Biosynthesis Particular

Once cyclic monoterpenes have been formed, they can be converted by minor modifications into other cyclic monoterpenes. As an example, let us consider the peppermint, which we have already mentioned. 

Geranyl pyrophosphate is converted to piperitenone via a series of unknown intermediates and this is then transformed into pulegone, menthone, and menthol in three hydrogenation steps (Fig. 78). The hydrogenation of pugelone to menthol via menthone can be carried out in a cell-free system. Additional monoterpenes, which can be integrated into the same biogenetic pattern as those mentioned, are also to be found in the peppermint. 

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Nucleotide biosynthetic pathways are tremendously important as intervention points for therapeutic agents. Many of the most widely used drugs in the treatment of cancer block steps in nucleotide biosynthesis, particularly steps in the synthesis ofDNA precursors. 

NADPH is used for reductive biosynthesis (particularly of fatty adds) and for protection against oxidative damage. 

Fats are composed of glycerol esterified to three fatty acids. Fats are derived from three primary sources (1) the diet (2) de novo biosynthesis, particularly in liver and (3) storage depots in adipocytes. Processes by which these sources are utilized in animals are summarized in Figure 18.3. Breakdown of fats by lipases yields fatty acids and glycerol. 

Amino acids mixtures stimulate aflatoxin biosynthesis, particularly asparagine and aspartic acid. Proline has been reported to stimulate conidial germination in a culture that was probably A. parasiticus, although reported as A. flavus (14). These investigators reported the greatest toxin formation with a mixture of amino acids followed by a mixture of proline plus glutamate or proline plus aspartate. The effect in the latter instances may have been due to the effect on conidial germination rather than a direct effect on aflatoxin biosynthesis. 

The stimulation of 6-ALA-S activity in response to Pb inhibition at steps downstream in heme biosynthesis, particularly Pb inhibition of 8-ALA-D,... 

Cytochrome P-450s are the best-known class of hydroxylation enzyme. Their active sites contain a heme iron that forms a highly activated oxygenating species that reacts by a radical mechanism. In higher animals, they function primarily in metabolite degradation as part of pathways that clear unnatural substances such as toxins and drugs. Hydroxylation inaeases polarity that facilitates further derivatization by other detoxification enzymes or excretion of the hydroxylated products. Other P-450 family members are involved in secondary metabolite biosynthesis, particularly in plants and microbial cells (Figure 1.6). 

Cellular protein biosynthesis involves the following steps. One strand of double-stranded DNA serves as a template strand for the synthesis of a complementary single-stranded messenger ribonucleic acid (mRNA) in a process called transcription. This mRNA in turn serves as a template to direct the synthesis of the protein in a process called translation. The codons of the mRNA are read sequentially by transfer RNA (tRNA) molecules, which bind specifically to the mRNA via triplets of nucleotides that are complementary to the particular codon, called an anticodon. Protein synthesis occurs on a ribosome, a complex consisting of more than 50 different proteins and several stmctural RNA molecules, which moves along the mRNA and mediates the binding of the tRNA molecules and the formation of the nascent peptide chain. The tRNA molecule carries an activated form of the specific amino acid to the ribosome where it is added to the end of the growing peptide chain. There is at least one tRNA for each amino acid. 

NAD and NADP are required as redox coen2ymes by a large number of enzymes and ia particular dehydrogenases (Fig. 6). NAD" is utilized ia the catabohe oxidations of carbohydrates, proteins, and fats, whereas NADPH2 is the coenzyme for anaboHc reactions and is used ia fats and steroid biosynthesis. NADP+ is also used ia the cataboHsm of carbohydrates (2). 

It iaterferes with the synthesis of the hyphal walls, the biosynthesis of nucleic acids, and the synthesis of chitin. The iateraction with microtubules has also been described. The sensitivity of a cell seems to depend particularly on the abiUty to form griseofulvin—nucleic acid complexes. Further information concerning griseofulvin is available (21). 

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. 

Role of polyketide synthases in biosynthesis of some heterocycles, in particular macrolides 97CRV2465. 

In biological reactions, the situation is different from that in the laboratory. Only one substrate molecule at a time is present in the active site of the enzyme where reaction takes place, and that molecule is held in a precise position, with coenzymes and other necessary reacting groups nearby. As a result, biological radical reactions are both more controlled and more common than laboratory or industrial radical reactions. A particularly impressive example occurs in the biosynthesis of prostaglandins from arachiclonic acid, where a sequence of four radical additions take place. The reaction mechanism was discussed briefly in Section 5.3. 

All three elimination reactions--E2, El, and ElcB—occur in biological pathways, but the ElcB mechanism is particularly common. The substrate is usually an alcohol, and the H atom removed is usually adjacent to a carbonyl group, just as in laboratory reactions. Thus, 3-hydroxy carbonyl compounds are frequently converted to unsaturated carbonyl compounds by elimination reactions. A typical example occurs during the biosynthesis of fats when a 3-hydroxybutyryl thioester is dehydrated to the corresponding unsaturated (crotonyl) thioester. The base in this reaction is a histidine amino acid in the enzyme, and loss of the OH group is assisted by simultaneous protonation. 

Mixed Claisen condensations (Section 23.8) also occur frequently in living organisms, particularly in the pathway for fatty-acid biosynthesis that we ll discuss in Section 29.4. Butyryl synthase, for instance, reacts with malonvl ACP in a mixed Claisen condensation to give 3-ketohexanoyl ACP. 

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