Proteins synthesis blockage

Sulforaphane nitrile (R(CN)-N=C = S) Pro-inflammatory protein synthesis blockage (For many inhibitors of NFKB-mediated iNOS COX expression see Tables 7.3 8.1) From Glucoraphanin Induces GST, NADPH quinone reductase [indirect AO] 14.4B... 

This drug has a direct amebicidal effect against trophozoites E. histolytica in tissues, and it is not active against cysts in either the lumen or intestinal walls, or in other organs. The mechanism of action of emetine consists of the blockage of protein synthesis in eukaryotic (but not in prokaryotic) cells. It inhibits the process of polypeptide chain formation. Protein synthesis is inhibited in parasite and mammalian cells, but not in bacteria. 

Activated PKB (Akt) phosphorylates the following proteins with the indicated anabolic consequences Bad phosphorylation yields P-Bad which then dissociates from a Bcl-2-Bcl-X] complex in the mitochondrial outer membrane and is sequestered by 14.3.3 proteins. Mitochondrial pore blockage by the Bad-free Bcl-2-Bcl-xL complex successively prevents cytochrome c release from mitochondria, blocks procaspase activation by cytochrome c and thus inhibits apoptosis and increases cell survival. Phosphorylation of p70S6 kinase by PKB results in activation of this PK, phosphorylation of ribosomal small subunit protein S6 and enhancement of translation (protein synthesis). Phosphorylation of glycogen synthase (GS) kinase 3 (GSK3) by PKB results in an inactive P-GSK3, a consequent increase in the amount of the active non-phosphorylated form of GS and increased glycogen synthesis. 

Phosphine is known to disrupt protein synthesis and enzymatic activity, particularly in lung and heart cell mitochondria. This can lead to a blockage of the mitochondrial electron transport chain. Phosphine may cause denaturing of various enzymes involved in cellular respiration and metabolism, and may be responsible for denaturing of the oxyhemoglobin molecule. 

An understanding of the biochemistry of peptidoglycan (PG murein) that comprises bacterial cell walls is very important medically since blockage of its synthesis was the first, and continues to be a primary, point of attack in the control of bacterial infection. In addition to inhibition of cell wall synthesis, antimicrobial drug s main mechanisms are interference with nucleic acid synthesis, inhibition of folate metabolism, and binding to ribosomes to disrupt protein synthesis (Table 16-2). 

The answer is c. (Murray, pp 123-148. Scriver, pp 2367-2424. Sack, pp 159-175. Wilson, pp 287-317.) The electron transport chain shown contains three proton pumps linked by two mobile electron carriers. At each of these three sites (NADH-Q reductase, cytochrome reductase, and cytochrome oxidase) the transfer of electrons down the chain powers the pumping of protons across the inner mitochondrial membrane. The blockage of electron transfers by specific point inhibitors leads to a buildup of highly reduced carriers behind the block because of the inability to transfer electrons across the block. In the scheme shown, rotenone blocks step A, antimycin A blocks step B, and carbon monoxide (as well as cyanide and azide) blocks step E. Therefore a carbon monoxide inhibition leads to a highly reduced state of all of the carriers of the chain. Puromycin and chloramphenicol are inhibitors of protein synthesis and have no direct effect upon the electron transport chain. 

Fig. 32-2. Cartoon depicting ricin (A—B) binding to coated pits on the surface of the cell (1), internalization via en-docytosis (2), and transport through the Golgi complex (3) and enzymatic inactivation of protein synthesis via cleavage of adenine residue (A4324), and blockage of elongation factor-2 binding (4). Arrows with indicate other possible routes of entry to the cytosol. Illustration Courtesy of Bob Wellner, PhD, Toxinology Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Md.

Narciclasine (22) halts protein synthesis by blockage of peptide-bond formation on the 60-S ribosomal subunit. The effect is specific for eucaryotic cells. Narciclasine inhibits Rauscher virus NIH/3T3 (Wink, 1993). Lycorine (8) blocks mitosis in the broad bean (Viciafaba). The mechanism appears to be related to inhibition of protein synthesis (Suffness and Cordell, 1985). Pretazettine (15) has been used in combination with DNA-binding and alkylating agents in the treatment of the Rauscher leukemia virus (Cordell, 1981 Martin, 1987). This alkaloid inhibits purified RNA-dependent DNA polymerase (reverse transcriptase) from avian myelo-... 

RUSS, U.L., OPPEEMM, H. and KOCH, G. Selective blockage of initiation of host protein synthesis in ERA virus-infected cells. Proc. Natl. Acad. Sci. U.S.A. (1975), li, 1258-1262. 

There are two issues of concern which are associated with irreversible MAOIs involving the display of liver toxicity, particularly with hydrazines, and the permanent inactivation of both MAO-A and -B isoforms. The replacement of MAOs requires protein synthesis which may take up to 14 days. From the antidepressant viewpoint, only a selective blockage of serotonin metabolism may be of interest in order to increase serotonin availability. However, this long-term effect significantly reduces metabolism of a variety of other biogenic amines, which leads to their accumulation, which is not necessarily desired. This leads to an excessive availability of tyramine and others, which ultimately leads to increased release of noradrenaline that may result in the stimulation of cardiovascular sympathetic nervous system activity. As a consequence, potentially fatal hypertensive crises and cerebral haemorrhage can occur (Fig. 18.22). This phenomenon has often been termed the cheese effect, in order to reflect the fact that tyramine is present in a variety of foods such as wine, cheese and other fermented food and drink products. It would appear, however, that under carefully controlled and restricted dietary conditions such a risk can be minimised. 

Chloro-9-cyclopentyl-8-azapurine inhibited synthesis of DNA, RNA, and protein in E. coli. Blockage of thymine-nucleotide formation was the first effect seen. Alkylation of enzymes by the 6-chloro substituent was suggested as a mechanism. This azapurine inhibited the RNA polymerase from E. coli, but not that from M. lysodeikticus. Formyltetrahydrofolate synthetases, of both mammalian and bacterial origins, were strongly inhibited. The same azapurine, at 0.3 mM, markedly inhibited the steroid-induced synthesis of A -3-ketosteroid isomerase in Pseudomonas testoster-oni ... 

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