Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.99.3 (diaphorase)
 5,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of p-toluyl m-nitro-piperazine on energy conservation processes in rat liver mitochondria is presented. The drug showed an inhibitory effect on the three segments of the respiratory chain and on the ATPase system. NADH oxidase and NADH dehydrogenase activity was inhibited 100%. The velocity and amplitude of swelling induced by glutamate, succinate, ascorbate + TMPD, and ATP was significantly changed by p-toluyl m-nitro-piperazine. It was suggested that the general action of the drug on mitochondrial metabolism would be concerning with modifications on mitochondrial membrane.
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PMID:Possible mechanism of action of piperazine derivatives on liver mitochondria. I--Effect of p-toluyl m-nitro-piperazine (p-TNP). 627 80

1. The standard O2-paradox has been studied in the Langendorff-perfused rat heart. 2. Perfusion of glucose-free saline under anoxia did not cause release of creatine kinase (CK) although, it is suggested, there was a progressive rise in [Ca2+]i. 3. Ca(2+)-depletion after anoxia caused CK release. 4. Prolonged anoxic perfusion (55 min) produced a markedly reduced release of CK on Ca(2+)-depletion because, it is suggested, of the reduction in substrates for the release mechanism. 5. No protection against the O2-paradox was found with oxygen radical scavengers and inhibitors. 6. Lowering [Ca2+]o during reoxygenation to 0.1 mM did not reduce CK release. 7. Neither 1 mM amiloride (Na+/H+ antiporter inhibitor) nor 2 x 10(-6) M 1-(5-isoquinolinesulphonyl) piperazine (protein kinase C inhibitor) reduced CK release, unlike their effects in the Ca(2+)-paradox. 8. An hypothesis for events in the O2-paradox in presented: anoxia causes a loss of Ca(2+)-homeostasis and a rise in [Ca2+]i thereby activating a transmembrane NAD(P) oxido-reductase/diaphorase (stage 1); the return of O2 synergistically activates this molecular complex and causes CK release (stage 2).
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PMID:Biochemical pathways of cell damage during the oxygen paradox of the rat heart. 810 57

Proliferating cells, including cancer cells, obtain serine both exogenously and via the metabolism of glucose. By catalyzing the first, rate-limiting step in the synthesis of serine from glucose, phosphoglycerate dehydrogenase (PHGDH) controls flux through the biosynthetic pathway for this important amino acid and represents a putative target in oncology. To discover inhibitors of PHGDH, a coupled biochemical assay was developed and optimized to enable high-throughput screening for inhibitors of human PHGDH. Feedback inhibition was minimized by coupling PHGDH activity to two downstream enzymes (PSAT1 and PSPH), providing a marked improvement in enzymatic turnover. Further coupling of NADH to a diaphorase/resazurin system enabled a red-shifted detection readout, minimizing interference due to compound autofluorescence. With this protocol, over 400,000 small molecules were screened for PHGDH inhibition, and following hit validation and triage work, a piperazine-1-thiourea was identified. Following rounds of medicinal chemistry and SAR exploration, two probes (NCT-502 and NCT-503) were identified. These molecules demonstrated improved target activity and encouraging ADME properties, enabling in vitro assessment of the biological importance of PHGDH, and its role in the fate of serine in PHGDH-dependent cancer cells. This manuscript reports the assay development and medicinal chemistry leading to the development of NCT-502 and -503 reported in Pacold et al. (2016).
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PMID:Discovery and optimization of piperazine-1-thiourea-based human phosphoglycerate dehydrogenase inhibitors. 2955 19