Negative allosteric effectors

PFK is activated by AMP (the precursor for ADP and ATP) and by F26BP (which also acts as a positive allosteric effector ) but is inhibited by ATP, citrate and lowered pH ( end products of the pathway), ATP and citrate acting as negative allosteric effectors . In contrast FBPase is activated by citrate (a positive allosteric effector ) and inhibited by the plenty signal F26BP (a negative allosteric effector ). 

This relatively small group of drug targets is especially important because, besides agonists and competitive antagonists, both positive and negative allosteric effectors have been developed with therapeutic relevancies. 

To avoid this waste of energy, the cell uses feedback inhibition, in which the product can shut off the entire pathway for its own s)mthesis. This is the result of the fact that the product, F, acts as a negative allosteric effector on one of the early enz)unes of the pathway. For instance, enzyme Ej may have an effector-binding site for E in addition to the active site that binds to A. When E is present in excess, it binds to the effector-binding site. This binding causes the active site to close so that it cannot bind to substrate A. Thus A is not converted to B. If no B is produced, there is no substrate for enzyme 2, and the entire pathway ceases to operate. The product, E, has turned off all the steps involved in its own s)mthesis, just as the heat produced by the furnace is ultimately responsible for turning off the furnace itself. 

Adenine is a negative, allosteric effector for the enzyme and at the same time also an effector of the cooperativity of V2 for thymidine. The originally negative substrate binding cooperativity of the enzyme for thymidine is transformed into a positive one. 

Common natural inhibitors of ribonucleotide reduction are the negative allosteric effectors dATP, dTTP, and to a lesser extent, dGTP. Several less defined substances interfering with dQOxyribonucleotide formation in vitro have been observed in extracts of yeast, wheat, and rodent cells . Some of these inhibitory fractions had spectral or chemical properties resembling nucleotides while others were tentatively identified as protein Celltilar as well as synthetic RNA efficiently inhibits ribonuc-... 

Citric acid a key metabolic intermediate in the tricarboxylic acid cycle. Its concentration also coordinates several other metabolic pathways. Sufficiently high concentrations of C.a. allosterically activate acetyl-CoA carboxylase (EC 6.4.1.2), the key enzyme in fatty acid biosynthesis. C. a. is a negative allosteric effector of 6-phosphofructokinase (EC 2.7.1.11), the key enzyme of glycolysis. C. a. forms complexes with various cations, particularly iron and calcium. In animals, dietary C. a. improves the utilization of dietary calcium. In bacteria, C. a. can be hydrolysed by ATP citrate lyase (EC 4.1.3.8) and citrate pro-(35)-lyase (EC 4.1.3.6) (Fig.). 

Allosteric interaction of enzyme and endproduct, which acts as a negative allosteric effector. 

Allosteric enzymes are regulated by molecules called effectors (also modifiers) that bind noncovalently at a site other than the active site. These enzymes are composed of multiple subunits, and the regula tory site that binds the effector may be located on a subunit that is not itself catalytic. The presence of an allosteric effector can alter the affinity of the enzyme for its substrate, or modify the maximal cat alytic activity of the enzyme, or both. Effectors that inhibit enzyme activity are termed negative effectors, whereas those that increase enzyme activity are called positive effectors. Allosteric enzymes usually contain multiple subunits, and frequently catalyze the commit ted step early in a pathway. 

Fig. 9-10 Behavior of an MWC allosteric enzyme in the presence of positive and negative heterotropic effectors. The activator term, y, in Eq. (9.62) causes the curve to become more hyperbolic, whereas the inhibitor term (j3) renders it more sigmoidal. The curves were constructed using Eq. (9.62) with L = 1,000 and n - 4.

The committed (rate-controlling) step is the biotin-dependent carboxylation of acetyl-CoA by acetyl-CoA carboxylase. Important allosteric effectors are citrate (positive) and long-chain acyl-CoA derivatives (negative). 

Allosteric effectors Molecules that bind to enzymes or protein carriers at sites other than the active or ligand binding site. On binding, allosteric effectors either positively or negatively affect the enzymatic activity or capability of the protein to bind its ligand. 

Many proteins are regulated by molecules which bind somewhere other than at the active site and either inerease or decrease protein activity. These allosteric ejfectors are often quite specific and may have either a positive or negative effect upon protein activity. C ass cdX feedback inhibition cycles in metabolism generally involve heterotropic allostery, in which a molecule produced near the end of a metabolic pathway acts as an allosteric effector to regulate a protein active earlier in the same pathway. Because of the need for very precise control of the energy charge of the cell, ATP and ADP serve as allosteric effectors for several of the proteins of glucose metabolism. Protons and ions act as allosteric effectors in many... 

Phosphofructokinase activity is sensitive to both positive and negative allosterism. For instance, when ATP is present in abundance, a signal that the body has sufficient energy, it binds to an effector binding site on phosphofructokinase. This inhibits the activity of the enzyme and, thus, slows the entire pathway. An abundance of AMP (adenosine monophosphate), which is a precursor of ATP, is evidence that the body needs to make ATP to have a sufficient energy supply. When AMP binds to an effector binding site on phosphofructokinase, enzyme activity is increased, speeding up the reaction and the entire pathway. 

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