Concerted inhibition

Another example is the concerted inhibition model illustrated in the following scheme ... 

Allosteric regulation can be considerably more complex. An example is the remarkable set of allosteric controls exerted on glutamine synthetase of E. coli (Fig. 22-6). Six products derived from glutamine serve as negative feedback modulators of the enzyme, and the overall effects of these and other modulators are more than additive. Such regulation is called concerted inhibition. 

Three major feedback mechanisms cooperate in regulating the overall rate of de novo purine nucleotide synthesis and the relative rates of formation of the two end products, adenylate and guanylate (Fig. 22-35). The first mechanism is exerted on the first reaction that is unique to purine synthesis—transfer of an amino group to PRPP to form 5-phosphoribosylamine. This reaction is catalyzed by the allosteric enzyme glutamine-PRPP amidotransferase, which is inhibited by the end products IMP, AMP, and GMP. AMP and GMP act synergisti-cally in this concerted inhibition. Thus, whenever either AMP or GMP accumulates to excess, the first step in its biosynthesis from PRPP is partially inhibited. 

The glutamine synthetase of E. coli is independently modulated by various products of glutamine metabolism (see Fig. 22-6). In this concerted inhibition, the extent of enzyme inhibition is greater than the sum of the separate inhibitions caused by each product. For E. coli grown in a medium rich in histidine, what would be the advantage of concerted inhibition ... 

Either end product alone has no effect at all on Ei, but when both are present, enzyme activity is markedly reduced. Concerted inhibition may be an extreme case of cooperative inhibition where the binding of one end product greatly increases the affinity of the enzyme for the other end product. That is, at low levels of I alone only a negligible amount of EI forms at low levels of X alone only a negligible amount of Ex forms. At low levels of I plus X a large proportion of the enzyme becomes tied up as the dead-end EIX and/or EIXS complexes. An alternate model for concerted inhibidon is as follows EI and EX bind S just as well as E EIS and EXS function just as well as ES, but EIX (formed only when I and X are both present) does not bind S, or EIXS is catalytically inactive. 

In experimental animals, initiation of OPIDN requires the concerted inhibition and aging of greater than 70% of neural NTE after single exposures [3,7,31],... 

Six products derived from glutamine serve as negative feedback modulators of the enzyme, and the overall effects of these and other modulators are more than additive. Such regulation is called concerted inhibition. 

Shiio, I. and Ozaki, H. (1968) Concerted inhibition of isocitrate dehydrogenase by glyoxylate plus oxalacetate. 

Sauer U, Eikmanns BJ (2005) The PEP-pyruvate-oxaloacetate node as the switch point forctubon flux distribution in bacteria. EEMS Microbiol Rev 29 765—794 Schrumpf B, Schwarzer A, Kalinowski J, Puhler A, Eggeling L, Sahm H (1991) A functionally split pathway for lysine synthesis in Corynebacterium glutamicium. J Bacteriol 173 4510-4516 Shiio I, Miyajima R (1969) Concerted inhibition and its reversal by end products of aspartate kinase in Brevibacterium flavum. J Biochem 64 849-859 Shinfuku Y, Sorpitipom N, Sono M, Furusawa C, Hirasawa T, Shimizu H (2009) Development and experimental verification of a genome-scale metaboUc model for Corynebacterium glutamicum. Microb Cell Fact 8 43-57... 

Yoshida A, Tomita T, Kurihara T, Fushinobu S, Kuzuyama T, Nishiyama M (2007) Structural insight into concerted inhibition of a2 32-type aspartate kinase from Corynebacterium glutamicum. J Mol Biol 368 521-536... 

Three hormones regulate turnover of calcium in the body (22). 1,25-Dihydroxycholecalciferol is a steroid derivative made by the combined action of the skin, Hver, and kidneys, or furnished by dietary factors with vitamin D activity. The apparent action of this compound is to promote the transcription of genes for proteins that faciUtate transport of calcium and phosphate ions through the plasma membrane. Parathormone (PTH) is a polypeptide hormone secreted by the parathyroid gland, in response to a fall in extracellular Ca(Il). It acts on bones and kidneys in concert with 1,25-dihydroxycholecalciferol to stimulate resorption of bone and reabsorption of calcium from the glomerular filtrate. Calcitonin, the third hormone, is a polypeptide secreted by the thyroid gland in response to a rise in blood Ca(Il) concentration. Its production leads to an increase in bone deposition, increased loss of calcium and phosphate in the urine, and inhibition of the synthesis of 1,25-dihydroxycholecalciferol. 

Hundreds of metabohc reac tions take place simultaneously in cells. There are branched and parallel pathways, and a single biochemical may participate in sever distinct reactions. Through mass action, concentration changes caused by one reac tion may effect the kinetics and equilibrium concentrations of another. In order to prevent accumulation of too much of a biochemical, the product or an intermediate in the pathway may slow the production of an enzyme or may inhibit the ac tivation of enzymes regulating the pathway. This is termed feedback control and is shown in Fig. 24-1. More complicated examples are known where two biochemicals ac t in concert to inhibit an enzyme. As accumulation of excessive amounts of a certain biochemical may be the key to economic success, creating mutant cultures with defective metabolic controls has great value to the produc tion of a given produc t. 

The fact that the conversion of (85) to (86) proceeds with greater than 90% retention of optical activity would seem to favor the concerted mechanism.(B9> However, Schuster and Brizzolara<61) have pointed out that the examination of molecular models clearly indicates that the angular methyl (or other group) would strongly inhibit the rotation that is necessary for formation of the new 1,5 bond in the lumiketone from other than the bottom side of the molecule ... 

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