Aminocoumarin antibiotics

The prenylated benzoic acid and the coumarin ring are derived from L-tyrosine. Walsh et al. proposed a biosynthetic pathway for coumarin formation in which NovH, a didomainal enzyme containing an adenylation (A) domain and a thiolation (T) domain, catalyzes L-tyrosyl-AMP formation. The A domain of NovH selects and 

The biosynthesis of prenylated benzoic acid 37 starts from prephenate, which is converted to 4HPP 38 catalyzed by novF. The prenylation with DMAPP is catalyzed by a prenyltransferase (gene novQ) [164]. Gene novR catalyzes the oxidative transformation to prenylated benzoic acid 37 [157]. The aminocumarin 36 is assembled with 3-prenyl-4-hydroxybenzoate 37 by novL. Subsequent methylation with SAM catalyzed by novO affords the compound 42. Gene novM catalyzes the assembly of the latter with dTDP-L-noviose 32. Finally, a 4 -(9-methyl transfer (gene novP) and a 3 -0 carbamyl transfer (gene novN) form novobiocin [165]. 

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Li S-M, Heide L (2005) New Aminocoumarin Antibiotics from Genetically Engineered Streptomyces Strains. Curr Med Chem 12 419... 

Heide L, Gust B, Anderle C et al (2008) Combinatorial biosynthesis, metabolic engineering and mutasynthesis for the generation of new aminocoumarin antibiotics. Curr Top Med... 

Fridman M, Balibar CJ, Lupoli T et al (2007) Chemoenzymatic formation of novel aminocoumarin antibiotics by the enzymes CouNl and CouN7. Biochemistry 46 8462-8471... 

Some examples are represented by the steps of the reactions that lead to the biosynthesis of novobiocin (the aminocoumarin antibiotic produced by Streptomyces spheroides and Streptomyces niveus) (Figure 1.15) [17, 18], lysergic acid (ergot... 

Aminocoumarin antibiotics such as novobiocin, clorobiocin, and coumermycin A1 are derived from different Streptomyces species and show a very potent antibacterial activity by inhibition of DNA gyrase. Gyrase inhibitors block DNA replication, induce the SOS repair system, and eventually cause bacterial cell death (Figure 6.32) [151-154], These antibiotics possess a 3-amino-4-hydroxy-coumarin and a substituted deoxysugar noviose as common feature, which is essential for their biological activity. The biosynthetic gene clusters for novobiocin, chlorobiocin, and coumermycin A1 have been cloned in Streptomyces coelicolor M512 [155,156]. 

Figure 632 Structures of aminocoumarin antibiotics novobiocin, clorobiocin, and coumennycin A1.

Pojer F, Li SM, Heide L (2002) Molecular cloning and sequence analysis of the clorobiocin biosynthetic gene cluster new insights into the biosynthesis of aminocoumarin antibiotics. Microbiology-Sgm 148 3901-3911... 

Pacholec, M., Tao, J. and Walsh, C.T. (2005) CouO and NovO C-methyltransferases for tailoring the aminocoumarin scaffold in coumermycin and novobiocin antibiotic biosynthesis. Biochemistry, 44, 14969-14976. 

A known strain of S. antibioticus was found to produce a compound designated simocyclinon D8 (44) [31]. The compound exhibits antibiotic activity against Gram-positive bacteria and cytostatic effects against various cancer cells. Its structure and biosynthesis were clarified on the basis of physical-chemical methods, mainly by ID and 2D NMR and ESI-MS. It was found that during its biosynthesis the incorporation of 180 into the aminocoumarine residue is probably catalyzed by a monooxygenase. 

Fig. 6.13 Structure of antibiotics that are generated using the p-hydroxylase CYP162 and CYP163 P450 enzymes. a The aminocoumarin novobiocin, the synthesis of which involves the P450 Novi (CYP163A1). Novi is a P-hydroxylase from S. spheroides that was shown to generate (25,3ii)-P-OH-tyrosine from amino acyl-bound tyrosine during novobiocin biosynthesis [243]. b The...

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