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Here, we propose a hypothesis for the biosynthesis of the bryostatins

16/12/2004 · Synthetic bryostatin analogues activate the RasGRP1 signaling pathway

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synthetic analogues of bryostatin 1, ..

Phylogenetic analysis of the amino acid sequences suggest that BryP AT1 is closely related to AT domains from bacterial FASs (). These discrete enzymes utilize malonyl-CoA as a substrate for fatty acid biosynthesis (). Other PKS trans-AT domains (MmpC AT2, PedD, RhiG AT2, LmnG, DifA) form a clade together with BryP AT1. Interestingly, BryP AT2 diverges from these FAS-related AT domains, and forms a clade with another group of trans-AT domains, including MmpC AT1 (), RhiG AT1 (), PedC (), and BaeD () that appears to be more closely related to embedded PKS AT domains (). While all trans-AT PKSs that have been sequenced to date have a discrete AT domain from the former category (e.g., related to FAS AT), only a few have a discrete AT from the latter category (e.g., PKS embedded AT). Of those with two or three AT domains [e.g., bryostatin (), mupirocin (), bacillaene (), myxovirescin A1 (), rhizoxin (), and pederin ()], two AT domains are encompassed on a single ORF for most of these clusters. However, it is unclear why some PKS gene clusters contain more than one trans-AT domain. As “Ca. Endobugula sertula” remains refractory to laboratory culture, it is not possible to assess function of the two AT domains comprising bryP by traditional gene disruption and complementation assays. Instead, a related surrogate system was employed to test functional rescue of AT activity.

Proposed biosynthesis of the bryostatins

Challenges in the development of bryostatins for biomedical and biotechnological application include the cultivation of the bacterial symbiont and heterologous expression of bryostatin biosynthesis genes.

expression of bryostatin biosynthesis ..

Total Synthesis of Bryostatin 1

The researchers say it appears that bryA may synthesize a portion of the pharmacologically active component of bryostatin and therefore may be useful in developing clinically useful bryostatin byproducts.

"The isolation of bryA represents a significant step forward inunderstanding bryostatin biosynthesis and eventually harnessing bry genes to produce bryostatins and derivatives inexpensively and in abundant quantities," the authors write in the paper, one of the first studies that describes such a cloning achievement from a marine symbiont organism.

15/11/2012 · Proposed biosynthesis of the bryostatins

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The bryostatins are protein kinase C modulators with unique structural features and potential anticancer and neurological activities. These complex polyketides were isolated from the marine bryozoan Bugula neritina, but recent studies indicate that they are produced by the uncultured symbiotic bacterium "Candidatus Endobugula sertula" ("E. sertula"). Here we present the putative biosynthetic genes: five modular polyketide synthase (PKS) genes, a discrete acyltransferase, a beta-ketosynthase, a hydroxy-methyl-glutaryl CoA synthase (HMG-CS), and a methyltransferase. The cluster was sequenced in two closely related "E. sertula" strains from different host species. In one strain the gene cluster is contiguous, while in the other strain it is split into two loci, with one locus containing the PKS genes and the other containing the accessory genes. Here, we propose a hypothesis for the biosynthesis of the bryostatins. Thirteen PKS modules form the core macrolactone ring, and the pendent methyl ester groups are added by the HMG-CS gene cassette. The resulting hypothetical compound bryostatin 0 is the common basis for the 20 known bryostatins. As "E. sertula" is to date uncultured, heterologous expression of this biosynthetic gene cluster has the potential of producing the bioactive bryostatins in large enough quantities for development into a pharmaceutical.

” is to date uncultured, heterologous expression of this biosynthetic gene cluster has the potential of producing the bioactive bryostatins in large enough quantities for development into a pharmaceutical.

Bryostatin 1 Synthesis « Naturalproductman’s Blog
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  • propose is active in bryostatin biosynthesis…

    In this study, we show that bryostatin stimulates the expression of the COX-2 gene and thereby PG biosynthesis

  • is active in bryostatin biosynthesis

    Total Synthesis of Bryostatin 16

  • Difficulty synthesising bryostatin 1 is limiting ..

    Total Synthesis of Bryostatin 16 (2008) ..

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Bryostatin analogues, synthetic methods and uses

AB - "Candidatus Endobugula sertula," the uncultivated bacterial symbiont of Bugula neritina, is the proposed source of the bryostatin family of anticancer compounds. We cloned a large modular polyketide synthase (PKS) gene complex from "Candidatus Endobugula sertula" and characterized one gene, bryA, which we propose is responsible for the initial steps of bryostatin biosynthesis. Typical PKS domains are present. However, acyltransferase domains are lacking in bryA, and β-ketoacyl synthase domains of bryA cluster with those of PKSs with discrete, rather than integral, acyltransferases. We propose a model for biosynthesis of the bryostatin D-lactate starter unit by the bryA loading module, utilizing atypical domains homologous to FkbH, KR, and DH. The bryA gene product is proposed to synthesize a portion of the pharmacologically active part of bryostatin and may be useful in semisynthesis of clinically useful bryostatin analogs.

Bryostatins: biological context and biotechnological prospects

N2 - "Candidatus Endobugula sertula," the uncultivated bacterial symbiont of Bugula neritina, is the proposed source of the bryostatin family of anticancer compounds. We cloned a large modular polyketide synthase (PKS) gene complex from "Candidatus Endobugula sertula" and characterized one gene, bryA, which we propose is responsible for the initial steps of bryostatin biosynthesis. Typical PKS domains are present. However, acyltransferase domains are lacking in bryA, and β-ketoacyl synthase domains of bryA cluster with those of PKSs with discrete, rather than integral, acyltransferases. We propose a model for biosynthesis of the bryostatin D-lactate starter unit by the bryA loading module, utilizing atypical domains homologous to FkbH, KR, and DH. The bryA gene product is proposed to synthesize a portion of the pharmacologically active part of bryostatin and may be useful in semisynthesis of clinically useful bryostatin analogs.

Bryostatins: biological context and biotechnological ..

Bryostatin-1 (bryostatin) is a macrocyclic lactone derived from Bugula neritina, a marine bryozoan. On the basis of the strength of in vitro and animal studies, bryostatin is being investigated as a possible treatment for a variety of human malignancies. Severe myalgias are a common dose-limiting side effect. Because cyclooxygenase-2 (COX-2)-derived prostaglandins can cause pain, we investigated whether bryostatin induced COX-2. Bryostatin (1-10 nM) induced COX-2 mRNA, COX-2 protein, and prostaglandin biosynthesis. These effects were observed in macrophages as well as in a series of human cancer cell lines. Transient transfections localized the stimulatory effects of bryostatin to the cyclic AMP response element of the COX-2 promoter. Electrophoretic mobility shift assays and supershift experiments revealed a marked increase in the binding of activator protein-1 (AP-1)(c-Jun/c-Fos) to the cyclic AMP response element of the COX-2 promoter. Pharmacological and transient transfection studies indicated that bryostatin stimulated COX-2 transcription via the protein kinase C→mitogen-activated protein kinase→AP-1 pathway. All-trans-retinoic acid, a prototypic AP-1 antagonist, blocked bryostatin-mediated induction of COX-2. Taken together, these results suggest that bryostatin-mediated induction of COX-2 can help to explain the myalgias that are commonly associated with treatment. Moreover, it will be worthwhile to evaluate whether the addition of a selective COX-2 inhibitor can increase the antitumor activity of bryostatin.

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