Genetic Characterization of the Chlorothricin Gene Cluster as a Model for Spirotetronate Antibiotic Biosynthesis

Jia, Xinying; Tian, Zhenhua; Shao, Lei; Qu, Xiaoqing; Zhao, Qunfei; Tang, Jingqun; Tang, Gong‐Li; Liu, Wen

doi:10.1016/j.chembiol.2006.03.008

Cited by 156 publications

(160 citation statements)

References 35 publications

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“…The deduced product of pctS shows significant homology to many type I PKSs. PctS exhibits head-totail homology to ChlB1 encoded in the chlorothricin biosynthetic gene cluster [19] and these have the characteristic type I PKS domains, including a ketosynthase (KS), acyltransferase (AT), dehydratase (DH), ketoreductase (KR), and acyl carrier protein (ACP). Both PctS and ChlB1 show higher homology to some iterative type I PKSs including 6-methylsalicylic acid synthase (6-MSAS) derived from fungi.…”

Section: Functional Analysis Of the Pctl Gene Encoding A Glycosyltranmentioning

confidence: 99%

“…Both PctS and ChlB1 show higher homology to some iterative type I PKSs including 6-methylsalicylic acid synthase (6-MSAS) derived from fungi. Since ChlB1 was confirmed to be involved in the 6-MSA formation [15,19], PctS could also catalyze the formation of 6-MSA as an iterative type I PKS (Fig. 3C).…”

Section: Functional Analysis Of the Pctl Gene Encoding A Glycosyltranmentioning

confidence: 99%

“…PctT is also highly homologous to ChlB3, ChlB6 [19], AviN [16], and CalO4 [17], all of which accompany with an iterative type I PKS. These homologous proteins were presumed to attach the starter unit, acetyl CoA, onto the corresponding PKSs, since FabH enzymes use an acyl-CoA rather than an acyl-ACP as the primer and catalyze the first condensation step in the pathway [55,56].…”

Section: Functional Analysis Of the Pctl Gene Encoding A Glycosyltranmentioning

confidence: 99%

“…In actinomycetes, this type of simple aromatic polyketides is generally biosynthesized by an iterative type I polyketide synthase (PKS) [15], which has been quite recently established and are encoded in the avilamycin [16], calicheamicin [17], neocarzinostatin [18], chlorothricin [19], biosynthetic gene clusters. Therefore, an iterative type I PKS was also anticipated to be involved in the biosynthesis of pactamycin.…”

Section: Introductionmentioning

confidence: 99%

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Cloning of the Pactamycin Biosynthetic Gene Cluster and Characterization of a Crucial Glycosyltransferase Prior to a Unique Cyclopentane Ring Formation

et al. 2007

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The biosynthetic gene (pct) cluster for an antitumor antibiotic pactamycin was identified by use of a gene for putative radical S-adenosylmethionine methyltransferase as a probe. The pct gene cluster is localized to a 34 kb contiguous DNA from Streptomyces pactum NBRC 13433 and contains 24 open reading frames. Based on the bioinformatic analysis, a plausible biosynthetic pathway for pactamycin comprising of a unique cyclopentane ring, 3-aminoacetophenone, and 6-methylsalicylate was proposed. The pctL gene encoding a glycosyltransferase was speculated to be involved in an N-glycoside formation between 3-aminoacetophenone and UDP-N-acetyl-a -D-glucosamine prior to a unique cyclopentane ring formation. The pctL gene was then heterologously expressed in Escherichia coli and the enzymatic activity of the recombinant PctL protein was investigated. Consequently, the PctL protein was found to catalyze the expected reaction forming b-N-glycoside. The enzymatic activity of the PctL protein clearly confirmed that the present identified gene cluster is for the biosynthesis of pactamycin. Also, a glycosylation prior to cyclopentane ring formation was proposed to be a general strategy in the biosynthesis of the structurally related cyclopentane containing compounds.

