Antimetabolic Action of 6-Aminonicotinamide on the Pentose Phosphate Pathway in the Brain

Herken, H.

doi:10.1007/978-1-349-01085-1_13

Cited by 29 publications

(14 citation statements)

References 4 publications

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“…Indeed, NAD(P)-binding domains usually show a relatively high degree of conservation among different enzymes. Contrary to this observation, potent and selective in vitro and in vivo inhibitors of different NAD(P)-dependent oxidoreductases have been found [112][113][114][115]. This finding can be rationalized by the concept that even subtle differences among the properties of the active sites of different dehydrogenases greatly affect their sensitivity toward different inhibitors.…”

Section: Future Directions: Defining Specific Ptfnr Inhibitorscontrasting

confidence: 48%

The Plant-Type Ferredoxin-NADP+ Reductase/Ferredoxin Redox System as a Possible Drug Target Against Apicomplexan Human Parasites

Seeber¹,

Aliverti²,

Zanetti

2005

CPD

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Apicomplexa are unicellular, obligate intracellular parasites of great medical importance. They include human pathogens like Plasmodium spp., the causative agent of malaria, and Toxoplasma gondii, an opportunistic parasite of immunosuppressed individuals and a common cause of congenital disease (toxoplasmosis). They alone affect several hundred million people worldwide so that new drugs, especially for plasmodial infections, are urgently needed. This review will focus on a recently emerged, potential drug target, a plant-type redox system consisting of ferredoxin-NADP(+) reductase (FNR) and its redox partner, ferredoxin (Fd). Both reside in an unique organelle of these parasites, named apicoplast, which is of algal origin. The apicoplast has been shown to be required for pathogen survival. In addition to other pathways already identified in this compartment, the FNR/Fd redox system represents a promising drug target because homologous proteins are not present in host organisms. Furthermore, a wealth of structural information exists on the closely related plant proteins, which can be exploited for structure-function studies of the apicomplexan protein pair. T. gondii and P. falciparum FNRs have been cloned, and the T. gondii enzyme was shown to be a flavoprotein active as a NADPH-dependent oxidoreductase. Both phylogenetic and biochemical analyses indicate that T. gondii FNR is similar in function to the isoform present in non-photosynthetic plastids whereby electron flow is from NADPH to oxidized Fd. The resulting reduced Fd is then presumably used as a reductant for various target enzymes whose nature is just starting to emerge. Among the likely candidates is the iron-sulfur cluster biosynthesis pathway, which is also located in the apicoplast and dependent on reducing power. Furthermore, lipoic acid synthase and enzymes of the isoprenoid biosynthetic pathway may be other conceivable targets. Since all these metabolic steps are vital for the parasite, blocking electron flow from FNR to Fd by inhibition of either FNR activity or its molecular interaction with Fd should also interfere with these pathways, ultimately killing the parasite. Although the three-dimensional structure of FNR from T. gondii is not yet known, experimental and computational evidence shows that apicomplexan and plant enzymes are very similar in structure. Furthermore, single amino acid changes can have profound effects on the enzyme activity and affinity for Fd. This knowledge may be exploited for the design of inhibitors of protein-protein interaction. On the other hand, specifically tailored NAD(P) analogues or mimetics based on previously described substances might be useful lead compounds for apicomplexan FNR inhibitors.

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Section: Future Directions: Defining Specific Ptfnr Inhibitorscontrasting

confidence: 48%

The Plant-Type Ferredoxin-NADP+ Reductase/Ferredoxin Redox System as a Possible Drug Target Against Apicomplexan Human Parasites

Seeber¹,

Aliverti²,

Zanetti

2005

CPD

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“…Treatment of Comeal Inflammation with Oxidative Inhibitors 6-Aminonicotinamide is an analogue of nicotinamide adenosine dinucleotide which promotes the accumulation of 6-phosphogluconate by inhibiting 6-phosphogluconate de hydrogenase [16]. This hexose monophos phate shunt inhibitor has been shown to markedly reduce the inflammation induced by retinal S-antigens as a good antiphlogistic agent but was toxic when systemically admin istered [12], Adenosine, in the presence of homocys teine thiolactone, inhibits transmethylation reactions.…”

Section: Discussionmentioning

confidence: 99%

Treatment of Experimental Acute Corneal Inflammation with Inhibitors of the Oxidative Metabolism

et al. 1993

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The authors studied the effect of topical 2% 6-aminonicotin-amide and 0.1 % adenosine on an experimental model of acute corneal inflammation. Luminol-enhanced chemiluminescence (LAC), as an indirect measurement of free-radical release, and computer-assisted planimetry of the corneal ulcer and its infiltrate were performed both ex vivo and in vivo on the fifth day following the induction of experimental alkali burn keratitis. The authors proved that both drugs significantly inhibited LAC both ex vivo and in vivo and that such treatments had also a significant beneficial effect on the evolution of the corneal ulcer and its infiltrate. To the best of the authors’ knowledge, this finding had not been previously reported in experimental corneal inflammation and may indicate that treatment with inhibitors of the oxidative metabolism could offer a new approach in the pharmacological modulation of acute corneal inflammation.

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“…6-AN is an analog of nicotinamide ade nine dinucleotide. It promotes the accumu lation of 6-phosphogluconate by inhibiting 6-phosphogluconate dehydrogenase [27], The accumulation of 6-phosphogluconate is severely toxic [28]. In addition, there may be blockage of glycolysis because of the inhibi- tion of phosphoglucoisomerase and poly-(ADP-ribose) polymerase [29].…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic Modulation of Acute Uveitis with Aminonicotinamide

Marak¹,

Sery

Gregerson

et al. 1990

Ophthalmic Res

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The hexose monophosphate shunt inhibitor 6-aminonicotinamide was observed to have an anti-inflammatory effect in the treatment of experimental uveitis. The electrons required for the reduction of molecular oxygen to superoxide radicals are generated by the pentose phosphate pathway in acute inflammatory cells. The inhibition of superoxide production is discussed as one of the potential antiphlogistic mechanisms.

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Antimetabolic Action of 6-Aminonicotinamide on the Pentose Phosphate Pathway in the Brain

Cited by 29 publications

References 4 publications

The Plant-Type Ferredoxin-NADP+ Reductase/Ferredoxin Redox System as a Possible Drug Target Against Apicomplexan Human Parasites

The Plant-Type Ferredoxin-NADP+ Reductase/Ferredoxin Redox System as a Possible Drug Target Against Apicomplexan Human Parasites

Treatment of Experimental Acute Corneal Inflammation with Inhibitors of the Oxidative Metabolism

Pharmacologic Modulation of Acute Uveitis with Aminonicotinamide

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