Biosynthesis active precursors

In addition to its role as an intermediate in cholesterol biosynthesis, isopentenyl pyrophosphate is the activated precursor of a huge array of biomolecules with diverse biological roles (Fig. 21-48). They include vitamins A, E, and K plant pigments such as carotene and the phytol chain of chlorophyll natural rubber many essential oils (such as the fragrant principles of lemon oil, eucalyptus, and musk) insect juvenile hormone, which controls metamorphosis dolichols, which serve as lipid-soluble carriers in complex polysaccharide synthesis and ubiquinone and plastoquinone, electron carriers in mitochondria and chloroplasts. Collectively, these molecules are called isoprenoids. More than... 

Another technique that is utilized to help ensure that label is incorporated into the pheromone is to apply the precursor at the same time as pheromone biosynthesis activating neuropeptide (PBAN). PBAN is a peptide hormone that regulates pheromone biosynthesis in most, but not all, moths. So, first it must be demonstrated that PBAN regulates pheromone production. In the case of the cabbage looper,... 

Sato Y., Ikeda M., Yamashita O. (1994) Neurosecretory cells expressing the gene for common precursor for diapause hormone and pheromone biosynthesis activating neuropeptide in the subesophageal ganglion of the silkworm, Bombyx mori. Gen. Comp. Endocrin. 96, 27-36. 

Biosynthetically-patterned microbiological transformations exploit the substrate flexibility of enzymes involved in the biosynthesis of secondary metabohtes. These biotransformations are sometimes known as analogue biosynthesis or precursor-directed biosynthesis. This approach to biotransformation can be useful in preparing analogues of biologically-active microbial metabolites for structure-activity studies, a feature that has been exploited with penicillins using a cloned isopenicillin N synthase. The structures of the substances that are transformed and of their products can also shed light on the stereo-electronic constraints of enzymatic steps and on the nature of biosynthetic intermediates, a feature that has been exploited in studies on the cyclization of squalene to the triterpenes and steroids. 

Contrast the biosynthesis of phosphoglycerides in bacteria and mammals. Note the significance of CDP-diacylglycerol and CDP-choline or CDP-ethanolamine, the activated precursors in these biosyntheses. 

Thromboxane production has been detected in several inflammatory conditions in inflamed joints such as urate arthritis [343] and rheumatoid arthritis [92] in carageenin induced pleurisy [91] and in burns [93,94,344]. The involvement of thromboxanes in burns has attracted particular attention. TXB2 has been demonstrated both in burn blister fluid and in lymph from the scalded limb [93,344] as well as in burned tissue [94] and the formation of the biologically active precursor, TXA 2, has been postulated as one factor responsible for the progressive dermal ischemia seen after burn injury, which may lead to extensive skin necrosis [94,344], The effects of three inhibitors of thromboxane biosynthesis on dermal ischemia were studied [345]. All compounds were found to increase dermal perfusion after scalding injury compared to untreated animals, which supports the theory of the deleterious influence of TXA2 upon dermal circulation in burned tissues. 

Battersby, A. R. and D. M. Foulkes, Alkaloid biosynthesis. Part VIII Use of optically active precursors for investigations on biosynthesis of morphine alkaloids, J. Chem. Soc., 3323-3332 (1965). 

Because brain cells cannot rely on blood supply for obfaining cholesterol, they have to produce it by de novo biosynthesis. The precursor of cholesferol is acetyl-CoA, which is an "activated" form of acefate, a two-carbon building unit. Two acetyl-CoA molecules form acetoacetyl-CoA, which subsequenfly reacfs wifh a third acetyl-CoA to generate a 6-carbon product called hydroxylmethylglutaryl-CoA (HMG-CoA) (Fig. 3.4). 

It has been well established that the enzymes required for the biosynthesis of the polymers of the outer membrane are localized in the inner membrane. Most importantly, the lipid-carrier molecules (poly-isoprenoid-phosphates) are found in this membrane. These molecules transfer newly synthesized, activated precursor molecules from the hydrophilic cytoplasmic environment into the lipophilic environment of the membrane, where the assembly into polymeric structures takes place. This assembly process is used for lipopolysaccharides, peptidoglycans, and capsular polysaccharides. In a subsequent step, the membrane-carrier molecules transfer the assembled polymers from the inner to the outer membrane. ... 

Biosynthesis. Two closely related genes encode the three mammalian tachykinins. The preprotachykinin A gene encodes both substance P and substance K, while the preprotachykinin B gene encodes neuromedin K (45—47). The active sequences are flanked by the usual double-basic amino acid residues, and the carboxy-terrninal amino acid is a glycine residue which is decarboxylated to an amide. As with most neuropeptide precursors, intermediates in peptide processing can be detected, but their biological activities are not clear (ca 1994). 

Amino-2 -deoxypurines. 2 -AmiQo-2 -deoxyadenosine (15) is a naturally occurring A[-nucleoside isolated from A.ctinomadura that shows antknycoplasmal activity (1,4). Adenosine is the direct precursor for its biosynthesis (30). 2 -Arnino-2 -deoxyguanosine (16), isolated from a strain of Enterobacter cloacae (1,4), shows the growth of HeLa S3 cells and Sarcoma 180 in vivo and has been tested for antibacterial activity. 

Ketoconazole. For treatment of systemic mycoses with amphotericin B or miconazole, the patient must be admitted to a hospital. This is not always possible, particularly in areas where systemic mycoses occur frequently, nor is it always desirable, because of the expense. For these reasons, it was desirable to find an antimycotic that combined safety and broad-spectmm activity with oral adraiinistration. Ketoconazole (10), which is orally active, met most of these requirements. This inhibitor of the ergosterol biosynthesis is an A/-substituted imidazole, that differs from its precursors by the presence of a dioxolane ring (6,7). Ketoconazole is rapidly absorbed in the digestive system after oral adrninistration. Sufficient gastric acid is required to dissolve the compound and for absorption. Therefore, medication that affects gastric acidity (for example, cimetidine and antacids) should not be combined with ketoconazole. 

A number of mitomycin analogues have been prepared by precursor-directed biosynthesis [104]. A range of amines were fed to S. caespitosus, and novel derivatives of mitomycin C (type I analogues) and mitomycin B (type II analogues) were identified and in some cases (42-46 and 52-56 Scheme 11.4) isolated and characterized. Antibiotic and antitumor activities were comparable to those of mitomycin C, with the type I analogues more active than the type II analogues. 

The carbon skeleton of helminthosporal can be accounted for from three isoprene units (XVI), but they cannot be formed by cyclization of a farnesol precursor, as the three units are not joined head to tail. There is the possibility that the aldehyde carbons were joined in the early stages of biosynthesis to form helminthosporane (XVII, XX) as an intermediate, followed by later oxidation to yield the dialdehydes. As a test of this hypothesis the actively growing fungus was fed mevalonic acid labeled with carbon-14 in the 2-position (mevalonic acid being a precursor of isoprene units) (2). Thus, three units of radioactivity should be incorporated, one being the... 

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