The two common polymorphic forms of human NRH‐quinone oxidoreductase 2 (NQO2) have different biochemical properties

Megarity, Clare F.; Gill, James R.E.; Caraher, Mary C.; Stratford, Ian J.; Nolan, Karen A.; Timson, David J.

doi:10.1016/j.febslet.2014.02.063

Cited by 27 publications

(31 citation statements)

References 62 publications

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“…was used. Intrinsic clearance, CL int ( V max / K m ), was calculated using experimentally determined V max and the published K m for DCPIP by NQO2 of 37 μM . Hepatic blood flow ( Q hepatic ) of 90 L/h, an average adult liver size of 1500 g and the cytosolic protein scaling parameter of 80.7 mg/g of liver were used.…”

Section: Methodssupporting

confidence: 56%

“…It would appear that NQO2 has consistently lower activity than NQO1 across all tissues and substrates . Suggested reasons for this include higher protein instability of NQO1, differential production and turnover rates of the enzymes and the commonality of NQO2 inhibitors in the human diet (e.g., resveratrol).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, genetic polymorphisms in the gene show signs of clinically important associations. These include polymorphisms associated with cancer prognosis, memory recall, and propensity for alcohol abuse . NQO2 is also required for TNF signaling, and could be involved in various immune and cell‐death response pathways, indeed NQO2‐null mice experience myeloid hyperplasia, ascribed in part to impaired apoptosis …”

Section: Discussionmentioning

confidence: 99%

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The ontogeny and population variability of human hepatic dihydronicotinamide riboside:quinone oxidoreductase (NQO2)

Riches

Liu

Berman

et al. 2017

J Biochem & Molecular Tox

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Dihydronicotinamide riboside:quinone oxidoreductase (NQO2) is an enzyme that performs reduction reactions involved in antioxidant defense. We hypothesized that NQO2 hepatic drug clearance would develop in children over time, similar to NQO1. Using human liver cytosol (n = 117), the effects of age, sex, ethnicity, and weight on NQO2 expression and activity were probed. No significant correlations were observed. Biochemical activity of NQO2 was as high at birth as in adults (0.23 ± 0.04 nmol/min/mg protein, mean ± SEM, range 0-1.83). In contrast, modeled hepatic clearance through the NQO2 pathway was up to 10% of adult levels at birth, reaching predicted adult levels (0.3 ± 0.03 L/h) at 14 years of age. Comparisons between NQO1 and NQO2 in the same livers showed that neither protein (P = 0.32) nor activity (P = 0.23) correlated, confirming both orthologs are independently regulated. Because hepatic clearance through NQO2 does not mature until teenage years, compounds detoxified by this enzyme may be more deleterious in children.

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Section: Methodssupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The ontogeny and population variability of human hepatic dihydronicotinamide riboside:quinone oxidoreductase (NQO2)

Riches

Liu

Berman

et al. 2017

J Biochem & Molecular Tox

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“…However, it is interesting to note that similar effects have also been observed in the related human enzyme NRH-quinone oxidoreductase 2 (NQO2) and the budding yeast quinone oxidoreductase Lot6p [88,89]. The crystal structure of NQO1 bound to dicoumarol shows that the ligand binds to both active sites, lying above the isoalloxazine ring of the FAD cofactors [90].…”

Section: Dicoumarol Also Inhibits Nqo1mentioning

confidence: 61%

Dicoumarol: A Drug which Hits at Least Two Very Different Targets in Vitamin K Metabolism

Timson

2017

CDT

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Dicoumarol, a symmetrical biscoumarin can be considered as the "parent" of the widely used anticoagulant drug, warfarin. The discovery of dicoumarol's bioactive properties resulted from an investigation into a mysterious cattle disease in the 1940s. It was then developed as a pharmaceutical, but was superseded in the 1950s by warfarin. Both dicoumarol and warfarin antagonise the blood clotting process through inhibition of vitamin K epoxide reductase (VKOR). This blocks the recycling of vitamin K and prevents the γ-carboxylation of glutamate residues in clotting factors.VKOR is an integral membrane protein and our understanding of the molecular mechanism of action of dicoumarol and warfarin is hampered by the lack of a three dimensional structure. There is consequent controversy about the membrane topology of VKOR, the location of the binding site for coumarin inhibitors and the mechanism of inhibition by these compounds. Dicoumarol (and warfarin) also inhibit a second enzyme, NAD(P)H quinone oxidoreductase 1 (NQO1). This soluble, cytoplasmic enzyme may also play a minor role in the recycling of vitamin K. However, its main cellular roles as an enzyme appear to be detoxification and the prevention of the build-up of reactive oxygen species. NQO1 is well characterised biochemically and structurally. Consequently, structurebased drug design has identified NQO1 inhibitors which have potential for the development of anticancer drugs. Many of these compounds are structurally related to dicoumarol and some have reduced "off target" effects. Therefore, it is possible that dicoumarol will become the "parent" of a second group of drugs.

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“…We have demonstrated, for the first time, negative cooperativity towards inhibitors in an FMN‐containing quinone oxidoreductase. This phenomenon has been previously observed in the mammalian FAD‐containing quinone oxidoreductases NQO1 and NQO2 (Rase et al ., ; Megarity et al ., ). The cooperativity towards resveratrol is mediated, at least in part, by an α‐helix which links the two active sites.…”

Section: Resultsmentioning

confidence: 97%

TheSaccharomyces cerevisiaequinone oxidoreductase Lot6p: stability, inhibition and cooperativity

2014

Self Cite

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Lot6p (EC 1.5.1.39; Ylr011wp) is the sole quinone oxidoreductase in the budding yeast, Saccharomyces cerevisiae. Using hexahistidine tagged, recombinant Lot6p, we determined the steady-state enzyme kinetic parameters with both NADH and NADPH as electron donors; no cooperativity was observed with these substrates. The NQO1 inhibitor curcumin, the NQO2 inhibitor resveratrol, the bacterial nitroreductase inhibitor nicotinamide and the phosphate mimic vanadate all stabilise the enzyme towards thermal denaturation as judged by differential scanning fluorimetry. All except vanadate have no observable effect on the chemical cross-linking of the two subunits of the Lot6p dimer. These compounds all inhibit Lot6p's oxidoreductase activity, and all except nicotinamide exhibit negative cooperativity. Molecular modelling suggests that curcumin, resveratrol and nicotinamide all bind over the isoalloxazine ring of the FMN cofactor in Lot6p. Resveratrol was predicted to contact an α-helix that links the two active sites. Mutation of Gly-142 (which forms part of this helix) to serine does not greatly affect the thermal stability of the enzyme. However, this variant shows less cooperativity towards resveratrol than the wild type. This suggests a plausible hypothesis for the transmission of information between the subunits and, thus, the molecular mechanism of negative cooperativity in Lot6p.

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The two common polymorphic forms of human NRH‐quinone oxidoreductase 2 (NQO2) have different biochemical properties

Cited by 27 publications

References 62 publications

The ontogeny and population variability of human hepatic dihydronicotinamide riboside:quinone oxidoreductase (NQO2)

The ontogeny and population variability of human hepatic dihydronicotinamide riboside:quinone oxidoreductase (NQO2)

Dicoumarol: A Drug which Hits at Least Two Very Different Targets in Vitamin K Metabolism

TheSaccharomyces cerevisiaequinone oxidoreductase Lot6p: stability, inhibition and cooperativity

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