Traditional approach for bioactive natural product discovery fractionation extraction Investigate bioactivity of extract Identify active fraction(s) and.

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Presentation transcript:

Traditional approach for bioactive natural product discovery fractionation extraction Investigate bioactivity of extract Identify active fraction(s) and determine structure(s) of compound(s)

Genome sequence of the model antibiotic- producer Streptomyces coelicolor M145 Nature (2002) 417,

Cryptic biosynthetic pathways encoded within the S. coelicolor genome

DEBS – an archetypal cis-AT polyketide synthase Nature (1990) 348, 176; Science (1991) 252, 671

Posttranslational ACP modification CoASH

Acyl transferase

Prediction of AT domain substrate specificity Haydock et al. FEBS Lett. (1995) 374, Banskota et al. J. Antibiot. (2006) 59, Malonyl-CoA Methylmalonyl-CoA

Ketosynthase 1

Ketosynthase 2 -CO 2

Keto reductase NADPH

Prediction of KR domain stereospecificity Keatinge-Clay, Chem. Biol. (2007) 14,

Dehydratase -H 2 O

Enoyl reductase NADPH

Prediction of ER domain stereospecificity Kwan et al., Chem. Biol. (2008) 15,

Thioesterase 1

Thioesterase 2