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See detailNAD(P)HX repair deficiency causes central metabolic perturbations in yeast and human cells
Becker-Kettern, Julia UL; Paczia, Nicole UL; Conrotte, Jean-François UL et al

in FEBS Journal (2018)

NADHX and NADPHX are hydrated and redox inactive forms of the NADH and NADPH cofactors, known to inhibit several dehydrogenases in vitro. A metabolite repair system that is conserved in all domains of ... [more ▼]

NADHX and NADPHX are hydrated and redox inactive forms of the NADH and NADPH cofactors, known to inhibit several dehydrogenases in vitro. A metabolite repair system that is conserved in all domains of life and that comprises the two enzymes NAD(P)HX dehydratase and NAD(P)HX epimerase, allows reconversion of both the S- and R-epimers of NADHX and NADPHX to the normal cofactors. An inherited deficiency in this system has recently been shown to cause severe neurometabolic disease in children. Although evidence for the presence of NAD(P)HX has been obtained in plant and human cells, little is known about the mechanism of formation of these derivatives in vivo and their potential effects on cell metabolism. Here, we show that NAD(P)HX dehydratase deficiency in yeast leads to an important, temperature-dependent NADHX accumulation in quiescent cells with a concomitant depletion of intracellular NAD+ and serine pools. We demonstrate that NADHX potently inhibits the first step of the serine synthesis pathway in yeast. Human cells deficient in the NAD(P)HX dehydratase also accumulated NADHX and showed decreased viability. In addition, those cells consumed more glucose and produced more lactate, potentially indicating impaired mitochondrial function. Our results provide first insights into how NADHX accumulation affects cellular functions and pave the way for a better understanding of the mechanism(s) underlying the rapid and severe neurodegeneration leading to early death in NADHX repair deficient children. [less ▲]

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See detailModeling the effects of commonly used drugs on human metabolism
Sahoo, Swagatika UL; Haraldsdottir, Hulda UL; Fleming, Ronan MT UL et al

in FEBS Journal (2014)

Metabolism contributes significantly to the pharmacokinetics and pharmacodynamics of a drug. In addition, diet and genetics have a profound effect on cellular metabolism under health and disease. Herein ... [more ▼]

Metabolism contributes significantly to the pharmacokinetics and pharmacodynamics of a drug. In addition, diet and genetics have a profound effect on cellular metabolism under health and disease. Herein, we assembled a comprehensive, literature-based drug metabolic reconstruction of the 18 most highly prescribed drug groups including statins, antihypertensives, immunosuppressants, and analgesics. This reconstruction captures in detail our current understanding of their absorption, intra-cellular distribution, metabolism, and elimination. We combined this drug module with the most comprehensive reconstruction of human metabolism, Recon 2, yielding Recon2_DM1796, which accounts for 2803 metabolites and 8161 reactions. By defining 50 specific drug objectives that captured the overall drug metabolism of these compounds, we investigated effects of dietary composition and inherited metabolic disorders on drug metabolism and drug-drug interactions. Our main findings include (i) shift in dietary patterns significantly affect statins and acetaminophen metabolism, (ii) disturbed statin metabolism contributes to the clinical phenotype of mitochondrial energy disorders, and (iii) the interaction between statins and cyclosporine can be explained by several common metabolic and transport pathways other than the previously established CYP3A4 connection. This work holds the potential for studying adverse drug reactions and designing patient-specific therapies. [less ▲]

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See detailThe hallmarks of Parkinson's disease.
Antony, Paul UL; Diederich, Nico UL; Krüger, Rejko UL et al

in FEBS Journal (2013)

Since the discovery of dopamine as a neurotransmitter in the 1950s, Parkinson's disease (PD) research has generated a rich and complex body of knowledge, revealing PD to be an age-related multifactorial ... [more ▼]

Since the discovery of dopamine as a neurotransmitter in the 1950s, Parkinson's disease (PD) research has generated a rich and complex body of knowledge, revealing PD to be an age-related multifactorial disease, influenced by both genetic and environmental factors. The tremendous complexity of the disease is increased by a non-linear progression of the pathogenesis between molecular, cellular, and organic systems. In this mini-review, we explore the complexity of PD and propose a systems-based approach, organizing the available information around cellular disease hallmarks. We encourage our peers to adopt this cell-based view with the aim of improving communication in interdisciplinary research endeavors targeting the molecular events, modulatory cell-to-cell signaling pathways, and emerging clinical phenotypes related to PD. This article is protected by copyright. All rights reserved. [less ▲]

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See detailVitamin C. Biosynthesis, recycling and degradation in mammals.
Linster, Carole UL; Van Schaftingen, Emile

in FEBS Journal (2007), 274(1), 1-22

Vitamin C, a reducing agent and antioxidant, is a cofactor in reactions catalyzed by Cu(+)-dependent monooxygenases and Fe(2+)-dependent dioxygenases. It is synthesized, in vertebrates having this ... [more ▼]

