Polyketides natural product biosynthesis

Du, L., Sanchez, C. andShen, B. (2001) Hybrid peptide—polyketide natural products biosynthesis and prospects toward engineering novel molecules. Metabolic Engineering, 3 (1), 78—95. 

Du L, Sanchez C, Shen B (2001). Hybrid peptide—polyketide natural products Biosynthesis and prospects towards engineering novel molecules. Metab. Eng. 3 78-95. 

Cytochrome P450 enzymes have been the subject of a number of recent reviews in which their mechanism and scope of action are covered in much detail [1, 6, 10, 11]. The reader is referred to these articles for a more thorough account of the mechanism and reactivity of cytochrome P450 enzymes, while we present a few representative examples of cytochrome P450-catalyzed epoxidation below. The enzymes we chose are all involved in the biosynthesis of polyketide natural products. Polyketides are a large, structurally diverse family of compounds and have provided a wealth of therapeutically useful drugs and drug leads. 

Stachowicz JJ (2001) Ecological perspectives on marine natural product biosynthesis. In McClintock JB, Baker BJ (eds) Marine chemical ecology. CRC, Boca Raton, FL Staunton J, Weissman KJ (2001) Polyketide biosynthesis a millennium review. Nat Prod Rep 18 380 116... 

Cell-free systems capable of in vitro synthesis of 6-methylsalicylic acid (6-MS A) and a related tetraketide, orsellinic acid, were developed long before the advent of recombinant DNA technologies in the field of natural product biosynthesis [113-115] (Fig. 5). Since then, the biosynthetic mechanisms and molecular recognition features of 6-methylsalicylic acid synthase (6-MSAS) have been extensively studied. 6-MSAS initiates synthesis with an acetyl group derived from acetyl Co A, extends the polyketide chain to a tetraketide via three decar-boxylative condensations of malonyl CoA-derived extender units, and uses NADPH to specifically reduce one of resulting carbonyls to a hydroxyl group. In its natural producer, Penicillium patulum, the product, 6-MSA is subsequently glycosylated to form the antibiotic patulin [116]. 

Du L, Shen B. Biosynthesis of hybrid peptide-polyketide natural products. Curr. Opin. Drug Discov. Devel. 2001 4 215-228. 

Termination of polyketide biosynthesis typically involves the TF mediated cleavage of the ACP-bound thioester, followed by cyclization to generate a macrolactone. Alternatively, the TF catalyzes the simple hydrolysis of the thioester to generate a linear free acid product. Here, we consider two of the relatively few known examples of polyketide natural products that are neither a macrocycle nor a free acid, but instead terminate with a double bond. 

Combinatorial biosynthesis, a new genetic tool for preparing polyketide natural products 04YGK1095. 

Tlie sequential reactions in elongating acyl transfers in the synthesis of polyketide natural products and non-ribosomal peptide antibiotics such as erythromycin, rapamycin, epotliilone, lovastatin, penicillins, cyclosporin and vancomycin resemble molecular solid-state assembly lines. Such multimodular enzymes may be utilized in combinatorial biosynthesis by way of reprogramming for the manufacture of unnaUiral analogs of natural products. 

T. Gulder, M. Freeman, J. Piel, The catalytic diversity of multimodultu- polyketide synthases natural product biosynthesis beyong textbook assembly rules. Top. Cum Chem. 1-53 (2011)... 

D. Yu, F. Xu, J. Zeng, J. Zhan, Type III polyketide synthases in natural product biosynthesis. lUBMB Life 64, 285-295 (2012)... 

Y.Q. Cheng, J.M. Coughlin, S.K. Lim, B, Shen, in Complex Enzymes in Microbitil Natural Product Biosynthesis, Part B Polyketides, Aminocoumarins and Carbohydrates. Methods in Enzymology, vol. 459 (Elsevier Academic Press Inc., New York, 2009), pp. 165-186... 

Within this chapter, we strived to introduce the mechanistic principles of polyketide core structure assembly. Despite the structural diversity of polyketide natural products, there are only few different catalytic domains facilitating a small number of basic reactions—common to all types of PKSs— that are crucial for product biosynthesis. By smart... 

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