Piericidins

R.R. Ramsay, M.J. Krueger, S.K. Youngster, M.R. Gluck, J.E. Casida, T.P. Singer, Interaction of 1-methyl-4-phenylpyridinium ion (MPP-h) and its analogs with the rote-none/piericidin binding site of NADH dehydrogenase, J. Neurochem. 56 (1991) 1184-1190. 

Amytal (a barbiturate drug), rotenone (a plant product commonly used as an insecticide), and piericidin A (an antibiotic) inhibit electron flow from the Fe-S centers of Complex I to ubiquinone (Table 19-4) and therefore block the overall process of oxidative phosphorylation. 

Piericidin A DCMU Competes with QB for binding site in PSII... 

Interaction of l-methyl-4-phenylpyridinium ion (MPP+) and its analogs with the rotenone/piericidin binding site ofNADH dehydrogenase. J. Neurochem. 56 1184-1190. 

An N-l-diene-l-aza-1,3-butadiene was employed in a Diels-Alder reaction to synthesize the key intermediate, a tetrasubstituted pyridine, in the total synthesis of the pyridine-base natural product, piericidin (Scheme 53) <2005JA15704>. The concerted cyclization conditions were surprisingly mild, considering the steric demand of the dienophile and that the aromatization was not successful under a variety of basic conditions, but the Lewis acid cleanly affected the transformation. 

Evidence for the existence of an a-glycerophosphate oxidase system with three phosphorylation sites and sensitive to rotenone and piericidin A. FEBS Letters, 10 109-12. 

The action of some inhibitors is indicated in Figure 17.4. It is sometimes difficult to pinpoint exactly where an inhibitor may act, however, because our knowledge of the composition and function of the four complexes is far from complete. Complex I inhibitors, such as rotenone, piericidin A, and the barbiturates, are believed to inhibit the transfer of elctrons from the Fe-S centers to UQ. In complex III, antimycin appears to inhibit the reduction of UQ by cytochrome b. Myxothiazol and 2,3-dimercaptopropanol (BAL) inhibit the transfer of electrons from UQH2 to Rieske s protein, because they destroy the Fe-S centers. The action of cyanide and azide on complex IV is also unclear, but it is believed that these substances combine with the Fe3+ moiety of the a3 heme prosthetic group. 

The hetero-DielsAlder reaction (hDA) using iminium species has been commonly used for the synthesis of reduced pyridines and pyridones . The aza-1,3-butadiene 107 was employed in hDA reaction to synthesize the key intermediate 108 in the total synthesis of the pyridine-based natural product piericidin (Scheme 60) <2005JA15704>. The reaction of Danishefskys diene with N-functionalized imine 109 in the presence of (A)-BINOL zinc complex has been utilized to produce 4-piperidones 110 in moderate to high enantioselectivity (Scheme 61) <2004SL711>. 

Piericidins are the first compounds obtained by the screening search for insecticidal natural products among microbial metabolites.10 They were isolated from Streptomyces mobaraensis in 1963,11 and many piericidin derivatives have been found in microbial metabolites until now.12 Piericidins are not used as insecticides practically, but are important biological reagents because they have specific inhibitory activity toward the mitochondrial electron transport chain protein nicotinamide adenine dinucleotide (NADH)-ubiquinone reductase (complex I).13 Piericidin Ax (1 in Figure 1) is biosynthesized as a polyketide,14 but genes responsible for its biosynthesis are not yet identified. Total synthesis of piericidins A (1) was reported recently.15... 

Piericidin A Streptomyces sp. (fungus) ubiquinone ETC - NADH-UQOR... 

Palmer et al. (91) have suggested that in addition to the above site, rotenone and piericidin A also inhibit electron transport immediately on the substrate side of cytochrome Ci. This view has not been accepted by others. Teeter et al. (9 ) have shown that secondary effects of rotenone and piericidin can be observed at other regions of the respiratory chain when high concentrations of the inhibitors are used, as by necessity did Palmer et al. in their EPR experiments. 

The studies of Morgan, Singer, and their colleagues (19, 22, 23, 88, 93, 94) with radioactive piericidin A and rotenone have led these authors to the following conclusions ... 

Other aspects of rotenone and piericidin inhibition studied by Singer and co-workers are related more to submitochondrial particles than to complex I. These studies have been compiled in reviews (22, 23) by these investigators and will not be detailed here. 

The differences in the reduction of respiratory components with NADH or NADPH as substrate is reflected in the degree of bleaching afforded by these substrates at 475 minus 510 nm in complex I and rotenone-or piericidin-treated submitochondrial particles. Thus, as seen in Fig. 16 (left-hand trace), addition of NADH doubles the bleaching at 475 minus 510 nm obtained by addition of NADPH to piericidin-treated particles. The middle trace shows a similar effect when NAD is added instead of NADH. This results from the presence of transhydrogenase activity, which yields NADH from NAD and excess NADPH. In the right-hand... 

Fig. 16. Effect of palmitoyl-coenzyme A on reduction of chromophores at 475 minus 510 nm in ETP via NADPH to NAD transhydrogenation. Conditions ETP, 22 mg protein/ml NADPH, 60 /iM NADH, 60 nM NAD, 140 tiM sodium succinate, 1.75 mAf piericidin A, 5.3 iiM antimycin A, 1 nM 2-thenoyltrifluoroacetone (TTFA), 1 mJVf palmitoyl-CoA (P-CoA), 200 /xM. From Hatefi and Hanstein (80).

The absence of rotenone-piericidin sensitivity and coupling site 1 in... 

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