Cytochrome P450-mediated hydroxylation is required for polyketide macrolactonization in stambomycin biosynthesis.
Many polyketide antibiotics contain macrolactones that arise from polyketide synthase chain release via thioesterase (TE) domain-catalyzed macrolactonization. The hydroxyl groups utilized in such macrolactonization reactions typically derive from reduction of β-ketothioester intermediates in polyketide chain assembly. The stambomycins are a group of novel macrolide antibiotics with promising anticancer activity that we recently discovered via rational activation of a silent polyketide biosynthetic gene cluster in Streptomyces ambofaciens. Here we report that the hydroxyl group utilized for formation of the macrolactone in the stambomycins is derived from cytochrome P450-catalyzed hydroxylation of the polyketide chain rather than keto reduction during chain assembly. This is a novel mechanism for macrolactone formation in polyketide antibiotic biosynthesis.
Department of Chemistry, University of Warwick, Coventry, UK.
Lijiang
L
Song
1] Université de Lorraine, Dynamique des Génomes et Adaptation Microbienne, UMR 1128, Vandoeuvre-lès-Nancy, France [2] INRA, Dynamique des Génomes et Adaptation Microbienne, UMR 1128, Vandoeuvre-lès-Nancy, France.
Luisa
L
Laureti
Department of Chemistry, University of Warwick, Coventry, UK.
Christophe
C
Corre
1] Université de Lorraine, Dynamique des Génomes et Adaptation Microbienne, UMR 1128, Vandoeuvre-lès-Nancy, France [2] INRA, Dynamique des Génomes et Adaptation Microbienne, UMR 1128, Vandoeuvre-lès-Nancy, France.
Pierre
P
Leblond
1] Université de Lorraine, Dynamique des Génomes et Adaptation Microbienne, UMR 1128, Vandoeuvre-lès-Nancy, France [2] INRA, Dynamique des Génomes et Adaptation Microbienne, UMR 1128, Vandoeuvre-lès-Nancy, France.
Bertrand
B
Aigle
Department of Chemistry, University of Warwick, Coventry, UK.
Gregory L
GL
Challis
D000903:Antibiotics, Antineoplastic / Q000096:biosynthesis / Q000737:chemistry*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006900:Hydroxylation; D018942:Macrolides / Q000737:chemistry*; D061065:Polyketides / Q000737:chemistry*
D000903:Antibiotics, Antineoplastic; D018942:Macrolides; D061065:Polyketides; C558881:stambomycin A; C558882:stambomycin B; C558883:stambomycin C; C558884:stambomycin D; D003577:Cytochrome P-450 Enzyme System