Disease relevance of Piericidin A

• Piericidin-resistant mutants of the bacterium Rhodobacter capsulatus have been isolated and the present work demonstrates that a single missense mutation at the level of the gene encoding the peripheral 49-kDa/NUOD subunit of Complex I is definitely associated with this resistance [1].
• IT-143-A and B, novel piericidin-group antibiotics produced by Streptomyces sp [2].
• Acute toxicities of these substances in mice were lower than that of piericidin A1 [3].
• In the course of a screening program for inhibitors of epidermal growth factor (EGF)-induced phosphatidylinositol turnover in human epidermoid carcinoma cell line A431, we discovered two novel compounds of the piericidin family from the culture broth and mycelia of a Streptomyces strain MJ288-OF3 [4].

High impact information on Piericidin A

• Piericidin A sensitive delta psi formation has been demonstrated to be coupled to the NADH-MQ1 oxidoreductase in membrane vesicles of T. thermophilus HB-8 [5].
• MPP+ and its analogues have been shown to block electron transport at or near the same site as two powerful inhibitors of mitochondrial respiration, rotenone and piericidin A [6].
• The lesser protection by the more lipophilic MPP+ analogs with longer alkyl chains may involve a different orientation in the hydrophobic cleft, allowing rotenone and piericidin to still bind even when the pyridinium cation is in a position to interrupt electron flow from NADH to coenzyme Q [7].
• Based on this original observation, we propose a model locating the binding site for piericidin (and quinone) at the interface between the hydrophilic and hydrophobic domains of Complex I [1].
• Relation of superoxide generation and lipid peroxidation to the inhibition of NADH-Q oxidoreductase by rotenone, piericidin A, and MPP+ [8].

Biological context of Piericidin A

• Glucopiericidins were more potent in inhibiting antibody formation than piericidin A1 in vitro [3].

Anatomical context of Piericidin A

• When submitochondrial particles completely inhibited by rotenone or piericidin A are treated with bovine serum albumin to remove spuriously bound inhibitor molecules without affecting those bound at the specific inhibition site, NADH-Q activity remains inhibited and lipid peroxidation occurs but superoxide formation ceases [8].
• It is shown that inhibitors of the respiratory chain (piericidin and myxothiazol) cause fission of mitochondria in HeLa cells and fibroblasts, whereas a mitochondria-targeted antioxidant (MitoQ) inhibits this effect [9].

Associations of Piericidin A with other chemical compounds

• Evidence that the inhibition sites of the neurotoxic amine 1-methyl-4-phenylpyridinium (MPP+) and of the respiratory chain inhibitor piericidin A are the same [10].
• A biphasic relationship was given by 2-heptyl-4-hydroxyquinoline N-oxide and piericidin A which was due to these compounds acting both as inhibitors of the respiratory chain and, at higher concentrations, as uncoupling agents [11].
• Melochinine does not reveal insecticidal activity as does its structural analogue piericidin A, a well known inhibitor of the mitochondrial respiratory chain [12].
• In living cells, MR-mediated PDT initiates a delayed ("dark") accumulation of ROS, which is accelerated by inhibitors of the respiratory chain (piericidin, rotenone and myxothiazol) and inhibited by MitoQ and diphenyleneiodonium (an inhibitor of flavin enzymes), indicating that flavin of Complex I is involved in the ROS production [13].
• When 0.035 mM NADPH instead of NADH was present during the pretreatment of submitochondrial particles with piericidine A, the amount of inhibitor per cluster 2 required to fully inhibit the initial NADH-oxidation activity extrapolated to 0 [14].

Analytical, diagnostic and therapeutic context of Piericidin A

• In P. denitrificans, the forward and reverse reactions show different sensitivity to piericidin and the titrations of both activities were curvilinear with apparent I(50) (expressed as mole of inhibitor per mole of enzyme) independent of the enzyme concentration [15].

References