The role of aldehyde reductase AKR1A1 in the metabolism of gamma-hydroxybutyrate in 1321N1 human astrocytoma cells

Alzeer, Samar; Ellis, Elizabeth M.

doi:10.1016/j.cbi.2011.01.018

Cited by 10 publications

(7 citation statements)

References 31 publications

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“…The data in this study support the notion that AKR1A1 is equivalent to this high Km aldehyde reductase, as silencing AKR1A1 did not have an impact on SSA reductase activity at endogenous (10 mM) concentration of SSA. These results agree with our previous results using an astroglial cell line, in which we demonstrated that AKR1A1 does not participate in the endogenous synthesis of GHB [40]. Previously, AKR7A2, another enzyme from the AKR superfamily, that has a lower Km for SSA [19], was demonstrated to be the dominant SSA reductase in the neuroblastoma cell line (SH-SY5Y) when concentrations of SSA are between 10 mM and 1 mM [33].…”

Section: Discussionsupporting

confidence: 94%

Metabolism of gamma hydroxybutyrate in human hepatoma HepG2 cells by the aldo-keto reductase AKR1A1

Alzeer

Ellis

2014

Biochemical Pharmacology

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Section: Discussionsupporting

confidence: 94%

Metabolism of gamma hydroxybutyrate in human hepatoma HepG2 cells by the aldo-keto reductase AKR1A1

Alzeer

Ellis

2014

Biochemical Pharmacology

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“…AKR1A1 has a role in ascorbic acid synthesis in rodents 7 and activity against gamma-hydroxybutyric acid (GHB)-related aldehydes in vitro 24 . But humans do not synthesize ascorbic acid, and AKR1A1 does not regulate GHB in vivo (Extended data Fig.7g) 25 . Therefore, the primary function of AKR1A1 had been a mystery 26 .…”

Section: Mainmentioning

confidence: 99%

Metabolic reprogramming by the S-nitroso-CoA reductase system protects against kidney injury

Zhou

Zhang

Anand

et al. 2018

Nature

165

162

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Endothelial nitric oxide (NO) synthase (eNOS) is protective against kidney injury, but the molecular mechanisms are poorly understood 1 , 2 . NO-based cellular signaling is generally mediated by protein S-nitrosylation, the oxidative modification of Cys residues to form S-nitrosothiols (SNOs). S-nitrosylation regulates proteins in all functional classes, and is controlled by enzymatic machinery including S-nitrosylases and denitrosylases that add and remove SNO from proteins, respectively 3 , 4 . We recently reported in Saccharomyces cerevisiae that the classic metabolic intermediate Co-enzymeA (CoA) serves as an endogenous source of SNOs through its conjugation with NO to form S-nitroso-CoA (SNO-CoA), and that S-nitrosylation of proteins by SNO-CoA is governed by its cognate denitrosylase, SNO-CoA reductase (SCoR) 5 . Mammals possess a functional homologue of yeast SCoR, an aldo-keto reductase family member (AKR1A1) 5 with an unknown physiological role. Here we report that the SNO-CoA/AKR1A1 (SCoR) system is highly expressed in renal proximal tubules where it transduces the activity of eNOS in reprogramming intermediary metabolism, thereby protecting kidneys from acute kidney injury (AKI). Specifically, AKR1A1 deletion in mice to reduce SCoR activity increased protein S-nitrosylation, protected against AKI and improved survival, whereas renoprotection was lost in Akr1a1 −/− / eNOS −/− mice. Metabolic profiling coupled with unbiased mass spectrometry-based SNO-protein identification revealed that protection by the SNO-CoA/SCoR system is mediated by inhibitory S-nitrosylation of pyruvate kinase M2 (PKM2) through a novel locus of regulation, thereby balancing fuel utilization (through glycolysis) with redox protection (through the pentose phosphate shunt). Targeted deletion of PKM2 from mouse proximal tubules recapitulated precisely the protective and mechanistic effects of S-nitrosylation in Akr1a1 −/− mice, whereas Cys-mutant PKM2 refractory to S-nitrosylation negated SNO-CoA bioactivity. Our discoveries provide a first physiological function of the SNO-CoA/SCoR system in mammals, reveal novel regulation of renal metabolism and of PKM2 in differentiated tissues in particular, and offer a new perspective on kidney injury with therapeutic implications.

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“…Activating the GABA shunt in the gerbil brain has been shown to protect against ischemic/reperfusion injury, a known generator of oxidative stress [59]. SSA may also be reduced to gammahydroxybutyrate (GHB) by the actions of an NADPH dependent aldehyde reductase, AKR7A2, although in the normal rat brain less than 0.15% of the metabolic flux from GABA takes this reductive pathway [18,60]. Levels of GHB are very low in whole adult rat brain, in the 2 nmol/gm range, and in the 13 nmol/gm range in postmortem human frontal cortex [61].…”

Section: Gaba Shuntmentioning

confidence: 99%

Sporadic Alzheimer's Disease: The Starving Brain

Mamelak

2012

JAD

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A reduction in cerebral glucose utilization is one of the earliest signs of Alzheimer's disease. Although the exact cause of this reduction is not known, gathering evidence suggests that it is part of a complex metabolic adaptation to oxidative stress during which glycolysis and oxidative phosphorylation are turned down, glucose metabolism is shifted to the pentose phosphate pathway to generate antioxidant reducing factors such as nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione, and the gamma-aminobutyric acid (GABA) shunt is activated to provide glutamate as an alternate source of energy. In the face of these adaptive metabolic changes, the Alzheimer brain runs short of energy and begins to digest itself. The very early induction of macroautophagy attests to the search for nutrients. In clinical trials, antioxidants alone have not been effectively able to influence the course of the disease as these agents do not meet the energy and nutritional requirements of the brain. Evidence is presented that gammahydroxybutyrate, a natural product of the GABA shunt, can provide the necessary energy, carbon, and antioxidant power and that its use may be able to delay the onset and progress of Alzheimer's disease.

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The role of aldehyde reductase AKR1A1 in the metabolism of gamma-hydroxybutyrate in 1321N1 human astrocytoma cells

Cited by 10 publications

References 31 publications

Metabolism of gamma hydroxybutyrate in human hepatoma HepG2 cells by the aldo-keto reductase AKR1A1

Metabolism of gamma hydroxybutyrate in human hepatoma HepG2 cells by the aldo-keto reductase AKR1A1

Metabolic reprogramming by the S-nitroso-CoA reductase system protects against kidney injury

Sporadic Alzheimer's Disease: The Starving Brain

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