MYO‐INOSITOL CATABOLISM IN HUMAN PENTOSURICS: THE PREDOMINANT ROLE OF THE GLUCURONATE‐XYLULOSE‐PENTOSE PHOSPHATE PATHWAY <sup>*</sup>

Hankes, L. V.; Politzer, W. M.; Touster, Oscar; Anderson, Louise E.

doi:10.1111/j.1749-6632.1970.tb56424.x

Cited by 30 publications

(24 citation statements)

References 22 publications

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“…MIOX, ALR1, gulonate dehydrogenase, xylulose reductase, and xylulose kinase) could be demonstrated in kidney tissues (Fig. 2D), which confirmed the existence of a G-X pathway in the kidney cortical tubules, as it has been described in the eye lens previously and is akin to the polyol pathway (25)(26)(27)(28).…”

Section: Resultssupporting

confidence: 63%

“…Treatment with siRNA partially normalized the NAD ϩ /NADH ratio in MIOX-transfected cells maintained under high glucose ambience, whereas scramble oligonucleotide had no significant effect (Fig. 4D, columns 7 and 8), suggesting that there are certain similarities with respect to the perturbation in the "cellular redox" that is seen with MIOX and aldose reductase, an enzyme expressed in renal tubules that plays a key role in glucose metabolism (26,27). The intimate relationship of MIOX with glucose metabolism and the pentose pathway gave us the impetus to investigate the cellular redox and the adaptive responses that are associated with such a scenario and the signaling events that lead to mitochondrial dysfunctions related to the pathogenesis of diabetic nephropathy.…”

Section: Effect Of Glucose On H 2 O 2 Generation and Relative Depletimentioning

confidence: 98%

“…MIOX is a non-heme di-iron enzyme that oxidizes myo-inositol to glucuronic acid via a G-X pathway (48), which also oxidizes the less abundant chiro isomer of inositol, and its metabolites enter the pentose pathway (24). MIOX is predominantly expressed in kidneys of pigs and humans (26,49); however, it remains to be investigated whether this enzyme is responsible for causing oxidant stress, particularly in the renal proximal tubules. After review of the G-X pathway ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Later, it was found to be a glycolytic enzyme, MIOX (24), which catabolizes myo-inositol to D-glucuronate via the glucuronate-xylulose (G-X) pathway as originally described in the eye lens (25), whereas it has been proposed to be operative in the kidney as well, and its metabolites enter into the pentose pathway (26,27). Past studies indicate that the promoter region of MIOX includes osmotic, carbohydrate, and oxidant/antioxidant response elements and that its transcription is heavily regulated by organic osmolytes, high glucose ambience, and oxidant stress (20,28,29).…”

Section: Diabetic Nephropathy (Dn)mentioning

confidence: 99%

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myo-Inositol Oxygenase Overexpression Accentuates Generation of Reactive Oxygen Species and Exacerbates Cellular Injury following High Glucose Ambience

Sun

Dutta

Xie

et al. 2016

Journal of Biological Chemistry

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increased ROS generation, depleted reduced glutathione, reduced GSH/GSSG ratio, and enhanced adaptive changes in the profile of the antioxidant defense system. These changes were also accompanied by mitochondrial dysfunctions, DNA damage and induction of apoptosis, accentuated activity of profibrogenic cytokine, and expression of fibronectin, the latter two being the major hallmarks of DN. These perturbations were largely blocked by various ROS inhibitors (Mito Q, diphenyleneiodonium chloride, and N-acetylcysteine) and MIOX/NOX4 siRNA. In conclusion, this study highlights a novel mechanism where MIOX under HG ambience exacerbates renal injury during the progression of diabetic nephropathy following the generation of excessive ROS via an unexplored G-X pathway.

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Section: Resultssupporting

confidence: 63%

Section: Effect Of Glucose On H 2 O 2 Generation and Relative Depletimentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Diabetic Nephropathy (Dn)mentioning

confidence: 99%

See 2 more Smart Citations

myo-Inositol Oxygenase Overexpression Accentuates Generation of Reactive Oxygen Species and Exacerbates Cellular Injury following High Glucose Ambience

Sun

Dutta

Xie

et al. 2016

Journal of Biological Chemistry

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“…In the glucuronate-xylulose pathway RSOR/MIOX initiates the processing of myo-inositol. Conceivably, during the intermediary steps of the latter metabolic pathway, L-gluconate dehydrogenase and D-xylulose reductase catalyze NAD ϩ to produce NADH, thus perturbing the redox balance (8,23). In line with this notion are our findings which indicate an increased NADH/NAD ϩ ratio, as reflected by the increased lactate/ pyruvate ratio in the culture media under high-glucose ambience (Fig.…”

