Biosynthetic studies of ascomycin (FK520): formation of the (1R,3R,4R)-3,4-dihydroxycyclohexanecarboxylic acid-derived moiety

Wallace, Kimberlee K.; Reynolds, Kevin A.; Koch, Kevin; McArthur, Hamish A. I.; Brown, Maria S.; Wax, Richard G.; Moore, Bradley S.

doi:10.1021/ja00104a063

Cited by 34 publications

(22 citation statements)

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“…2). In light of the present findings, it would be worthwhile to investigate the in vitro activity of those enzymes thought to catalyze the latter reaction (20)(21)(22)(23)(24)(25) to obtain definitive evidence for or against their acting as chorismatases, rather than shikimate dehydratases.…”

Section: Phylogenetic Analysis Of Fkbo/rapk Reveals a Superfamily Of mentioning

confidence: 91%

“…2), which is activated by an ATPdependent adenylation domain in the loading module of the polyketide synthase, transferred to the acyl carrier protein domain of this module, and then reduced in situ by an adjacent enoylreductase domain (20). The route to DHCHC from shikimate remains unknown, but it has been suggested, based on extensive isotope labeling and heterologous gene expression analysis of related pathways in other bacteria (21)(22)(23)(24)(25), to involve the pathway shown in Fig. 2.…”

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confidence: 99%

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Biosynthesis of the immunosuppressants FK506, FK520, and rapamycin involves a previously undescribed family of enzymes acting on chorismate

Andexer

Kendrew²,

Nur‐e‐Alam³

et al. 2011

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

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The macrocyclic polyketides FK506, FK520, and rapamycin are potent immunosuppressants that prevent T-cell proliferation through initial binding to the immunophilin FKBP12. Analogs of these molecules are of considerable interest as therapeutics in both metastatic and inflammatory disease. For these polyketides the starter unit for chain assembly is (4 R ,5 R )-4,5-dihydroxycyclohex-1-enecarboxylic acid derived from the shikimate pathway. We show here that the first committed step in its formation is hydrolysis of chorismate to form (4 R ,5 R )-4,5-dihydroxycyclohexa-1,5-dienecarboxylic acid. This chorismatase activity is encoded by fkbO in the FK506 and FK520 biosynthetic gene clusters, and by rapK in the rapamycin gene cluster of Streptomyces hygroscopicus . Purified recombinant FkbO (from FK520) efficiently catalyzed the chorismatase reaction in vitro, as judged by HPLC-MS and NMR analysis. Complementation using fkbO from either the FK506 or the FK520 gene cluster of a strain of S. hygroscopicus specifically deleted in rapK (BIOT-4010) restored rapamycin production, as did supplementation with (4 R ,5 R )-4,5-dihydroxycyclohexa-1,5-dienecarboxylic acid. Although BIOT-4010 produced no rapamycin, it did produce low levels of BC325, a rapamycin analog containing a 3-hydroxybenzoate starter unit. This led us to identify the rapK homolog hyg5 as encoding a chorismatase/3-hydroxybenzoate synthase. Similar enzymes in other bacteria include the product of the bra8 gene from the pathway to the terpenoid natural product brasilicardin. Expression of either hyg5 or bra8 in BIOT-4010 led to increased levels of BC325. Also, purified Hyg5 catalyzed the predicted conversion of chorismate into 3-hydroxybenzoate. FkbO, RapK, Hyg5, and Bra8 are thus founder members of a previously unrecognized family of enzymes acting on chorismate.

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Section: Phylogenetic Analysis Of Fkbo/rapk Reveals a Superfamily Of mentioning

confidence: 91%

mentioning

confidence: 99%

Biosynthesis of the immunosuppressants FK506, FK520, and rapamycin involves a previously undescribed family of enzymes acting on chorismate

Andexer

Kendrew²,

Nur‐e‐Alam³

et al. 2011

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

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“…2 is widely distributed in microorganisms and plants where shikimic acid is a precursor for the biosynthesis of primary metabolites such as aromatic amino acids and folic acid and a great many other aromatic compounds. Since the basic element of all aromatic compounds-benzene ring-is formed in plants and microorganisms through the shikimate pathway, shikimic acid is an extremely essential compound in plants and microbes [54][55][56][57]. Only a limited number of plant phenols have aromatic rings that are synthesized through another mechanism, that is, the polyketide condensation of acetate units [58].…”

Section: Shikimic Acid In Living Organismsmentioning

confidence: 99%

Shikimic acid: review of its analytical, isolation, and purification techniques from plant and microbial sources

et al. 2011

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“…The starter unit is normally activated as acetyl-CoA (as in pimaricin [79]), or malonyl-CoA (as in nystatin [80] or amphotericin [81]), but other polyenes use other carboxylic acid-CoA esters as starters, like the butiryl-CoA in rimocidin, or the isobutiryl-CoA in dermostatin. Others, such as the triene immunosuppressant rapamycin [82,83] use Fig. (6).…”

Section: The Diversity Of Polyene Macrolidesmentioning

confidence: 99%

Polyene Macrolide Antibiotic Biosynthesis

Aparicio¹,

Mendes²,

Antón³

et al. 2004

CMC

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Polyenes constitute a large class of natural metabolites produced by giant multifunctional enzymes in a process resembling fatty acid biosynthesis. Like fatty acids, polyene macrolides and other polyketides are assembled by decarboxylative condensations of simple carboxylic acids. But while fatty acid intermediates are fully reduced, polyene macrolide intermediates suffer the suppression of reduction or dehydration reactions at given biosynthetic steps. In the last years, much progress has been made in our understanding of the linear and modular organization of the gene clusters, and the enzymes encoded by them, responsible for the biosynthesis of these macrocyclic metabolites. This know-how about the rules that govern polyene chain growth has provided the basis for the first rational manipulations of these fascinating systems for the production of engineered derivatives and promises a new era of novel polyene development, which will hopefully yield new molecules with improved pharmacological properties.

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Biosynthetic studies of ascomycin (FK520): formation of the (1R,3R,4R)-3,4-dihydroxycyclohexanecarboxylic acid-derived moiety

Cited by 34 publications

References 0 publications

Biosynthesis of the immunosuppressants FK506, FK520, and rapamycin involves a previously undescribed family of enzymes acting on chorismate

Biosynthesis of the immunosuppressants FK506, FK520, and rapamycin involves a previously undescribed family of enzymes acting on chorismate

Shikimic acid: review of its analytical, isolation, and purification techniques from plant and microbial sources

Polyene Macrolide Antibiotic Biosynthesis

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