Enzyme feedback inhibition

Many enzymes xmAexgo feedback inhibition, in which a high concentration of enzyme reaction prodnct slows down or stops enzyme activity. Compare the action of a furnace thermostat to enzyme feedback inhibition. 

Catecholamine biosynthesis begins with the uptake of the amino acid tyrosine into the sympathetic neuronal cytoplasm, and conversion to DOPA by tyrosine hydroxylase. This enzyme is highly localized to the adrenal medulla, sympathetic nerves, and central adrenergic and dopaminergic nerves. Tyrosine hydroxylase activity is subject to feedback inhibition by its products DOPA, NE, and DA, and is the rate-limiting step in catecholamine synthesis the enzyme can be blocked by the competitive inhibitor a-methyl-/)-tyrosine (31). 

In this scheme, F symbolizes an essential metabolite, such as an amino acid or a nucleotide. In such systems, F, the essential end product, inhibits enzyme 1, xAie first step in the pathway. Therefore, when sufficient F is synthesized, it blocks further synthesis of itself. This phenomenon is called feedback inhibition or feedback regulation. 

In die metabolic pathway to an amino add several steps are involved. Each step is die result of an enzymatic activity. The key enzymatic activity (usually die first enzyme in the synthesis) is regulated by one of its products (usually die end product, eg die amino add). If die concentration of die amino add is too high die enzymatic activity is decreased by interaction of die inhibitor with the regulatory site of die enzyme (allosteric enzyme). This phenomenon is called feedback inhibition. 

Enzymes in the pathway to L-phenylalanine are subject to feedback inhibition by products (amino adds) arising from pathway intermediates. 

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. 

Feedback inhibition refers to inhibition of an enzyme in a biosynthetic pathway by an end product of that pathway. For example, for the biosynthesis of D from A catalyzed by enzymes EnZj through Enz3,... 

Figure 9-4. Sites of feedback inhibition in a branched biosynthetic pathway. Si-Sj are intermediates in the biosynthesis of end products A-D. Straight arrows represent enzymes catalyzing the indicated conversions. Curved arrows represent feedback loops and indicate sites of feedback inhibition by specific end products.

Figure 9-5. Multiple feedback inhibition in a branched biosynthetic pathway. Superimposed on simple feedback loops (dashed, curved arrows) are multiple feedback loops (solid, curved arrows) that regulate enzymes common to biosynthesis of several end products.

Acetyl-CoA carboxylase is an allosteric enzyme and is activated by citrate, which increases in concentration in the well-fed state and is an indicator of a plentiful supply of acetyl-CoA. Citrate converts the enzyme from an inactive dimer to an active polymeric form, having a molecular mass of several milhon. Inactivation is promoted by phosphorylation of the enzyme and by long-chain acyl-CoA molecules, an example of negative feedback inhibition by a product of a reaction. Thus, if acyl-CoA accumulates because it is not esterified quickly enough or because of increased lipolysis or an influx of free fatty acids into the tissue, it will automatically reduce the synthesis of new fatty acid. Acyl-CoA may also inhibit the mitochondrial tricarboxylate transporter, thus preventing activation of the enzyme by egress of citrate from the mitochondria into the cytosol. 

Since biosynthesis of IMP consumes glycine, glutamine, tetrahydrofolate derivatives, aspartate, and ATP, it is advantageous to regulate purine biosynthesis. The major determinant of the rate of de novo purine nucleotide biosynthesis is the concentration of PRPP, whose pool size depends on its rates of synthesis, utilization, and degradation. The rate of PRPP synthesis depends on the availabihty of ribose 5-phosphate and on the activity of PRPP synthase, an enzyme sensitive to feedback inhibition by AMP, ADP, GMP, and GDP. 

As the rate-limiting enzyme, tyrosine hydroxylase is regulated in a variety of ways. The most important mechanism involves feedback inhibition by the catecholamines, which compete with the enzyme for the pteridine cofactor. Catecholamines cannot cross the blood-brain barrier hence, in the brain they must be synthesized locally. In certain central nervous system diseases (eg, Parkinson s disease), there is a local deficiency of dopamine synthesis. L-Dopa, the precursor of dopamine, readily crosses the blood-brain barrier and so is an important agent in the treatment of Parkinson s disease. 

Section 5.3.2.3) combined with over-expression of IPPI resulted in enhanced astaxanthin accnmnlation to 1.4 mg/g dry cell weight (DCW). Further increases to 45 mg/g DCW were obtained by random mutagenesis of GGPPS, perhaps by altering enzyme response to substrate-level feedback inhibition. 

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... 

Aiming at a computer-based description of cellular metabolism, we briefly summarize some characteristic rate equations associated with competitive and allosteric regulation. Starting with irreversible Michaelis Menten kinetics, the most common types of feedback inhibition are depicted in Fig. 9. Allowing all possible associations between the enzyme and the inhibitor shown in Fig. 9, the total enzyme concentration Er can be expressed as... 

Aspartate transcarbamoylase (ATCase) from Escherichia coli is the most studied and best known regulatory enzyme. Yates and Pardee (1956) were the first to propose that the activity of ATCase is controlled by end product inhibition. This feedback inhibition was later studied in more detail by Gerhart and Pardee (1961, 1962, 1963). The three-dimensional structure of ATCase was determined by Lip-scombe and his coworkers [Wiley etal. (1971), Wiley and Lipscomb (1968), Warren etal. (1973)]. 

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... 

Metabolism is tightly regulated by a number of mechanisms feedback inhibition, compartmentalization, covalent modification of enzymes (e.g., phosphorylation), and hormone action, among others. 

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... 

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