UNIVERSITY OF KENTUCKY
Grant: $7,403 - National Institutes of Health - May. 29, 2009
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Award Description: Gilvocarcins and jadomycins are angucyclin-derived anticancer drugs/antibiotics possessing unique molecular frames, whose common biosynthetic key step is an oxidative rearrangement catalyzed by a closely related set of enzymes. The gilvocarcins, produced by various Streptomyces strains including Streptomyces griseoflavus Go 3592, represent a distinct family of interesting aryl C-glycoside antitumor drugs with a coumarin-based aromatic core that promote specific DNA interactions when photoactivated by near UV light. This class of anticancer drugs shows excellent antitumor activity and remarkably low toxicity. Its unprecedented molecular architecture in conjunction with its unique biological activity makes the gilvocarcins an excellent target for biosynthetic studies and the development of novel, photoactivatable anticancer drugs through combinatorial biosynthesis. The drugs may be useful for the treatment of special cancers, such as brain tumors, colon, skin, lung, and prostate cancers or leukemia. The jadomycins are antibiotics/antifungals, whose structure is characterized by an unusual insertion of an amino acid building block after an oxidative bond breakage. Previous biosynthetic studies suggest for both, gilvocarcins and jadomycins, a pathway dominated by a type-2 polyketide synthase (PKS), leading initially to an angucycline type drug intermediate, which then oxidatively rearranges into the final molecular frame. Selected intriguing post-PKS tailoring steps, namely the oxidative rearrangement (gilvocarcin and jadomycin biosynthesis), the unusual C-glycosylation step (gilvocarcin biosynthesis), and the formation of the vinyl group side chain of gilvocarcin V, are key biosynthetic features responsible for the generation of structural elements, which are essential for the unique biological activity of the gilvocarcin drugs. The investigation of these cascades of post-PKS tailoring biosynthetic key reactions, found in both the jadomycin and gilvocarcin biosyntheses, is a main goal of the research, since it as an interesting model for post-PKS enzyme complexes, their mechanisms, interactions, substrate binding/passing modes etc. Thi s topic has never been studied in detail despite the importance of such tailoring steps for the biological activity of polyketide drugs. The understanding of these biosynthetic steps, and the enzymes responsible for their execution will ultimately pave the way for the generation of more potential and more selective drugs through combinatorial biosynthetic methods. The following specific aims will be addressed: (1) Characterization of the late steps of the gilvocarcin and jadomycin biosynthesis; (2) Generation of new gilvocarcin analogues by inactivation and recombination of selected post-PKS tailoring genes; (3) Characterization of key enzymes of the gilvocarcin and the related jadomycin biosynthetic pathway to understand their mechanism-of-action and substrate specificity range, their interaction; and (4) assessment of the antitumor activity of gilvocarcin and newly generated analogues from specific aim 2. The long-term goal of this research is to develop improved anticance r drugs for the treatment of special cancers. The ARRA supplement request is to obtain support for a summer undergraduate research student. This student will pursue studies outlined under Specific Aims 1 and 3 of the parent proposal, to further characterize the biosynthetic pathway of the anti-cancer antibiotic gilvocarcin V. The student will be involved in both (i) organic synthetic studies towards key biosynthetic intermediates or model analogues, and (ii) enzyme studies to investigate the synthetic compounds as substrates of selected enzymes. Synthetic model studies were not proposed in the parent grant, but are a logical extension of the proposed studies, and likely the only way to shed light into a biosynthetic black box performed by an enzyme complex.
Project Description: As defined in the Award Description field.
Infrastructure Description: N/A
Jobs Summary: A 3rd year chemistry student from Transsylvania University, Lexington, Kentucky, was employed and worked in the PI's lab over the summer, for 12 weeks total. This student worked closely with another graduate student (4th year) and post-doctoral scholar. This student worked on a model synthesis for a putative key intermediate of the gilvocarcin pathway. The student and Graduate Student managed to complete the synthesis of the first model compound, but yield optimization and further expansion of the methods towards model compounds closer to the expected biosynthesis intermediate are still ongoing. Once more material is available, the model compounds will be tested as intermediates and as substrates of downstream biosynthetic enzymes. If everything works out, new gilvocarcin analogues can be generated through a semisynthesis/mutasynthesis protocol. Considering that the country needs more scientists, either as researchers, as teachers or servicing the community, the ARRA summer research program had a significant impact, namely winning one student, over for a higher education career in science. (Total jobs reported: 1)
Project Status: More than 50% Completed
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