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

2. Genome sequence of the model antibiotic- producer Streptomyces coelicolor M145 Nature (2002) 417, 141-147

3. Cryptic biosynthetic pathways encoded within the S. coelicolor genome

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

5. Posttranslational ACP modification CoASH

6. Acyl transferase

7. Prediction of AT domain substrate specificity Haydock et al. FEBS Lett. (1995) 374, 246-248 Banskota et al. J. Antibiot. (2006) 59, 168-176 Malonyl-CoA Methylmalonyl-CoA

8. Ketosynthase 1

9. Ketosynthase 2 -CO 2

10. Keto reductase NADPH

11. Prediction of KR domain stereospecificity Keatinge-Clay, Chem. Biol. (2007) 14, 898-908

12. Dehydratase -H 2 O

13. Enoyl reductase NADPH

14. Prediction of ER domain stereospecificity Kwan et al., Chem. Biol. (2008) 15, 1231-1240

15. Thioesterase 1

16. Thioesterase 2