Polyketide pathway metabolities derived from

Despite the thousands of secondary metabolites made by microorganisms, they are synthesized from only a few key precursors in pathways that comprise a relatively small number of reactions and which branch off from primary metabolism at a limited number of points. Acetyl-CoA and propionyl-CoA are the most important precursors in secondary metabolism, leading to polyketides, terpenes, steroids, and metabolites derived from fatty acids. Other secondary metabolites are derived from intermediates of the shikimic acid pathway, the tricarboxylic acid cycle, and from amino acids. The regulation of the biosynthesis of secondary metabolites is similar to that of the primary processes, involving induction, feedback regulation, and catabolite repression [6]. 

Although the metabolic engineering of beta-lactams by combining p-lactam encoding genes from various sources [95,123] is still in an explorative state, the study of polyketide pathways and the creation of polyketide antibiotic derivatives is more advanced. 

Alkaloids are derived from many biosynthetic pathways, including those of amino acid, polyketide, shikimic acid, acetate, and terpenoid metabolism. In this book, a broad perspective is adopted simple amines, nitrogenous bases of terpenoid origin, neutral compounds such as colchicine, and purines are all considered to be alkaloids. Many alkaloids are poisonous to mammals and a large number are medicinally useful. 

Enzymatic syntheses within the microfluidic platform were also reported. The construction and novel compound synthesis from a synthetic metabolic pathway consisting of a type HI polyketide synthase (PKS) known as 1,3,6,8-tetrahydroxynaphthalene synthase (THNS) from Streptomyces coelicolor and soybean peroxidase (SBP) in a microreactor were performed (Fig. 5) [11]. THNS immobilized to Ni-NTA agarose beads was prepacked into a microfluidic channel, while SBP was covalently attached to the walls of a second microfluidic channel precoated with a reactive poly(maleic anhydride) derivative. The result was a tandem, two-step hiochip that enabled synthesis of novel polyketide derivatives. The first microchan-nel, consisting of THNS, resulted in the conversion of malonyl-CoA to flaviolin in yields of up to 40% with a residence time of 6 min. This conversion is similar to that obtained in several-milliliter batch reactions after 2 h. Linking this microchannel to the SBP microchannel results in biflaviolin synthesis. During the course of this work, we discovered that the substrate specificity of THNS could be manipulated by simply changing the reaction pH. As a result, the starter acyl-CoA specificity can be broadened to yield a series of truncated pyrone products. When combined with variations in the ratio of acyl-CoA and... 

In studying biosynthetic pathways, we have to identify (a) the ultimate source in primary metabolism from which the compound of interest derives (for example, fatty acid, polyketide, or others in the following chapters), and (b) the intermediates through which a final product is formed. With so much accumulated knowledge, and with only a few pathways used by nature, the first task of finding the ultimate source is usually not at all difficult. The second objective may be very difficult and subject to all sorts of pitfalls and false clues. 

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