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|Piericidin A (AR-054) is a natural mitochondrial NADH-ubiquinone oxidoreductase (complex I) inhibitor. Piericidin A is a potent neurotoxin and inhibits mitochondrial respiration by disrupting the elec...||Inquiry|
BOC Sciences provides various toxins used as payloads for antibodies conjugation to form ADCs.
NADH-ubiquinone oxidoreductase, also called complex I, is the largest multiprotein complex of the mitochondrial respiratory chain. It couples electron transfer between NADH and ubiquinone to proton transport across the bacterial cytoplasmic membrane and the mitochondrial inner membrane. As the first enzyme of the mitochondrial electron transport chain, complex I catalyzed beta-NADH oxidation by ubiquinone and coupled to transmembrane proton translocation. Moreover, complex I contains a flavin mononucleotide (FMN) at the active site for NADH oxidation, with up to eight iron-sulfur (FeS) clusters and at least one ubiquinone binding site. This complex is composed of three specialized modules: (i) a hydrophilic NADH oxidation module, which constitutes the import mechanism; (ii) a hydrophobic module that anchors the enzyme in the membrane and is required for proton transport; (iii) a connector that connects the other two modules.
NADH-ubiquinone oxidoreductase (complex I) conserves energy from NADH oxidation, coupled to ubiquinone reduction as a proton motive force across the inner membrane. It catalyzes NADPH oxidation, NAD+ reduction, and hydride transfers from reduced to oxidized nicotinamide nucleotides. Complex I coupled with oxidoreduction reaction to actively transport four protons across the mitochondrial inner membrane. This enzyme is present in the inner membrane of eukaryotic mitochondria and the plasma membrane of bacteria, such as rhodobacter capsulatus. Whereas the mitochondrial enzyme contains up to 43 different subunits, the bacterial enzyme comprises only 13-14 subunits and can be considered the minimal core Complex I paradigm. Among the different cofactors of Complex I, ubiquinone plays a significant role: (i) as a substrate, it is the final acceptor of electrons from NADH-oxidation; (ii) as a tightly bound cofactor, quinone has been proposed to participate in electron recycling and/or proton transport processes carried out by Complex I.
Fig. 1. Structure of NADH-ubiquinone Oxidoreductases (Complex I).
Ubiquinone oxidoreductases are single subunit enzymes capable of transferring electrons from NADH to ubiquinone without contributing to the proton gradient across the respiratory membrane. Various inhibitors targeting complex I, such as Rotenone, Piericidin A, and Pyridaben, are considered to bind at or close to the quinone binding site(s). As quinones and complex I inhibitors share a hydrophobic nature, the binding site for these species has long been considered to be buried in the membrane domain.