3pd). The corresponding triplets (T) are also calculated and compared with their S states utilizing the on-top pair density and the S-T difference on-top pair density. A relationship between the geometry of a S biradical, its stability, and its biradical character is established using the on-top pair density and calculated S-T splittings. Through-bond coupling between the single electrons of the S biradical can be enhanced by the incorporation of a N atom into para-didehydrobenzene 1 due to lowering of antibonding orbitals, shortening of ring bonds by anomeric effect, and increased overlap between the interacting orbitals. Strong through-bond interactions lead to a stabilization of the S state and an increase of the S-T splitting. Because through-bond interactions also determine the degree of coupling between the single electrons, stabilization of the S biradical, and an increase of the S-T splitting always means a lowering of the biradical character and the H abstraction ability, which is relevant for the use of N-containing enediynes and their biradicals in connection with the design of new antitumor drugs. The S para-didehydropyridine biradical 2 is strongly stabilized and, therefore, has only reduced biradical character. However, the latter can be enhanced by protonation, because this always leads to a lengthening of ring bonds and a reduction of the overlap between interacting orbitals. In the weakly acidic medium of a tumor cell, S biradicals containing an amidine group can be protonated to yield S biradicals with high biradical character (low S-T splittings, small changes in bond alternation relative to the T state), which will abstract H atoms from the DNA of a tumor cell.

show abstract

Enediyne Biosynthesis and Self-Resistance: A Progress Report

Cited by 49 publications

References 86 publications

Rapid PCR amplification of minimal enediyne polyketide synthase cassettes leads to a predictive familial classification model

Rapid PCR amplification of minimal enediyne polyketide synthase cassettes leads to a predictive familial classification model

Genes for Production of the Enediyne Antitumor Antibiotic C-1027 in Streptomyces globisporus Are Clustered with the cagA Gene That Encodes the C-1027 Apoprotein

Thepara-didehydropyridine,para-didehydropyridinium, and related biradicals?a contribution to the chemistry of enediyne antitumor drugs

Contact Info

Product

Resources

About