Bongkrekic acid

Table 7.3. Effects of various inhibitors on [a32P]ADP uptake into E. coli cells expressing several adenine nucleotide carriers. E. coli cells were preincubated for 10 min with lysozyme (2.5 mg/ml) to allow penetration of the reagents across the outer membrane. The inhibitors used were bongkrekic acid (BKA, 50 pM), carboxyatractyloside (CAT, 1 mM), N-elhylmaleimide (NEM, 1 mM), pyridoxal 5 -phosphate (PLP, 2 mM), and mersalyl (100 pM). [a32P]ADP uptake by AAC2(A.t.), AACKN.sp.), HMP31(Tg.), and ANTI (H.h.) was measured at a substrate concentration of 10, 100, 50, and 200 pM, respectively (Voncken et al. 2002 Tjaden et al. 2004 Leroch et al. 2005 Leroch 2006)...

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-... 

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. 

As an illustration of the flexibility available in making secondary alcohols, one synthesis of bongkrekic acid, a highly toxic compound that inhibits transport across certain membranes in the... 

L-Bongkrekic acid) Pseudomonas cocovenenans ADP/ ATP-TR [very toxic]... 

Bongkrekic acid is a toxic compound produced by Pseudomonas cocovenenans, and isolated from a mold that grows on bongkrek, a fermented Indonesian coconut dish, (a) Label each double bond in bongkrekic acid as E or Z. (b) Label each tetrahedral stereogenic center as R or S. (c) How many stereoisomers are possible for bongkrekic acid ... 

ATP-ADP translocase is specifically inhibited by very low concentrations of atractyloside (a plant glycoside) or bongkrekic acid (an antibiotic from a mold). Atractyloside binds to the translocase when its nucleotide site faces the cytosol, whereas bongkrekic acid binds when this site faces the mitochondrial matrix. Oxidative phosphorylation stops soon after either inhibitor is added, showing that ATP-ADP translocase is essential. 

The essential role of cytochrome c release from injured mitochondria in the activation of caspase 9 has been alluded to above. This pathway is especially important in proapoptotic stimuli that are not initiated by surface receptors for apoptosis, such as UV irradiation, and may involve mitochondrial dependent pathways [83]. Continued respiration in the presence of an open mitochondrial pore may result in the generation of reactive oxygen species. Release of cytochrome c may be mediated by the opening of the mitochondrial FT pore, a non-selective channel whose composition is only partially defined [84]. Inhibitors of FT pore opening, such as cyclosporine, which binds to the adenine nucleotide translocator (ANT), a component of the FT pore, and bongkrekic acid, as well as Bcl-2, prevent cytochrome c release and inhibit apoptosis [85] whereas activators of the FT pore, such as atractyloside and Bax induce it [86]. Oxidants can rupture the outer membrane of mitochondria and release caspase-activating proteins [87]. Some studies have shown cytochrome c release before collapse of the mitochondrial membrane potential [83] suggesting alternate control of the FT pore. Many, but not all, of the members of the Bd-2 family of proteins reside in the inner mitochondrial membrane, form ionic channels in hpid membranes and increase rates of proton extrusion in mitochondria [88] and thus may control the FT pore. The antiapoptotic and mitochondrial affects of Bd-2 are independent of caspase activity as they occur in the presence of caspase inhibitors and also in yeast that lack caspases [86]. 

Inhibitors of adenine nucleotide (ATP/ADP) translocation. Bongkrekic acid binds to the ATP binding site, whereas atractyloside binds to the ADP binding site of the translocator. 

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