Metabolic pathways biosynthesis

Although the interior of a prokaryotic cell is not subdivided into compartments by internal membranes, the cell still shows some segregation of metabolism. For example, certain metabolic pathways, such as phospholipid synthesis and oxidative phosphorylation, are localized in the plasma membrane. Also, protein biosynthesis is carried out on ribosomes. 

Metabolic disorders of urea biosynthesis, while extremely rare, illustrate four important principles (1) Defects in any of several enzymes of a metabolic pathway enzyme can result in similar clinical signs and symptoms. (2) The identification of intermediates and of ancillary products that accumulate prior to a metabolic block provides insight into the reaction that is impaired. (3) Precise diagnosis requires quantitative assay of the activity of the enzyme thought to be defective. (4) Rational therapy must be based on an understanding of the underlying biochemical reactions in normal and impaired individuals. 

Mutka, S.C., Bondi, S.M., Carney, J.R. et al. (2006) Metabolic pathway engineering for complex polyketide biosynthesis in Saccharomyces cerevisiae. FEMS Yeast Research, 6, 4047. 

Several mutant strains of R. eutropha that were made to possess defective competing metabolic pathways with the PHA biosynthetic pathway were developed for the enhanced PHA production. The isocitrate dehydrogenase leaky mutant of R. eutropha accumulated P(3HB) more favorably at a lower car-bon/nitrogen molar ratio and at a lower carbon concentration than the parent strain [82]. In batch culture, the final cell and P(3HB) concentrations, and P(3HB) yield on glucose were slightly increased. Also, in the P(3HB-co-3HV) biosynthesis, the molar fraction of 3HV and the 3HV yield on propionic acid increased due to the enhanced conversion of propionic acid to 3-hydroxyvaleryl-CoA rather than to acetyl-CoA and C02 in this mutant. Another mutant R. eu-... 

Assuming that the metabolic pathways are similar in the biosynthesis of related isocyanoterpenes, these studies remain difficult, due in part to the competitive formation of other secondary metabolites. In addition to the common trio (-NC, NCS, -NHCHO) of the nitrogenous functions found attached to these skeletons, analogs such as -CN, -CNO, and -SCN foreshadow the complexity of identifying and selecting specific precursors to be targeted for incorporation into the family of marine isonitriles. 

Fig. 6. The metabolic pathway for lysine biosynthesis in Escherichia coli, which contains a missing enzyme that is not found in the genome.

Both the aldol and reverse aldol reactions are encountered in carbohydrate metabolic pathways in biochemistry (see Chapter 15). In fact, one reversible transformation can be utilized in either carbohydrate biosynthesis or carbohydrate degradation, according to a cell s particular requirement. o-Fructose 1,6-diphosphate is produced during carbohydrate biosynthesis by an aldol reaction between dihydroxyacetone phosphate, which acts as the enolate anion nucleophile, and o-glyceraldehyde 3-phosphate, which acts as the carbonyl electrophile these two starting materials are also interconvertible through keto-enol tautomerism, as seen earlier (see Section 10.1). The biosynthetic reaction may be simplihed mechanistically as a standard mixed aldol reaction, where the nature of the substrates and their mode of coupling are dictated by the enzyme. The enzyme is actually called aldolase. 

The pentose phosphate pathway (PPP, also known as the hexose monophosphate pathway) is an oxidative metabolic pathway located in the cytoplasm, which, like glycolysis, starts from glucose 6-phosphate. It supplies two important precursors for anabolic pathways NADPH+H+, which is required for the biosynthesis of fatty acids and isopren-oids, for example (see p. 168), and ribose 5-phosphate, a precursor in nucleotide biosynthesis (see p. 188). 

Antimetabolites are enzyme inhibitors (see p. 96) that selectively block metabolic pathways. The majority of clinically important cytostatic drugs act on nucleotide biosynthesis. Many of these are modified nucleobases or nucleotides that competitively inhibit their target enzymes (see p. 96). Many are also incorporated into the DNA, thereby preventing replication. 

An attractive hypothesis is the independent evolution in bacteria of their diffusible individualites and the currently recognized secondary metabolic pathways, in parallel with their surface components and their biosynthesis. An indicator for this would be the use of the same gene pool. The theory would include all substances that play a role in the build-up of glycan and other modified surface layers, lipids, murein, (glyco-) proteins (e.g., S-layers), polysaccharides, teichoic... 

The final product(s) generated by a sequence of enzyme-catalyzed steps within a metabolic pathway. End products frequently act as potent inhibitors of the first commited step in a metabolic pathway leading to their synthesis. End products are also known to accelerate the rate of another metabolic pathway leading to a different set of end products. The highly coordinated biosynthesis of adenine and guanine nucleotides provides examples of negative and positive effects of end products of each pathway. 

---