Biosynthetic processes

Since ivermectin (= 22,23-dihydroavermectin B ) is obtained by catalytic reduction of avermectin B, the same procedure using tritium gas convenientiy affords tritiated ivermectin (22,23- [JT]-22,23-dihydroavermectin B ). The preparation of a tritiated derivative containing a 22,23-double bond starts with the readily available 5-ketone, which is reduced with [JT]-sodium borohydride stereospecificaHy to a 5- [JT]-derivative (40). Carbon-14 labeled avermectins can be obtained by a biosynthetic process using sodium (l- C)propionate as labeled precursor (48). 

Until now we have viewed the TCA cycle as a catabolic process because it oxidizes acetate units to COg and converts the liberated energy to ATP and reduced coenzymes. The TCA cycle is, after all, the end point for breakdown of food materials, at least in terms of carbon turnover. However, as shown in Figure 20.22, four-, five-, and six-carbon species produced in the TCA cycle also fuel avariety of biosynthetic processes. a-Ketoglutarate, succinyl-CoA, fumarate, and oxaloacetate are all precursors of important cellular species. (In order to par-... 

FIGURE 20.22 The TCA cycle provides intermediates for nmnerons biosynthetic processes in the cell. 

Situated as it is between glycolysis and the electron transport chain, the TCA cycle must be carefully controlled by the ceil. If the cycle were permitted to run unchecked, large amounts of metabolic energy could be wasted in overproduction of reduced coenzymes and ATP conversely, if it ran too slowly, ATP would not be produced rapidly enough to satisfy the needs of the cell. Also, as just seen, the TCA cycle is an important source of precursors for biosynthetic processes and must be able to provide them as needed. 

It may seem surprising that isocitrate dehydrogenase is strongly regulated, because it is not an apparent branch point within the TCA cycle. However, the citrate/isocitrate ratio controls the rate of production of cytosolic acetyl-CoA, because acetyl-CoA in the cytosol is derived from citrate exported from the mitochondrion. (Breakdown of cytosolic citrate produces oxaloacetate and acetyl-CoA, which can be used in a variety of biosynthetic processes.) Thus, isocitrate dehydrogenase activity in the mitochondrion favors catabolic TCA cycle activity over anabolic utilization of acetyl-CoA in the cytosol. 

Plants (particularly seedlings, which cannot yet accomplish efficient photosynthesis), as well as some bacteria and algae, can use acetate as the only source of carbon for all the carbon compounds they produce. Although we saw that the TCA cycle can supply intermediates for some biosynthetic processes, the... 

Vnother pathway of glucose catabolism, the pentose phosphate pathway, is the primary source of N/ E)PH, the reduced coenzyme essential to most reductive biosynthetic processes. For example, N/VDPH is crucial to the biosynthesis of... 

Cells require a constant supply of N/ X)PH for reductive reactions vital to biosynthetic purposes. Much of this requirement is met by a glucose-based metabolic sequence variously called the pentose phosphate pathway, the hexose monophosphate shunt, or the phosphogluconate pathway. In addition to providing N/VDPH for biosynthetic processes, this pathway produces ribos 5-phosphate, which is essential for nucleic acid synthesis. Several metabolites of the pentose phosphate pathway can also be shuttled into glycolysis. 

This portion of the pathway begins with an isomerization and an epimeriza-tion, and it leads to the formation of either D-ribose-5-phosphate or D-xylulose-5-phosphate. These intermediates can then be converted into glycolytic intermediates or directed to biosynthetic processes. 

In designing a process we have the choice of using the whole organism or specific enzymes isolated from it. As always both options have pro s and cons. Broadly speaking we could say that biosynthetic processes mostly rely on whole cells, whereas biotransformations can be catalysed by whole cells and by enzyme preparations. 

GPCR function has been shown to be regulated by several different mechanisms. The number of receptors on the plasma membrane may be regulated by transcription, mRNA stability, biosynthetic processing, and protein stability. In addition, the function of receptors in the plasma membrane can be influenced by regulatory phosphorylation and by association with other proteins that determine the subcellular location of receptors relative to other signaling molecules. 

