Malonate is a reversible inhibitor of succinate dehydrogenase. Succinate dehydrogenase plays a central role in the Krebs cycle and is part of complex II of the electron transport chain. Striatal injections of malonate produced dose-dependent excitotoxic lesions that were attenuated by competitive and noncompetitive NMDA antagonists. Co-injection with succinate blocks lesions due to its effect on succinate dehydrogenase (Greene et al. 1993). More studies have shown that co-injection of subtoxic malonate with nontoxic concentrations of NMDA, AMPA, and l-glutamate produces large lesions, suggesting that metabolic inhibition exacerbates NMDA and non-NMDA receptor-mediated excitation in vivo Sexual toxicity (Greene and Greenamyre 1995). NMDAR antagonists reduced glutamate toxicity by 40%, but non-NMDAR antagonists had no effect, suggesting that NMDARs may play an important role in conditions of impaired metabolism in vivo.
Bill et al. (1993a) showed that malonate lesion was accompanied by a marked decrease in ATP levels and a marked increase in lactate in vivo, as shown by chemical shift magnetic resonance imaging. Furthermore, they showed that pretreatment with coenzyme Q10 or nicotinamide blocked malonate-induced ATP depletion and thus the lesion (Beal et al., 1994). Histological studies showed that lesions did not affect NADPH-diaphorase neurons and somatostatin concentrations, consistent with observations in HD (Beal et al., 1989, 1993b).
Based on studies of malonate decarboxylase from Klebsiella pneumoniae and citrate lyase from E. 24 is a dephosphorylated coenzyme A 11 formed by a unique 1 → 2 glycosidic bond between its ribose moiety with ATP. This reaction is catalyzed by the MdcB or CitG proteins, depending on the system. In the case of malonate decarboxylase, the formed dePCoA-RibPPP binds to the MdcG protein in a strong but non-covalent interaction to form MdcGi. The protein complex reacts with MdcC (ACP of the malonate decarboxylase complex) and transfers 2′-(5″-phosphoribosyl)-3′-dephospho-CoA to it, possibly via the active site Serine and ribosyl triphosphate moiety, with release of pyrophosphate.