Vitamin C, a reducing agent and antioxidant, is a cofactor in reactions catalyzed by Cu(+)-dependent monooxygenases and Fe(2+)-dependent dioxygenases. It is synthesized, in vertebrates having this capacity, from d-glucuronate. The latter is formed through direct hydrolysis of uridine diphosphate (UDP)-glucuronate by enzyme(s) bound to the endoplasmic reticulum membrane, sharing many properties with, and most likely identical to, UDP-glucuronosyltransferases. Non-glucuronidable xenobiotics (aminopyrine, metyrapone, chloretone and others) stimulate the enzymatic hydrolysis of UDP-glucuronate, accounting for their effect to increase vitamin C formation in vivo. Glucuronate is converted to l-gulonate by aldehyde reductase, an enzyme of the aldo-keto reductase superfamily. l-Gulonate is converted to l-gulonolactone by a lactonase identified as SMP30 or regucalcin, whose absence in mice leads to vitamin C deficiency. The last step in the pathway of vitamin C synthesis is the oxidation of l-gulonolactone to l-ascorbic acid by l-gulonolactone oxidase, an enzyme associated with the endoplasmic reticulum membrane and deficient in man, guinea pig and other species due to mutations in its gene. Another fate of glucuronate is its conversion to d-xylulose in a five-step pathway, the pentose pathway, involving identified oxidoreductases and an unknown decarboxylase. Semidehydroascorbate, a major oxidation product of vitamin C, is reconverted to ascorbate in the cytosol by cytochrome b(5) reductase and thioredoxin reductase in reactions involving NADH and NADPH, respectively. Transmembrane electron transfer systems using ascorbate or NADH as electron donors serve to reduce semidehydroascorbate present in neuroendocrine secretory vesicles and in the extracellular medium. Dehydroascorbate, the fully oxidized form of vitamin C, is reduced spontaneously by glutathione, as well as enzymatically in reactions using glutathione or NADPH. The degradation of vitamin C in mammals is initiated by the hydrolysis of dehydroascorbate to 2,3-diketo-l-gulonate, which is spontaneously degraded to oxalate, CO(2) and l-erythrulose. This is at variance with bacteria such as Escherichia coli, which have enzymatic degradation pathways for ascorbate and probably also dehydroascorbate. [less ▲]

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See detailGlucuronate, the precursor of vitamin C, is directly formed from UDP-glucuronate in liver
Linster, Carole UL; Van Schaftingen, Emile

in FEBS Journal (2006), 273(7), 1516-27

The conversion of UDP-glucuronate to glucuronate, usually thought to proceed by way of glucuronate 1-phosphate, is a site for short-term regulation of vitamin C synthesis by metyrapone and other ... [more ▼]

The conversion of UDP-glucuronate to glucuronate, usually thought to proceed by way of glucuronate 1-phosphate, is a site for short-term regulation of vitamin C synthesis by metyrapone and other xenobiotics in isolated rat hepatocytes. Our purpose was to explore the mechanism of this effect in cell-free systems. Metyrapone and other xenobiotics stimulated, by approximately threefold, the formation of glucuronate from UDP-glucuronate in liver extracts enriched with ATP-Mg, but did not affect the formation of glucuronate 1-phosphate from UDP-glucuronate or the conversion of glucuronate 1-phosphate to glucuronate. This and other data indicated that glucuronate 1-phosphate is not an intermediate in glucuronate formation from UDP-glucuronate, suggesting that this reaction is catalysed by a 'UDP-glucuronidase'. UDP-glucuronidase was present mainly in the microsomal fraction, where its activity was stimulated by UDP-N-acetylglucosamine, known to stimulate UDP-glucuronosyltransferases by enhancing the transport of UDP-glucuronate across the endoplasmic reticulum membrane. UDP-glucuronidase and UDP-glucuronosyltransferases displayed similar sensitivities to various detergents, which stimulated at low concentrations and generally inhibited at higher concentrations. Substrates of glucuronidation inhibited UDP-glucuronidase activity, suggesting that the latter is contributed by UDP-glucuronosyltransferase(s). Inhibitors of beta-glucuronidase and esterases did not affect the formation of glucuronate, arguing against the involvement of a glucuronidation-deglucuronidation cycle. The sensitivity of UDP-glucuronidase to metyrapone and other stimulatory xenobiotics was lost in washed microsomes, even in the presence of ATP-Mg, but it could be restored by adding a heated liver high-speed supernatant or CoASH. In conclusion, glucuronate formation in liver is catalysed by a UDP-glucuronidase which is closely related to UDP-glucuronosyltransferases. Metyrapone and other xenobiotics stimulate UDP-glucuronidase by antagonizing the inhibition exerted, presumably indirectly, by a combination of ATP-Mg and CoASH. [less ▲]

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