8"-Hydroxypactamycin and 7-deoxypactamycin, new members of the pactamycin group.

Dobashi, Kazuyuki; Isshiki, Kunio; Sawa, Tsutomu; Obata, Tamami; Hamada, Masa; Naganawa, Hiroshi; Takita, Tomohisa; Takeuchi, Tomio; Umezawa, Hamao; Bei, Hongsheng; Zhu, Bo; Cun, Tong; Xu, Wensi

doi:10.7164/antibiotics.39.1779

Cited by 18 publications

(11 citation statements)

References 2 publications

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“…[3] In addition, a number of pactamycin analogues isolated from S. pactum and related strains have also been reported. [4,5] Other interesting aminocyclopentitol-containing natural products include allosamidin (12), a chitinase inhibitor isolated from Streptomyces sp. no.…”

Section: Introductionmentioning

confidence: 99%

Deciphering Pactamycin Biosynthesis and Engineered Production of New Pactamycin Analogues

et al. 2009

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Pactamycin is an aminocyclopentitol-derived natural product that has potent antibacterial and antitumor activities. Sequence analysis of an 86 kb continuous region of the chromosome from Streptomyces pactum ATCC 27456 revealed a gene cluster involved in the biosynthesis of pactamycin. Gene inactivation of the Fe-S radical SAM oxidoreductase (ptmC) and the glycosyltransferase (ptmJ), individually abrogated pactamycin biosynthesis; this confirmed the involvement of the ptm gene cluster in pactamycin biosynthesis. The polyketide synthase gene (ptmQ) was found to support 6-methylsalicylic acid (6-MSA) synthesis in a heterologous host, S. lividans T7. In vivo inactivation of ptmQ in S. pactum impaired pactamycin and pactamycate production but led to production of two new pactamycin analogues, de-6-MSA-pactamycin and de-6-MSA-pactamycate. The new compounds showed equivalent cytotoxic and antibacterial activities with the corresponding parent molecules and shed more light on the structure-activity relationship of pactamycin.

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Section: Introductionmentioning

confidence: 99%

Deciphering Pactamycin Biosynthesis and Engineered Production of New Pactamycin Analogues

et al. 2009

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“…Genetic engineering studies have reignited promise for medicinal application as 7-deoxy-and 8″-hydroxy-derivatives were isolated and displayed diminished cytotoxity (11–14). In the context of the work described herein, it is worth noting that Lu et al contend that the structural complexity of 1 renders these and related structural modifications “inaccessible by synthetic organic chemistry” (12).…”

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confidence: 99%

Enantioselective Synthesis of Pactamycin, a Complex Antitumor Antibiotic

Malinowski

Sharpe

Johnson

2013

Science

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Medicinal application of many complex natural products is precluded by the impracticality of their chemical synthesis. Pactamycin, the most structurally-intricate aminocyclopentitol antibiotic, displays potent anti-prolific properties across multiple phylogenetic domains, but is highly cytotoxic. A limited number of analogs produced by genetic engineering technologies show reduced cytotoxicity against mammalian cells, renewing promise for therapeutic applications. For decades, an efficient synthesis of pactamycin amenable to analog derivatizations has eluded researchers. Herein, we present a short asymmetric total synthesis of pactamycin. An enantioselective Mannich reaction/symmetry-breaking reduction sequence was designed to enable assembly of the entire carbon core skeleton in under five steps and control critical three-dimensional (stereochemical) functional group relationships. This modular route totals fifteen steps and is immediately amenable for structural analog synthesis.

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“…Structurally, it contains a highly decorated aminocyclopentitol ring structure, an aminoacetophenone, a 6-methylsalicylyl, and a dimethyl urea moiety. Other congeners of pactamycin have been isolated from the cultures of S. pactum; they differ from pactamycin mainly in the structure of the side chains or the presence of a cyclic carbamate (e.g., pactamycate) or a cyclic urea (e.g., pactalactam) (Figure 1) (Hara et al 1964, Dobashi et al 1986, Hurley et al 1986, Iwatsuki et al 2012. The carbamate and cyclic urea derivatives appear to form non-enzymatically during cultivation and/or isolation processes, and the modifications are likely to be responsible for their diminished growth inhibitory activity (Rinehart et al 1980).…”

Section: Introductionmentioning

confidence: 99%

The secondary metabolite pactamycin with potential for pharmaceutical applications: biosynthesis and regulation

Eida

Mahmud

2019

Appl Microbiol Biotechnol

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The antitumor antibiotic pactamycin is a highly substituted aminocyclopentitol-derived secondary metabolite produced by the soil bacterium Streptomyces pactum. It has exhibited potent antibacterial, antitumor, antiviral, and antiprotozoal activities. Despite its outstanding biological activities, the complex chemical structure and broad-spectrum toxicity have hampered its development as a therapeutic, limiting its contribution to biomedical science to a role as a molecular probe for ribosomal function. However, detailed understanding of its biosynthesis and how the biosynthesis is regulated has made it possible to tactically design and produce new pactamycin analogues, some of which have shown improved pharmacological properties. This mini-review describes the biosynthesis, regulation, engineered production, and biological activities of pactamycin and its congeners. It also highlights the suitability of biosynthetic methods as a feasible approach to generate new analogues of complex natural products and underscores the importance of utilizing biosynthetic enzymes as tools for chemoenzymatic production of structurally diverse bioactive compounds.

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8"-Hydroxypactamycin and 7-deoxypactamycin, new members of the pactamycin group.

Cited by 18 publications

References 2 publications

Deciphering Pactamycin Biosynthesis and Engineered Production of New Pactamycin Analogues

Deciphering Pactamycin Biosynthesis and Engineered Production of New Pactamycin Analogues

Enantioselective Synthesis of Pactamycin, a Complex Antitumor Antibiotic

The secondary metabolite pactamycin with potential for pharmaceutical applications: biosynthesis and regulation

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