Aromatase, polyketide

Figure 6 (A) Reactions catalyzed by aromatic cyclases and aromatases. These enzymes control the diverse cyclization patterns of aromatic polyketides and in general display high regioselectivity and substrate specificity. (B) Examples of known products with different cyclization patterns that are accessible via the thioesterase (TE) domain of DEBS.

Fig. 4. Polyketide biosynthesis by gene products of the act PKS cluster. Presence of the KS/AT, CLF, and ACP is sufficient for the production of two 16-carbon polyketides, SEK4 and SEK4b both in vivo [ 103] and in vitro [107]. In the presence of the act ketoreductase (KR), aromatase (ARO) and cyclase (CYC), the octaketide intermediate is converted into DMAC. DMAC can be converted into 8-methoxy DMAC both in vivo and in vitro through the S-adenosylmethionine (Adomet)-dependent action of the tcmO methyltransferase [207]...

Figure 4. Organization of representative type 1, II, and III polyketide synthases. Upper modular arrangement of DEBS 1,2,3 subunits Center orientation and arrangement of open reading frames in actinorhodin gene cluster Lower chalcone synthase subunit. AT, acyltransferase ACP, acyl carrier protein KS, ketosynthase KR, ketoreductase DH, dehydratase ER, enoyl reductase TE, thioesterase TA, tailoring enzyme R/T, regulatory/transport related AR aromatase CY, cyclase.

Type II PKS complexes are comprised at a minimum of four types of subunits encoded by discrete open reading frames acyl carrier protein, ketosynthase a, ketosynthase p (also referred to as chain length factor ), and a malonyl CoA acyltransferase responsible for loading acyl-CoA extender units on to the acyl carrier protein subunit (34 Fig. 4). Additional subunits containing ketoreductase, cyclase, or aromatase activity may also occur in more complex type II synthases. Typically, the four core subunits (acyl carrier protein, ketosynthase a, ketosynthase p, and malonyl-CoA acyltransferase) participate in the iterative series of condensation reactions until a specified polyketide chain length is achieved, then folding and cyclization reactions yielding the final... 

McDaniel, R., S. Ebert-Khosia, D.A. Hopwood, and C. Khosla (1994b). Engineered biosynthesis of novel polyketides actVJI and actIV genes encode aromatase and cyclase enzymes, respectively. J. Am. Chem. Soc. 116 10855-10859. 

The anthracycline core is assembled from acetyl imits in the form of malonyl-CoA by an iterative, type II polyketide synthase (Metsa-Ketela et al. Anthracycline Biosynthesis Genes, Enzymes and Mechanisms , this volume) followed by aromatase, cyclase and tailoring enzymes, which produce the tetracycUc ring structure from the imstable polyketide chain as shown in Scheme 1. 

The nascent polyketide chain must then be folded into the tetracyclic structure. Again, the exact details of chain folding have not been deduced for any polyketide structure, but a ketoreductase (for which Actlll is the paradigm) and aromatase/cyciase enzyme (or enzymes) are known to be important (102). For oxytetracycline (Figure 7), 0lcY2-l (ketoreductase) and otcDl (aromatase) are the likely candidates, although others may also be involved. 

Alvarez MA, Fu H, Khosla C, Hopwood DA, Bailey JE. Engineered biosynthesis of novel polyketides Properties of the whiE aromatase/cyclase. Bio/Technol 1996 14 335-338. 

Fig. 6. In vitro synthesis of actinorhodin biosynthetic intermediates and its shunt metabolites from acetyl CoA and malonyl CoA by the ActIORFI,2,3 polyketide synthase complex, the Actlll ketoreductase, the ActVII aromatase, ActIV cyclase, and the TcmO methyltransferase...

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