New salicylic acid derivatives, double inhibitors of glycolate oxidase and lactate dehydrogenase, as effective agents decreasing oxalate production
María Dolores Moya-GarzónBarbara Rodriguez-RodriguezCristina Martín-HiguerasFrancisco Franco-MontalbánMiguel X. FernandesJosé A. Gómez-VidalÁngel L. PeyEduardo SalidoMónica Díaz‐Gavilán
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Abstract:
The synthesis and biological evaluation of double glycolate oxidase/lactate dehydrogenase inhibitors containing a salicylic acid moiety is described. The target compounds are obtained in an easily scalable two-step synthetic procedure. These compounds showed low micromolar IC50 values against the two key enzymes in the metabolism of glyoxylate. Mechanistically they behave as noncompetitive inhibitors against both enzymes and this fact is supported by docking studies. The biological evaluation also includes in vitro and in vivo assays in hyperoxaluric mice. The compounds are active against the three types of primary hyperoxalurias. Also, possible causes of adverse effects, such as cyclooxygenase inhibition or renal toxicity, have been studied and discarded. Altogether, this makes this chemotype with drug-like structure a good candidate for the treatment of primary hyperoxalurias.Keywords:
Docking (animal)
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Two NADP-specific "malic" enzymes have been found to be present in Neurospora crassa. They have different pH optima and are influenced differently by some metabolites and inhibitors. The pH 8.0 "malic" enzyme appears during the early stages of growth and is inhibited by fructose 1,6-diphosphate while the pH 10.0 "malic" enzyme appears during the later stages of growth and is inhibited by aspartate. Both enzymes are repressed by acetate and pyruvate and their activities are inhibited by glyoxylate and oxaloacetate. The metabolic function of the enzymes is discussed.
Malic enzyme
Malate dehydrogenase
Neurospora
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Metabolic pathway
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Lyase
Tricarboxylic acid
Isocitrate dehydrogenase
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In lower animals such as marine invertebrates and crustaceans, urate is degraded to NH_3 and CO_2 as follows. Urate is degraded to allantoin by uricase (EC1.7.3.3); allantoin is then degraded by allantoinase (EC3.5.2.5) to allantoate, which is degraded to ureidoglycollate and urea by allantoicase (EC3.5.3.4). Ureidoglycollate is further degraded to glyoxylate and another molecule of urea by ureidoglycollate lyase (EC4.3.2.3). Urea formed is degraded to NH_3 and CO_2 by urease (EC3.5.1.5). However, the degradation of urate is much less complete in higher animals. It is generally accepted that during animal evolution, all of the urate degrading enzymes (uricase, allantoinase, allantoicase, ureidoglycollate lyase and urease) were lost in humans, anthropoid apes and New World monkeys, and all of the allantoin-degrading enzymes (allantoinase, allantoicase, ureidoglycollate lyase and urease) were lost in other mammals. However, surprisingly, ureidoglycollate lyase has been found in livers of rat, bovine and monkey, and in various tissues of rat. Ureidoglycollate lyase was highly purified and characterized from the heavy mitochondrial fraction of rat, bovine and monkey liver. The apparent Km values of the mammalian enzymes for ureidoglycollate were much higher than that of fish liver ureidoglycollate lyase. The mammalian enzymes differed from the fish liver enzyme in enzymic, physical and immunological properties.
Allantoin
Lyase
Urate Oxidase
ATP citrate lyase
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A Specific Association Between the Glyoxylic‐Acid‐Cycle Enzymes Isocitrate Lyase and Malate Synthase
There is accumulating evidence that metabolic pathways are organized in vivo as multienzyme clusters or metabolons. To assess interactions between consecutive enzymes of a pathway in vitro , it is usually essential to modify the physical properties of water around the enzymes, e.g. by immobilizing the latter onto a solid support. Such immobilized enzyme preparations can be embedded in agarose gels and used for affinity electrophoresis [Beeckmans, S., Van Driessche, E. & Kanarek, L. (1989) Eur. J. Biochem. 183 , 449–454; Beeckmans, S., Van Driessche, E. & Kanarek, L. (1990) J. Cell. Biochem. 43 , 297–306]. In this study we use the aforementioned technique to investigate the association between two plant glyoxylic acid cycle enzymes, i.e. isocitrate lyase and malate synthase. A specific histochemical staining technique is described for both enzymes. Affinity electrophoresis using either isocitrate lyase or malate synthase as the immobilized enzyme clearly shows that associations are formed between both enzymes. Moreover, experiments with metabolically unrelated enzymes prove that the observed interaction is specific.
Malate synthase
Fumarase
Glyoxylic acid
Lyase
Malate dehydrogenase
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Tricarboxylic acid
Acetyl-CoA
Bioorganic chemistry
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Several enzymes have been assayed in Methylobacterium organophilum grown on different substrates. The enzymes which are involved in growth on C1 compounds were induced by methanol and not repressed by succinate. When succinate-grown bacteria were resuspended in medium containing methanol, four enzymes unique to growth on C1 compounds (hydroxypyruvate reductase, serine-glyoxylate aminotransferase, methanol dehydrogenase and glycerate kinase) were fully induced by the time growth began. When methanol-grown bacteria were resuspended in medium containing succinate, all four enzyme activities decreased. Several mutants unable to grow on C1 compounds were examined for deficiencies in the enzymes specific for growth on these compounds. Seven of the mutants were pleiotropic, and six were not revertible by chemical mutagens, suggesting the possibility of genetic linkage or the presence of a regulon for the genes involved in C1 metabolism.
Methylobacterium
Regulon
Methanol dehydrogenase
Acetate kinase
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NADP-linked isocitrate dehydrogenase (EC 1.1.1.42), a key enzyme of the tricarboxylic acid cycle, was purified 672-fold as a nearly homogeneous protein from the copper-tolerant wood-rotting basidiomycete Fomitopsis palustris. The purified enzyme, with a molecular mass of 115 kDa, consisted of two 55-kDa subunits, and had the Km of 12.7, 2.9, and 23.9 microM for isocitrate, NADP, and Mg2+, respectively, at the optimal pH of 9.0. The enzyme had maximum activity in the presence of Mg2+, which also helped to prevent enzyme inactivation during the purification procedures and storage. The enzyme activity was competitively inhibited by 2-oxoglutarate (K(i), 127.0 microM). Although adenine nucleotides and other compounds, including some of the metabolic intermediates of glyoxylate and tricarboxylic acid cycles, had no or only slight inhibition, a mixture of oxaloacetate and glyoxylate potently inhibited the enzyme activity and the inhibition pattern was a mixed type.
Isocitrate dehydrogenase
Tricarboxylic acid
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