Arsenic pathway

An important tool for elucidating the steps in the pathway was the use of metabolie inhibitors. Adding an enzyme inhibitor to a cell-free extract caused an accumulation of intermediates in the pathway prior to the point of inhibition (Figure 18.12). Each inhibitor was specific for a particular site in the sequence of metabolic events. As the arsenal of inhibitors was expanded, the individual steps in metabolism were revealed. 

Yang H-C, J Cheng, TM Finan, BP Rosen, H Bhattacharjee (2005) Novel pathway for arsenic detoxification in the legume symbiont Sinorhizobium meliloti. J Bacterial 187 6991-6997. 

In the preceding sections it has been shown — using the imidazolides as examples - that azolides can be prepared easily by a number of different reaction pathways. In view of the higher or lower reactivities of other members of the azolide family it becomes evident that this class of compounds contributes to a powerful arsenal in synthetic organic chemistry. The various reactions these azolides undergo are dealt with in detail in the chapters that follow. Since imidazolides are utilized for most of the azolide reactions, certain additional information is provided here for this particular group of the azolides. 

The reaction wtih As4, generated by vaporization of metallic arsenic into cold toluene, has so far been reported only for l.101 Two principal products (79%) were formed in 1 3 ratio the bicyclobutane 72 and the remarkable compound 73 (Scheme 19). The structure of the latter was established by X-ray crystallography. It appears to be an intermediate on the reaction pathway, since long heating at 95°C converted it completely to 72. 

A common pathway has been tentatively put forward to account for both the arsenic and phosphorus reaction products (Scheme 20). Breaking of two bonds to one of the atoms in the P4 or As4 tetrahedron would lead... 

Platinum complexes are cytotoxic agents yet the paradigm in cancer chemotherapy has moved to a more targeted approach, with special emphasis on signaling pathways. In this respect a remarkable story is that of arsenic trioxide, As203 (Trisenox, Cell Therapeutics Inc, Seattle, USA) which was approved by the FDA in September 2000 for treatment of acute promomyelo-cytic leukemia (APL) in patients who have relapsed or are refractory to retinoid and anthracycline chemotherapy. An estimated 1,500 new cases of APL are diagnosed yearly in the US, of which an... 

Thomas, D. J., Waters, S. B., and Styblo, M., Elucidating the pathway for arsenic methyla-tion, Toxicol. Appl. Pharmacol., 198, 319, 2004. 

Simeonova, P. P. et al., c-Src-dependent activation of the epidermal growth factor receptor and mitogen-activated protein kinase pathway by arsenic. Role in carcinogenesis, J. Biol. Chem., 277, 2945, 2002. 

Liao, W. T. et al., Arsenic induces human keratinocyte apoptosis by the FAS/FAS ligand pathway, which correlates with alterations in nuclear factor-kappa B and activator protein-1 activity, J. Invest. Dermatol, 122,125, 2004. 

Barchowsky, A. et al., Low levels of arsenic trioxide stimulate proliferative signals in primary vascular cells without activating stress effector pathways, Toxicol. Appl. Pharmacol., 159, 65, 1999. 

Tanaka-Kagawa, T. et al., Arsenite and arsenate activate extracellular signal-regulated kinases 1/2 by an epidermal growth factor receptor-mediated pathway in normal human keratinocytes, Br. J. Dermatol., 149, 1116, 2003. 

Figure 8.16 Arsenic and nitrogen compete for electrons both for and from the natural relay cycles in the body. The overall rate at which electrons are transferred by the nitrogen will alter when arsenic competes for them. The arsenic is poisonous, since these two pathways yield different products...

The answer is A. This patient exhibits several signs of acute arsenic exposure, including the cholera-like gastrointestinal symptoms and probable dehydration. He may currently be in hypovolemic shock and beginning chelation therapy is the only recourse. Arsenic is a metabolic toxin because it inhibits enzymes that require lipoic acid as a coenzyme the PDH complex, the a-ketoglutarate dehydrogenase complex, and trans-ketolase of the pentose phosphate pathway. 

Crameri, A., S.A.Raillard, E.Bermudez and W.P.Stenuner. (1998) Molecular evolution of an arsenate detoxification pathway by DNA shuffling. Nature, 391, 288-291. 

According to Challenger (127), arsenate is transformed to trimethyl-arsine by the mold Scopulariopsis brevicaulis, by sequential reduction and oxidative methylation of the arsenic species (Fig. 7). The proposed intermediates in the pathway were MMA, DMA, and TMAO. Although Challenger could not detect these compounds, when they were added to a culture of S. brevicaulis trimethylarsine was formed. Challenger (129) considered that the likely source of methyl groups was S-adeno-sylmethionine (AdoMet), which had previously been identified as an... 

The source of the electrons in the reduction of arsenic outlined in Fig. 7 is not known, but a sound model involving reduction by thiols has been proposed (133). A reexamination of Challenger s proposed methylation pathway looked at the effects of adding low levels of As(III), As(V), MMA, and DMA to cultures of two microorganisms including... 

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