Atractyloside

Atractyloside inhibits oxidative phosphorylation by inhibiting the transporter of ADP into and ATP out of the mitochondrion (Figure 12-10). 

Atractyloside and bongkrekate inhibit the entry of ADP into the mitochondria. After all the ADP in the mitochondria has been converted to ATP, oxidative phosphorylation stops, since the ATP that s made can t get out and new ADP can t get in from the outside. 

A nucleotide transporter (located in the outer mitochondrial membrane) that mediates one-for-one transloca-tion/exchange of cytosolic ADP for mitochondrial ATP. This translocase is potently inhibited by atractyloside and bonkregic acid. 

Permeability transition pore Opening by reactive oxygen species, reactive nitrogen species, bile adds, ihio crosslinkers, atractyloside, betu-liniate, lonidamidem various anticancer drugs, to collapse mitochondrial membrane potential and activate mitochondrial apoptotic pathway... 

Toxicity. Atractyloside, a diterpenoid glycoside that occurs naturally in plants, may be present at levels as high as 600 mg/kg of dried plant material. Gonsumption of plants containing atractyloside or carboxyatractyl-oside has caused fatal renal proximal tubule necrosis and/or centrilobular hepatic necrosis in man and farm animals. Although pure atractyloside and crude plant extracts disrupt carbohydrate homeostasis and induce similar pathophysiological lesions in the kidney and liver, it is also possible that the toxicity of atractyloside may be confounded by the presence of other natural constituents in plants. Atractyloside competitively inhibits the adenine nucleoside... 

Fontana, G., G. Mantia, P. Vetri, F. Venturella, V. Hopps, and G. Cascio. Effects on the carbohydrate metabolism of coffee atractylosides . Fitote-rapia 1994 65(1) 29-33. 

Inhibition of ATP-ADP exchange Atractyloside Inhibits adenine nucleotide translocase... 

In the previous section we mentioned the ADP/ATP transporter, and it is also shown in Figure 17.2. This system allows the export of ATP and import of ADP. Because ATP and ADP have net charges of -4 and -3, respectively, at pH 7, the transport is not electroneutral and must occur at the expense of the membrane potential. Atractyloside and bongkrekic acid are inhibitors of this system, the former binding to the ADP binding site of the porter and the latter to the ATP site. Associated with ADP/ATP transport is the transport of P which must enter the mitochondrion to participate in ATP formation. Several systems for transport-... 

Thomson, R.H., 1971, Naturally occurring quinones. Academic Press, New York Vancompemolle, K., van Herreweghe, F., Pynaert, G., van de Craen, M., De Vos, K., Totty, N., Sterling, A., Fiers, W., Vandenabeele, P., and Grooten, J., 1998, Atractyloside-induced release of cathepsin B, a protease with caspase-processing activity. FEBSLett, 438 ISO-158... 

ATP out of and ADP into the mitochondrion. Translocation is inhibited by two well-known toxins, atractyloside and bongkrekic acid, the former a glucoside found in the Mediterranean thistle and the latter produced by a Pseudomonas bacterium. 

Phosphorylation of ADP to ATP by mitochondria is driven by an electrochemical proton gradient established across the inner mitochondrial membrane as a consequence of vectoral transport of protons from NADH and succinate during oxidation by the respiratory chain (see Chapter 17). Hence, lipophilic weak acids or bases (such as 2,4-dinitrophenol) that can shuttle protons across membranes will dissipate the proton gradient and uncouple oxidation from ADP phosphorylation. Intrami-tochondrial ADP can be rate-limiting as demonstrated by inhibition of the mitochondrial adenosine nucleotide carrier by atractyloside. Inhibition of ATP synthesis... 

The chemistry of atractyloside has been reviewed. A further relative (87) of cafestol has been isolated from green coffee beans. Sideritis (Labiatae) species have continued to attract attention as a source of diterpenoids. The comparative phytochemistry of Canary Island species has been reviewed. A number of 15-hydroxykaurenes (88)—(90) have been isolated from S. crispata, S. ilicifolia, and S. tragoriganum together with the atisine (91) and beyerene (92) derivatives, ent-18-Acetoxy-3/8,7a,15/S-trihydroxykaur-16-ene has also been obtained from S. scardica. 

F. Piozzi in Atractyloside, Chemistry, Biochemistry and Toxicology , ed. R. Santi and S. Luciani,... 

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