Feedback inhibition, of enzyme

Figure 11-3 Feedback inhibition of enzymes involved in the biosynthesis of threonine, isoleucine, methionine, and lysine in E. coli. These amino acids all arise from L-aspartate, which is formed from oxaloacetate generated by the biosynthetic reactions of the citric acid cycle (Fig. 10-6). Allosteric inhibition. Q Repression of transcription of the enzyme or of its synthesis on ribosomes.

Table 1. Examples of Feedback Inhibition of Enzymes Involved in Biosynthetic Pathways...

Auxotrophic mutant lack one or more enzymes involved in the synthesis of amino acids (such as tyrosine). This prevents accumulation of the amino acid and thus avoids feedback inhibition of enzymatic steps in the L-phenylalanine pathway. 

The phorbol esters are useful for studying the function of PKC since they mimic the stimulatory effects of DAG on the enzyme. These tumor-promoting plant products and their synthetic derivatives are able to penetrate intact cells. Many inferences regarding the intracellular actions of PKC are based on results of studies on whole-cell preparations with the phorbol esters. These substances, like DAG, may produce feedback inhibition of signal transduction at a number of metabolic levels. Results of experiments using phorbol esters in whole cells are thus often complex and must be interpreted cautiously. Notwithstanding this consideration, based upon... 

Product Z binds to the first enzyme and forms a complex that is catalytically inactive. That shuts down the biosynthetic pathway. Should the amount of product Z diminish, the inhibition will be relieved and the pathway will again become active. This is an example of feedback inhibition of a metabolic pathway and is... 

To provide a mechanism for the feedback inhibition of these enzymes, the allosteric model was put forward in 1963. It was proposed that the enzyme that regulates the flux through a pathway has two distinct binding sites, the active site and a separate site to which the regulator binds. This was termed the allosteric site. The word allosteric means different shape , which in the context of this mechanism means a different shape from the substrate. The theory further proposed that when the regnlator binds to the allosteric site, it canses a conformational change in... 

Finasteride inhibits 5a-reductase, the enzyme converting T. into dihydrotestosterone (DHT). Thus, the androgenic stimulus is reduced in those tissues in which DHT is the active species (e.g., prostate). T.-dependent tissues or functions are not or hardly affected (e.g., skeletal muscle, negative feedback inhibition of gonadotropin secretion, and libido). Finasteride can be used in benign prostate hyperplasia to shrink the gland and, possibly, to improve micturition. 

Cumulative Feedback Inhibition In cumulative feedback inhibition, the end products can inhibit the reaction of the target enzyme separately. Many textbooks erroneously indicate that the cumulative feedback inhibition of E. coli glutamine synthetase involves separate regulatory sites for each feedback inhibitor. See Cumulative Feedback Inhibition... 

Fig. 2.2. Feedback inhibition of a metabolic pathway. In feedback inhibition, the final product, E, of a metabolic path acts as an inhibitor of an early reaction in a cycle, which in the figure leads eventually to the formation of E with the aid of enzymes El, E2, etc. E acts as an effector on the enzymes El and E2 to inhibit their activity.

The flow of metabolites through the citric acid cycle is under stringent regulation. Three factors govern the rate of flux through the cycle substrate availability, inhibition by accumulating products, and allosteric feedback inhibition of the enzymes that catalyze early steps in the cycle. 

The most responsive regulation of amino acid synthesis takes place through feedback inhibition of the first reaction in a sequence by the end product of the pathway. This first reaction is usually irreversible and catalyzed by an allosteric enzyme. As an example, Figure 22-21 shows the allosteric regulation of isoleucine synthesis from threonine (detailed in Fig. 22-15). The end product, isoleucine, is an allosteric inhibitor of the first reaction in the sequence. In bacteria, such allosteric modulation of amino acid synthesis occurs as a minute-to-minute response. 

The reaction catalyzed by aspartate carbamoyl transferase, and the feedback inhibition of this enzyme in E. coli by the end product of the pathway, CTP. The series of small arrows represents additional... 

FIGURE 3.3 L-Phenylalanine-mediated feedback inhibition of wild-type Escherichia coli K12 prephenate dehydratase (JN302) and four feedback inhibition-resistant enzyme variants (JN305-JN308). Activity is expressed as a percentage of normal wild-type enzyme activity. 

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