Enzyme synthesis, control

The nature of the molecular defect Is unclear and presumably lies In the repression mechanism for the gene controlling formation of the enzyme protein. Exposure to any of the drugs listed In Table V results In further marked de-repressIon of enzyme synthesis and severe porphyria. 

Although tremendous progress has been made in characterizing the enzymes that control the synthesis and metabolism of cyclic nucleotides in the nervous system, our understanding of the regulation and interaction of these systems is far from complete. Work is now needed to definitively characterize, for each of these enzyme sub-types, its unique distribution pattern in the brain as well as its distinct functional and regulatory properties. 

In both cases, the mixed anhydride is used to synthesize ATP from ADP. Hydrolysis of the anhydride liberates more energy than the hydrolysis of ATP to ADP and, therefore, can be linked to the enzymic synthesis of ATP from ADP. This may be shown mechanistically as a hydroxyl group on ADP acting as nucleophile towards the mixed anhydride, and in each case a new phosphoric anhydride is formed. In the case of succinyl phosphate, it turns out that GDP rather than ADP attacks the acyl phosphate, and ATP production is a later step (see Section 15.3). These are enzymic reactions therefore, the reaction and the nature of the product are closely controlled. We need not concern ourselves why attack should be on the P=0 rather than on the C=0. 

Expression of the HMG GoA reductase gene is controlled by a sterol-dependent transcription factor, which increases enzyme synthesis in response to low cholesterol levels. 

Some enzymes and carriers are synthesized only in response to the presence of the sugar, or of a structurally similar compound these enzymes and carriers are said to be inducible. Contrariwise, enzyme synthesis may be repressed by an increase in the concentration of ATP, or of some other metabolite. Induction and repression of enzymes and carriers provide two important kinds of control in metabolic regulation. 

The flow of intermediates through metabolic pathways is controlled by 1bir mechanisms 1) the availability of substrates 2) allosteric activation and inhibition of enzymes 3) covalent modification of enzymes and 4) induction-repression of enzyme synthesis. This scheme may at first seem unnecessarily redundant however, each mechanism operates on a different timescale (Figure 24.1), and allows the body to adapt to a wde variety of physiologic situations. In the fed state, these regulatory mechanisms ensure that available nutrients are captured as glycogen, triacylglycerol, and protein. 

Figure 11-1 Some control elements for metabolic reactions. Throughout the book modulation of the activity of an enzyme by allosteric effectors or of transcription and translation of genes is indicated by dotted lines from the appropriate metabolite. The lines terminate in a minus sign for inhibition or repression and in a plus sign for activation or derepression. Circles indicate direct effects on enzymes, while boxes indicate repression or induction of enzyme synthesis.

Synthesis of many enzymes is repressed most of the time. The appearance of an enzyme at a particular stage in the life of an organism as well as the differing distributions of isoenzymes within differentiated tissue result from derepression. The control of enzyme synthesis may also be exerted during the splicing of transcripts and at the translational level as well. These control mechanisms are often relatively slow, with response times of hours or even days. However, effects on the synthesis of some hormones, such as insulin (Section G), may be observed within a few minutes. 

Alkaline pyrophosphatase dependent on Mg2+ was found in every sample examined from a broad spectrum of the plant kingdom (SI). Plants which fix C02 by the dicarboxylic acid pathway have characteristic high levels of alkaline pyrophosphatase in their chloroplasts presumably this performs the rather specific function of driving the synthesis of phosphoenolpyruvate, the immediate precursor of C02 fixation (32). Biosynthesis of the maize chloroplast enzyme is controlled by light acting through the phytochrome system (S3). Pyrophosphatase from spinach chloroplasts has been partially purified (34, 35). 

In allosteric enzymes, the activity of the enzyme is modulated by a non-covalently bound metabolite at a site on a protein other than the catalytic site. Normally, this results in a conformational change, which makes the catalytic site inactive or less active. Covalent modulated enzymes are interconverted between active and inactive forms by the action of other enzymes, some of which are modulated by allosteric-type control. Both of these control mechanisms are responsive to changes in cell conditions and typically the response time in allosteric control is a matter of seconds as compared with minutes in covalent modulation. A third type of control, the control of enzyme synthesis at the transcription stage of protein synthesis (see Appendix 5.6), can take several hours to take effect. 

Fig. 5.38. The control of protein (enzyme) synthesis at the level of DNA transcription.

Fig. 5.39. The control of enzyme synthesis by catabolite repression. A control region of the lac operon contains the CAP binding site within the promoter region...

Cells regulate their metabolic activities by controlling rates of enzyme synthesis and degradation and by adjusting the activities of specific enzymes. Enzyme activities vary in response to changes in pH, temperature, and the concentrations of substrates or products, but also can be controlled by covalent modifications of the protein or by interactions with activators or inhibitors. 

Before closing we should point out that, over an extended period, dietary conditions can alter the levels of enzymes involved in fatty acid metabolism. For example, the concentrations of fatty acid synthase and acetyl-CoA carboxylase in rat liver are reduced four- to fivefold after fasting. When a rat is fed a fat-free diet, the concentration of fatty acid synthase is 14-fold higher than in a rat maintained on standard rat chow diet. Current evidence indicates that the levels of these enzymes are governed by the rate of enzyme synthesis, not degradation. It appears that synthesis of the enzyme, in turn, is controlled by the rate of transcription of DNA into mRNA. A question of current interest is how this transcription of DNA is regulated. 

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