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. This 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 anticancer drugs for the treatment of special cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102102-05
Application #
7584055
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Program Officer
Fu, Yali
Project Start
2005-05-01
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2011-03-31
Support Year
5
Fiscal Year
2009
Total Cost
$246,853
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Tam, Heng Keat; Härle, Johannes; Gerhardt, Stefan et al. (2015) Structural characterization of O- and C-glycosylating variants of the landomycin glycosyltransferase LanGT2. Angew Chem Int Ed Engl 54:2811-5
Tibrewal, Nidhi; Pahari, Pallab; Wang, Guojun et al. (2012) Baeyer-Villiger C-C bond cleavage reaction in gilvocarcin and jadomycin biosynthesis. J Am Chem Soc 134:18181-4
Shaaban, Khaled A; Ahmed, Tamer A; Leggas, Markos et al. (2012) Saquayamycins G-K, cytotoxic angucyclines from Streptomyces sp. Including two analogues bearing the aminosugar rednose. J Nat Prod 75:1383-92
Kharel, Madan K; Rohr, Jürgen (2012) Delineation of gilvocarcin, jadomycin, and landomycin pathways through combinatorial biosynthetic enzymology. Curr Opin Chem Biol 16:150-61
Tibrewal, Nidhi; Downey, Theresa E; Van Lanen, Steven G et al. (2012) Roles of the synergistic reductive O-methyltransferase GilM and of O-methyltransferase GilMT in the gilvocarcin biosynthetic pathway. J Am Chem Soc 134:12402-5
Kharel, Madan K; Pahari, Pallab; Shaaban, Khaled A et al. (2012) Elucidation of post-PKS tailoring steps involved in landomycin biosynthesis. Org Biomol Chem 10:4256-65
Patrikainen, Pekka; Kallio, Pauli; Fan, Keqiang et al. (2012) Tailoring enzymes involved in the biosynthesis of angucyclines contain latent context-dependent catalytic activities. Chem Biol 19:647-55
Pahari, Pallab; Kharel, Madan K; Shepherd, Micah D et al. (2012) Enzymatic total synthesis of defucogilvocarcin M and its implications for gilvocarcin biosynthesis. Angew Chem Int Ed Engl 51:1216-20
Shaaban, Khaled A; Shepherd, Micah D; Ahmed, Tamer A et al. (2012) Pyramidamycins A-D and 3-hydroxyquinoline-2-carboxamide; cytotoxic benzamides from Streptomyces sp. DGC1. J Antibiot (Tokyo) 65:615-22
Nunez, Luz E; Nybo, Stephen E; Gonzalez-Sabin, Javier et al. (2012) A novel mithramycin analogue with high antitumor activity and less toxicity generated by combinatorial biosynthesis. J Med Chem 55:5813-25

Showing the most recent 10 out of 36 publications