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Section: Functional Analysis Of the Pctl Gene Encoding A Glycosyltranmentioning

confidence: 99%

Section: Functional Analysis Of the Pctl Gene Encoding A Glycosyltranmentioning

confidence: 99%

Section: Functional Analysis Of the Pctl Gene Encoding A Glycosyltranmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cloning of the Pactamycin Biosynthetic Gene Cluster and Characterization of a Crucial Glycosyltransferase Prior to a Unique Cyclopentane Ring Formation

et al. 2007

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“…During our characterization work, gene cluster sequences of the biosynthetically related compounds chlorothricin (4) 37 and tetronomycin (8) 38 were reported, and a pathway for chlorothricin biosynthesis was proposed. 37 The availability of these sequences provided an opportunity to use sequence comparison and identify the core set of genes responsible for formation of the spirotetronate moiety. This analysis has revealed shared biosynthetic features between the glycerate component of spirotetronate natural products and the methoxymalonate unit found in several polyketidederived natural products.…”

mentioning

confidence: 99%

Elucidation of the Kijanimicin Gene Cluster: Insights into the Biosynthesis of Spirotetronate Antibiotics and Nitrosugars

et al. 2007

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The antibiotic kijanimicin produced by the actinomycete Actinomadura kijaniata has a broad spectrum of bioactivities as well as a number of interesting biosynthetic features. To understand the molecular basis for its formation and to develop a combinatorial biosynthetic system for this class of compounds, a 107.6 kb segment of the Actinomadura kijaniata chromosome containing the kijanimicin biosynthetic locus was identified, cloned, and sequenced. The complete pathway for the formation of TDP-L-digitoxose, one of the two sugar donors used in construction of kijanimicin, was elucidated through biochemical analysis of four enzymes encoded in the gene cluster. Sequence analysis indicates that the aglycone kijanolide is formed by the combined action of a modular Type-I polyketide synthase (PKS) and a conserved operon involved attachment and intramolecular cyclization of a glycerate-derived three-carbon unit, which forms the core of the spirotetronate moiety. The genes involved in the biosynthesis of the unusual deoxysugar D-kijanose [2,3,4,6-tetradeoxy-4-(methylcarbamyl)-3-C-methyl-3-nitro-D-xylo-hexopyranose], including one encoding a flavoenzyme predicted to catalyze the formation of the nitro group, have also been identified. This work has implications for the biosynthesis of other spirotetronate antibiotics and nitro sugar-bearing natural products, as well as for future mechanistic and biosynthetic engineering efforts.Kijanimicin (1) is a spirotetronate antibiotic isolated from Actinomadura kijaniata, a soil actinomycete. It has a broad spectrum of antimicrobial activity against Gram-positive bacteria, anaerobes, and the malaria parasite Plasmodium falciparum, 1 and also shows antitumor activity. 2 The structure of kijanimicin (1) consists of a pentacyclic core, which is equipped with four L-digitoxose (2) units and a rare nitro sugar, 2,3,4,6-tetradeoxy-4-(methylcarbamyl)-3-C-methyl-3-nitro-D-xylo-hexopyranose, commonly known as D-kijanose (3). More than sixty kijanimicin-related spirotetronate-type compounds have been reported. Most are made by strains of high-GC Gram positive bacteria (Actinomycetes), including Streptomyces, 3-8 Micromonospora, 9-12 Actinomadura, 1,13,14 Saccharothrix, 15 and Verrucosispora. 16 A species of Bacillus has also been identified as a producer of a member of this class of compounds. 17 Nearly all members of this class exhibit both antibacterial and antitumor activities, and many possess other biological activities. Well-known examples include chlorothricins (4), the anticholesterolemic agents; 18,19 tetronothiodin, a cholecystokinin B (CCK-B) inhibitor; 4 MM46115, an antiviral drug effective against parainfluenzae virus 1 and 2; 13 and tetrocarcins (5) and arisostatins, both of which have been shown to have therapeutic potential as inducers of apoptosis. 20-23 In a recent study, a collection of tetrocarcin analogues was prepared synthetically and some of them showed improved apoptosis-inducing activity. 24 Hence, compounds of this class have broad therapeutic potential wort...

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Pathway and Enzyme Engineering and Applications for Glycodiversification

Zhao

Liu²

2010

Enzyme Technologies

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Genetic Characterization of the Chlorothricin Gene Cluster as a Model for Spirotetronate Antibiotic Biosynthesis

Cited by 156 publications

References 35 publications

Cloning of the Pactamycin Biosynthetic Gene Cluster and Characterization of a Crucial Glycosyltransferase Prior to a Unique Cyclopentane Ring Formation

Cloning of the Pactamycin Biosynthetic Gene Cluster and Characterization of a Crucial Glycosyltransferase Prior to a Unique Cyclopentane Ring Formation

Elucidation of the Kijanimicin Gene Cluster: Insights into the Biosynthesis of Spirotetronate Antibiotics and Nitrosugars

Pathway and Enzyme Engineering and Applications for Glycodiversification

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