Human insulin is derived from a biosynthetic process using strains of Escherichia coli (recombinant DNA, rDNA). Human insulin appears to cause fewer allergic reactions than does insulin obtained from animal sources. Insulin analogy, insulin lispro, and insulin aspart are newer forms of human insulin made by using recombinant DNA technology and are structurally similar to human insulin. 

Hayes, J.M. (2001). Fractionation of carbon and hydrogen isotopes in biosynthetic processes. 

Given the information in the previous two sections, it is now possible to summarize what we know of the biosynthetic processes that lead to the formation of active MoFe protein. 

In addition to their roles in proteins and polypeptides, amino acids participate in a wide variety of additional biosynthetic processes. 

Adenosylmethionine, the methyl group donor for many biosynthetic processes, also participates direcdy in spermine and spermidine biosynthesis. 

In contrast to the wide range of antibacterial antibiotics, there are very few antifungal antibiotics that can be used systemically. Lack of toxicity is, as always, of paramount importance, but the differences in structure of, and some biosynthetic processes in, fungal cells (Chapter 2) mean that antibacterial antibiotics are usually inactive against fungi. 

As noted, the alkaloid yield from the Beocin plants was low, which the authors suggested might be caused by the poor soil in which the plants were growing (Popovic et ah, 1992). One could ask whether the soil conditions to which they refer might be influential in the overall alkaloid biosynthetic processes in this species. It would be of interest to see experimental studies aimed at determining the effect of soil components on these processes. In the present case, it may be a lack of, or reduction in the activity of, the oxidase(s) necessary for the dimerization process (required to form the bibenzyldihydroisoquinolines) to occur. It is also possible that the lack of dimeric alkaloids may simply reflect a concentration effect caused by the edaphic conditions. These questions should be accessible to experiment. 

The in vivo transformation of [6-14C]strictosidine (19) to gelsemine in Gelsemium sempervirens was claimed with an incorporation of 0.47% (33). This provides another experimental support to the proposal that strictosidine appears to be the original precursor in the biosynthesis of monoterpenoid indole alkaloids, although the detailed pathway of this biosynthetic process still remains obscure. 

Bacteria, being procaryotic, do not show compartmentation of the biosynthetic processes. The genome of a bacterium relates directly to the cytoplasm of the cell. Transcription into mRNA can lead directly to translation, and the processes of transcription and translation are not carried out in separate organelles. Animal cells, being eucaryotic, show compartmentation of the transcription and translation processes. Transcription of the genome into mRNA occurs in the nucleus, whereas translation occurs in the cytoplasm. The messenger RNA in the eucaryote is usually modified by adding to it... 

After treatment of XXXVI with aqueous barium hydroxide, the liquor contained formic, methoxyacetic, and ethoxyacetic acids, methoxyacetone, and ethoxyacetone, produced by the two modes of cleavage XXXVIa and XXXVIb. Formic acid was converted with red mercuric oxide to carbon dioxide this was recovered as barium carbonate, the radioactivity of which was a measure of the C14 incorporated into Cl of kojic acid in the biosynthetic process. The alkoxyacetones were removed from the liquor by steam distillation, and converted to iodoform and a mixture of methoxy- and ethoxy-acetic acids. The iodoform was recovered by filtration its radioactivity indicated the proportion of C14 incorporated into C4. The alkoxy-... 

These investigations shed considerable light on the synthesis of the Y-pyrone ring however, it is unlikely that any conclusions regarding the biosynthetic process could be drawn from them. 

All bacteria utilize nutrients as sources of the energy required for all of the biosynthetic processes that bacteria use for their maintenance and reproduction. Bacteria... 

Similarly, five closely related melanocortin receptors that respond to various peptides derived from the POMC precursor have been identified (Fig. 18-7) [24]. As expected, the receptor on adrenal cortical cells responds best to ACTH, which normally stimulates adrenal steroidogenesis, and the receptor on melano cytes responds best to aMSH, which causes skin darkening. However, the pattern of melanocortin receptor expression in the brain is not simply explained by the known patterns of peptide expression in the brain or by the known effects of POMC-derived peptides when applied to various brain regions. With this number of peptide receptors, it is obvious that production of final peptide products must be precisely controlled and that different biosynthetic processing pathways can dramatically affect the biological activity observed (Figs 18-5,18-7). 

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