Malate dehydrogenase inhibition

Figure 5 Model of phosphorus (P) deficiency-induced physiological changes associated with the release of P-mobilizing root exudates in cluster roots of white lupin. Solid lines indicate stimulation and dotted lines inhibition of biochemical reaction sequences or mclaholic pathways in response to P deliciency. For a detailed description see Sec. 4.1. Abbreviations SS = sucrose synthase FK = fructokinase PGM = phosphoglueomutase PEP = phosphoenol pyruvate PE PC = PEP-carboxylase MDH = malate dehydrogenase ME = malic enzyme CS = citrate synthase PDC = pyruvate decarboxylase ALDH — alcohol dehydrogenase E-4-P = erythrosc-4-phosphate DAMP = dihydraxyaceConephos-phate APase = acid phosphatase.

Anderson BM, Noble C Jr, Gregory EM. 1977. Kepone inhibition of malate dehydrogenases. J Agric Food Chem 25(3) 485-489. 

Random bi-substrate reactions can be distinguished from ordered reactions experimentally. The final reaction product can inhibit the overall reaction by competing with only the first (leading) substrate of the reaction. The reaction involving malate dehydrogenase outlined above is ordered and is inhibited by excess NADH, which competes with a normal leading-substrate NAD for binding to the enzyme. NADH does not, however, compete with the malate. 

Rowley, G.L. Rubenstein, K.E. Huisjen, J. UUman, E.F. Mechanism by which antibodies inhibit hapten-malate dehydrogenase conjugates. J. Biol. Chem. 1975, 250, 3759-3766. 

A second type of EMIT has been developed using the enzyme malate dehydrogenase as the enzymatic label. Research has shown that thyroxine competitively inhibits malate dehydrogenase. A conjugate prepared with thyroxine covalently bound close to the enzyme s active site shows very low specific activity that can be restored by binding of the thyroxine to arcP -thyroxine antibody. In this very specific assay for thyroxine, enzyme activity increases upon antibody binding, so that in a competitive assay for free thyroxine, activity decreases with increasing free thyroxine concentration. 

Product inhibition is a cause of nonlinearity of reaction progress curves during fixed-time methods of enzyme assay. For example, oxaloacetate produced by the action of aspartate aminotransferase inhibits the enzyme, particularly the mitochondrial isoenzyme. The inhibitory product may be removed as it is formed by a coupled enzymatic reaction malate dehydrogenase converts the oxaloacetate to malate and at the same time oxidizes NADH to NADL... 

The drug has high tendency to bind with various proteins and, therefore, may interfere with the energy metabolism, calcium transport and phosphorylation-dephosphorylation reactions [110]. Walter and co-workers [111-113] have found that suramin inhibits lactate dehydrogenase, malate dehydrogenase, malic enzyme and protein-kinase. Jaffe [114], showed that it also interferes with the folate metabolism of the helminths. 

Figure 9.8. The malate dehydrogenase dimer, indicating the location of the active sites in each protein plus the dimer interface. Malate dehydrogenase demonstrates substrate inhibition that has been attributed to subunit interactions and allosteric regulation by citrate, although the crystal structure of the protein reveals the absence of a separate allosteric site for citrate. See color insert.

Inhibits alanine racemase, malate dehydrogenase, pyridoxamine pyruvate transami. 

Their acute toxicity to mammals is low, but the two active substances may cause dermatitis. In rats fed daily on a diet containing quinomethionate a high cumulative toxicity was observed. A dietary level of 500 mg/kg for 90 days reduced body-weight, caused hypertrophy of the liver, and inhibited acetoacetate synthesis and the microsomal enzymes. It primarily inhibited the function of the HS-enzymes (pyruvate dehydrogenase, succinate dehydrogenase, malate dehydrogenase and a-ketoglutarate oxidase) (Carlson and DuBois, 1970). 

The reversible inhibition of mitochondrial malate dehydrogenase by oxaloacetate (>0.25 mM) has been studied in some detail (95). It is noncompetitive toward NADH. A dead-end abortive complex, which would cause uncompetitive inhibition, and a nonproductive binary complex of enzyme and oxaloacetate, to account for the competitive element of the inhibition, were postulated. The mechanism in Eq. (15) involving an active complex EB is an alternative interpretation for these results and for the less pronounced oxaloacetate inhibition observed with the cytoplasmic enzyme (55). Cytoplasmic malate dehydrogenases from several tissues and species are less susceptible to oxaloacetate inhibition than the mitochondrial enzymes (96,97) and, in the case of the chicken heart enzymes, more susceptible to malate inhibition (97). Activation by high concentrations of malate has been observed with the mitochondrial enzyme from bovine heart (98,99). 

ATP, ADP, and AMP inhibit the malate dehydrogenase from E. coli but in an allosteric manner 86). Sanwal has suggested that in the case of MDH from E. coli there is an additional (allosteric) site for NADH and the adenine nucleotides affect activity by binding at this site (s) 86). 

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