Planta Med 2013; 79 - PA4
DOI: 10.1055/s-0033-1348552

Identification of the Lomaiviticin Biosynthetic Gene Cluster and Fermentation Profile Improvement Studies in “Salinispora pacifica” Strains DPJ-0016 and DPJ-0019

JE Janso 1, BA Haltli 1, AS Eustaquio 1, K Kulowski 1, H He 1, VS Bernan 1, FE Koehn 1
  • 1World-Wide Medicinal Chemistry, Pfizer Global Research & Development, 445 Eastern Pt. Rd, Groton, CT & 401 N. Middletown Rd, Pearl River, NY, USA

The DNA-damaging compound, lomaiviticin A (1), was originally isolated from a marine actinomycete, “Micromonospora lomaivitiensis” LL-37I366 (reclassified as “Salinispora pacifica”)1. 1 exhibited potent cytoxicity (IC50 72 nM to 7.3 pM) against a panel of 24 cancer cell lines. Recently, lomaiviticins C-E (2 – 4) containing a single diazo group, were reported from “S. pacifica” strain DPJ-00192, which also produces the potent mTOR inhibitor neolymphostin A3. Interestingly, 2 – 4 were found to be as much as 100 fold less potent than 1. In this study we report the identification and annotation of the lomaiviticin biosynthetic gene cluster (lom) in “S. pacifica” strain DPJ-0016. An insertional inactivation of the ketosynthase alpha (KSα) was performed in “S. pacifica” strain DPJ-0019. The production of lomaiviticins was abolished in DPJ-0019 mutants confirming that the lom gene cluster does indeed encode the biosynthesis of lomaiviticins. Subsequently, fermentation media were developed to favor production of either the lomaiviticins or the neolymphostins in DPJ-0019.

References:

[1] He H et al (2001)J. Am. Chem. Soc. 123: 5362 – 5363.

[2] Woo CM et al (2012)J. Am. Chem. Soc. 134: 15285 – 15288.

[3] Miyanaga A et al (2011)J. Am. Chem. Soc. 133: 13311 – 13313.