Cooperative inhibition

Tortora G, Caputo R, Damiano V, et al. Specific Inhibition of EGFR Tyrosine Kinase with ZD1839 ( Iressa ) Combined with a Protein Kinase a Antisense and the Novel Taxane IDN5109 Causes Cooperative Inhibition of Tumour Growth and Angiogenesis. Proceedings of the AACR, Vol. 42, March 2001. abstract 4315. 

ZO204 Buimovici-Klein, E., V. Mohan, M. Lang, E. Fenamore, Y. Inada, and L. Z. Cooper. Inhibition of HIV replication in lymphocyte cultures of virus-positive subjects in the presence of sho-saiko-to, an oriental plant extract. Antiviral Res 1990 14(4/5) 279-286. 

Ansari, S., El-Mezgueldi, M., and Marston, S. (2003). Cooperative inhibition of actin filaments in the absence of tropomyosin./. Muscle Res. Cell. Motil. 24, 513-520. 

Murakami, G., Watabe, T., Takaoka, K., Miyazono, K., and Imamura, T. 2003. Cooperative inhibition of bone morphogenetic protein signaling by Smurf 1 and inhibitory Smads. Mol. Biol. Cell. 14 2809-2817. 

Each end product, I and X, inhibits Ei. At saturating levels of either one, the velocity can be driven to zero. Mixtures of I and X at low concentrations are more inhibitory than the same total specific concentration of I or X alone. That is, if 35% inhibition is observed at [I] = 6 Kj and [X] = 0 and if 35% inhibition is observed at [X] = 6 Kx and [I) = 0, then at [I] = 3 Ki plus [X] = 3 Kx, the inhibition will be greater than 35%. Cooperative inhibition implies that I and X are not mutually exclusive. Both end products can combine with Ei simultaneously to form dead-end EIX and/or EIXS complexes. 

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. 

Cooperative inhibition Growth-dependent changes in pattern... 

Although each of the branched-chain amino acids will inhibit plant growth to some extent, the combination of leucine plus valine or leucine plus isoleucine is particularly effective (Table VII,B). In contrast, the combination of all three branched-chain amino acids or valine plus isoleucine is only slightly inhibitory. An explanation of these effects is provided by examination of the known regulatory mechanisms associated with the biosynthetic pathways (Fig. 8). Leucine plus valine cooperatively inhibits both acetohy-droxyacid synthase and plant growth (Miflin, 1969a,b). Inhibition of the enzyme would result in an isoleucine limitation. Since inhibition of the enzyme by either leucine or valine may be enhanced by the presence of isoleucine, the combination of leucine plus isoleucine would tend to limit valine biosyn-... 

FIGURE 19.8 At high [ATP], phosphofruc-tokinase (PFK) behaves cooperatively, and the plot of enzyme activity versus [frnctose-6-phos-phate] is sigmoid. High [ATP] thus inhibits PFK, decreasing the enzyme s affinity for frnc-tose-6-phosphate. 

Supra-additivity This is a special case of cooperation where the blockade of a single receptor is not sufficient to reduce the overall response. Capsaicin-induced nonadrenergic, noncholinergic contraction in the guinea pig ileum or common bile duct can be inhibited only when at least two different TK receptors are blocked (e.g., NKX + NK2, NKX + NK3, NK2 + NK3)... 

Multiple feedback loops can provide additional fine control. For example, as shown in Figure 9—5, the presence of excess product B decteases the tequitement for substrate 3. Howevet, Sj is also tequited fot synthesis of A, C, and D. Excess B should thetefote also curtail synthesis of all font end products. To circumvent this potential difficulty, each end product typically only partially inhibits catalytic activity. The effect of an excess of two or more end products may be strictly additive or, alternatively, may be greater than their individual effect (cooperative feedback inhibition). 

Amir, H. et ah. Lycopene and 1,25-dihydroxyvitamin D3 cooperate in the inhibition of cell cycle progression and induction of differentiation in HL-60 leukemic cells, Nutr. Cancer, 33, 105, 1999. 

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