Macromolecular inhibitors

Howell, D. S., Pita, J. C., Marquez, J. F., Gatter, R. A. Demonstration of macromolecular inhibitor (s) of calcification and nucleational factor (s) in fluid from calcifying sites in cartilage. J. Clin. Invest. 48, 630 (1969)... 

D. Stable Complexes—Inhibition—Activation 1. Macromolecular Inhibitors... 

S.A. Gillmob, T. Takeuchi, S.Q. Yang, C.S. Craik, R.J. Fletterick, Compromise and accommodation in ecotin, a dimeric macromolecular inhibitor of serine proteases. /. Mol. Biol. 2000, 299, 993-1003. 

S.Q. Yang, C.S. Craik, Engineering bi-dentate macromolecular inhibitors for trypsin and urokinase-type plasminogen... 

Garcia-Calvo M, et al. Inhibition of human caspases by peptide-based and macromolecular inhibitors. J. Biol. Chem. 1998 273 32608-32613. 

The ubiquitous occurrence of proteinases is accompanied by a similar distribution of fairly specific proteins that inhibit these enzymes. In normal health, there is a delicate balance between the levels of enzymes and their macromolecular inhibitors. This balance is particularly important in the blood-clotting clot-lysis scheme. Since the total volume of blood in the adult human body is only about 5 1, a massive response is required in the event of an injury that results in a rapid haemorrhage. Some positive feedback is present in the blood-clotting mechanism in order to achieve this rapid response, but clearly this must be sensitively controlled by endogenous inhibitors if a thrombosis is not to occur. 

F. Rypdcek, W. R. Banks, D. Noskovd and G. A. Digenis, Synthetic macromolecular inhibitors of human-leukocyte elastase. 1. Synthesis of peptidyl carbamates boimd to water-soluble polymers — poly-a,jS-[N-(2-hydroxyethyl)-D,L-aspartamide] and poly-a-[N -(2-hydroxyethyl)-L-glutamine],/. Med. Chem., 37, 1850-1856 (1994). 

Reaction with a macromolecular inhibitor of trypsin Reaction with a cyclic imidocarbonate derivative of Sephadex... 

For many proteins, a purified protein standard is ideal and straightforward to incorporate since the concentration is known. However, in reality such standard/ sample accord is often not possible to obtain because the antigen contained in the sample may be a mixture of species. For example, it may come in a variety of molecular sizes (e.g. monomeric versus oligomeric forms of immimoglobulin A), or it may exist in complexes with other molecules (e.g. a protease bound to a macromolecular inhibitor, or a ligand bound to its soluble receptor), or as a... 

A purification and some properties of proteinase A from yeast are described. A specific macromolecular inhibitor of proteinase A from yeast cytosol has been isolated and shown to be a protein (molecular weight 7,700) consisting of a majority of polar amino acids. Proline, arginine, cysteine and tryptophan were not detected in the inhibitor. Possible biological functions of proteinase A and the proteinase A-inhibitor (and of other yeast proteinases and their inhibitors) in the following processes are discussed general protein turnover, catabolite inactivation of enzymes, enzyme degradation at starvation and at transition to spore formation, and activation of pre-enzymes and precursor proteins by limited proteolysis. 

Fujita K, Murakami Y, Hayashi S (1982) A macromolecular inhibitor of the antizyme to ornithine decarboxylase. Biochem J 204 647-652... 

As already shown, it is technically possible to incorporate additive functional groups within the structure of a polymer itself, thus dispensing with easily extractable small-molecular additives. However, the various attempts of incorporation of additive functionalities into the polymer chain, by copolymerisation or free radical initiated grafting, have not yet led to widespread practical use, mainly for economical reasons. Many macromolecular stabiliser-functionalised systems and reactive stabiliser-functionalised monomers have been described (cf. ref. [576]). Examples are bound-in chromophores, e.g. the benzotriazole moiety incorporated into polymers [577,578], but also copolymerisation with special monomers containing an inhibitor structural unit, leading to the incorporation of the antioxidant into the polymer chain. Copolymers of styrene and benzophenone-type UV stabilisers have been described [579]. Chemical combination of an antioxidant with the polymer leads to a high degree of resistance to (oil) extraction. 

Scheme 2 Bolland-Gee scheme of free radical oxidation of polymer pH. P denotes macromolecular chain, InH is chain-breaking inhibitor, D peroxide decomposer and parameters above arrows are the corresponding rate constants.

Figure 12.2 Effect of a translational inhibitor on in vivo macromolecular syntheses. Levels of ( ) Protein, (O) RNA, ( ) DNA, and (A) cell wall synthesized by B. subtilis in vivo after addition of the antibiotic (time 0). In each case, the level of synthesis in the presence of the antibiotic is normalized with respect to the level obtained in its absence and plotted as a function of the time elapsed after the addition of the antibiotic. The figure is taken from Brandi et al. (2006a).

TNF-a elicits a wide range of responses in cells and tissues. Apart from causing the lysis of certain tumours (by mechanisms probably related to the ability of the target to induce the synthesis of the mitochondrial manganese-dependent superoxide dismutase, Mn-SOD), it can also kill normal cells. These effects on normal cells are more apparent when biosynthesis is blocked - for example, by the addition of inhibitors of macromolecular bio-... 

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