Investigation of early tailoring reactions in the oxytetracycline biosynthetic pathway.

Investigation of early tailoring reactions in the oxytetracycline biosynthetic pathway. Research Abstract Details 

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Investigation of early tailoring reactions in the oxytetracycline biosynthetic pathway. Abstract Text:

Wenjun Zhang,Kenji Watanabe,Clay C C Wang,Yi Tang,

Tetracyclines are aromatic polyketides biosynthesized by bacterial type II polyketide synthases. The amidated tetracycline backbone is biosynthesized by the minimal polyketide synthases and an amidotransferase homologue OxyD. Biosynthesis of the key intermediate 6-methylpretetramid requires two early tailoring steps, which are cyclization of the linearly fused tetracyclic scaffold and regioselective C-methylation of the aglycon. Using a heterologous host (CH999)/vector pair, we identified the minimum set of enzymes from the oxytetracycline biosynthetic pathway that is required to afford 6-methylpretetramid in vivo. Only two cyclases (OxyK and OxyN) are necessary to completely cyclize and aromatize the amidated tetracyclic aglycon. Formation of the last ring via C-1/C-18 aldol condensation does not require a dedicated fourth-ring cyclase, in contrast to the biosynthetic mechanism of other tetracyclic aromatic polyketides, such as daunorubicin and tetracenomycin. Acetyl-derived polyketides do not undergo spontaneous fourth-ring cyclization and form only anthracene carboxylic acids as demonstrated both in vivo and in vitro. OxyF was identified to be the C-6 C-methyltransferase that regioselectively methylates pretetramid to yield 6-methylpretetramid. Reconstitution of 6-methylpretetramid in a heterologous host sets the stage for a more systematic investigation of additional tetracycline downstream tailoring enzymes and is a key step toward the engineered biosynthesis of tetracycline analogs.

Investigation of early tailoring reactions in the oxytetracycline biosynthetic pathway. Publishing Authors By Initials

W Zhang,K Watanabe,CC Wang,Y Tang,

For similar bacteria: endospore-forming bacteria: gram-positive endospore-forming bacteria: gram-positive endospore-forming rods: streptomycetaceae: streptomyces: streptomyces coelicolor research abstracts see: bacteria: endospore-forming bacteria: gram-positive endospore-forming bacteria: gram-positive endospore-forming rods: streptomycetaceae: streptomyces: streptomyces coelicolor research

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Investigation of early tailoring reactions in the oxytetracycline biosynthetic pathway. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: The Journal of biological chemistry

VOLUME: 282

Page Numbers: 25717-25

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 12

MONTH: 07

YEAR: 2007

Investigation of early tailoring reactions in the oxytetracycline biosynthetic pathway. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985121

Investigation of early tailoring reactions in the oxytetracycline biosynthetic pathway. Keywords Mesh Terms:

KEYWORDS: Streptomyces coelicolor

MESH TERMS: genetics

Chemical & Substance for Abstract: Investigation of early tailoring reactions in the oxytetracycline biosynthetic pathway. Information

Substance Name: Polyketide Synthases

Registry Number: 79956-01-7

Grant and Affiliation Information for Investigation of early tailoring reactions in the oxytetracycline biosynthetic pathway.

AFFILIATION: Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California 90095, USA.

Country: United States

AGENCY: United States NIGMS

GRANT: R01-GM75857

ACRONYM: GM

MEDLINETA: J Biol Chem

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