Section: Discussionsupporting

confidence: 79%

Pathobiology of renal-specific oxidoreductase/myo-inositol oxygenase in diabetic nephropathy: its implications in tubulointerstitial fibrosis

Xie

Sun

Oates

et al. 2010

American Journal of Physiology-Renal Physiology

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Xie P, Sun L, Oates PJ, Srivastava SK, Kanwar YS. Pathobiology of renal-specific oxidoreductase/myo-inositol oxygenase in diabetic nephropathy: its implications in tubulointerstitial fibrosis. Am J Physiol Renal Physiol 298: F1393-F1404, 2010. First published March 24, 2010 doi:10.1152/ajprenal.00137.2010.-Renal-specific oxido-reductase/myoinositol oxygenase (RSOR/MIOX) is expressed in renal tubules. It catabolizes myo-inositol and its expression is increased in diabetic mice and in LLC-PK 1 cells under high-glucose ambience. Aldose reductase (AR) is another aldo-keto reducase that is expressed in renal tubules. It regulates the polyol pathway and plays an important role in glucose metabolism, osmolyte regulation, and ECM pathobiology via the generation of advanced glycation end products, reactive oxygen species, and activation of transforming growth factor (TGF)-␤. In view of the similarities between AR and RSOR/MIOX, the pathobiology of RSOR/MIOX and some of the cellular pathways affected by its overexpression were investigated. An increased expression of fibronectin was noted by transfection of LLC-PK 1 cells with pcDNA3.1-RSOR/MIOX. Similar changes were observed in LLC-PK 1 cells under high-glucose ambience, and they were notably lessened by RSOR/MIOX-small interfering (si) RNA treatment. The changes in tubulointerstitial fibronectin expression were also observed in the kidneys of db/db mice having high levels of RSOR. The pcDNA3.1-RSOR/MIOX transfectants had an increased NADH/NAD ϩ ratio, PKC and TGF-␤ activity, Raf1:Ras association, and p-ERK phosphorylation. These changes were significantly reduced by the inhibitors of PKC, aldose reductase, Ras farnesylation, and MEK1. Similar increases in various the above-noted parameters were observed under high-glucose ambience. Such changes were partially reversed with RSOR-siRNA treatment. Expression of Ecadherin and vimentin paralleled in cells overexpressing RSOR/ MIOX or subjected to high-glucose ambience. These studies suggest that RSOR/MIOX modulates various downstream pathways affected by high-glucose ambience, and conceivably it plays a role in the pathobiology of tubulointerstitium in diabetic nephropathy.fibronectin; db/db mice; sorbinil DIABETES MELLITUS IS A COMMON metabolic disorder in which hyperglycemia afflicts injury on multiple organ systems in humans, and frequent lesions that have been well described include diabetic microangiopathy, neuropathy, retinopathy, and nephropathy (6,33,47,54). The changes in the kidney occur in more than one-third of the patients with diabetes mellitus, and they have been exhaustively described in the literature (27,46,51,53,57,62). The hyperglycemia-induced renal changes may be acute and reversible or chronic and irreversible in nature, and these kidney lesions may serve as a prototypical example that would be applicable to other mammalian organ systems. The acute metabolic changes include increased activity of the polyol pathway, altered redox state of pyridine nucleotides (NADPH:NADP ϩ and NADH:NAD ϩ ratios), pert...

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NADPH‐dependent 5‐keto‐D‐gluconate reductase is a part of the fungal pathway for D‐glucuronate catabolism

Kuivanen

Richard

2017

FEBS Letters

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NADPH‐dependent 5‐keto‐D‐gluconate reductase was identified as a missing element in the pathway for D‐glucuronate catabolism in fungi. The disruption of the gene, gluF, by CRISPR/Cas9 in the filamentous fungus Aspergillus niger resulted in a strain unable to catabolise D‐glucuronate. The purified GluF protein was characterized and k cat and K m values of 23.7 ± 1.8 s−1 and 3.2 ± 0.1 mm for 5‐keto‐D‐gluconate, respectively, were determined. The enzyme is reversible and is active with NADP+ and D‐gluconate. We suggest a pathway for D‐glucuronate catabolism with the intermediates L‐gulonate, 2‐keto‐L‐gulonate, L‐idonate, 5‐keto‐D‐gluconate, D‐gluconate and D‐gluconate‐6‐phosphate which is a part of the pentose phosphate pathway. A fungal enzyme activity for the conversion of L‐gulonate to 2‐keto‐L‐gulonate remains to be identified.

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MYO‐INOSITOL CATABOLISM IN HUMAN PENTOSURICS: THE PREDOMINANT ROLE OF THE GLUCURONATE‐XYLULOSE‐PENTOSE PHOSPHATE PATHWAY ^*

Cited by 30 publications

References 22 publications

myo-Inositol Oxygenase Overexpression Accentuates Generation of Reactive Oxygen Species and Exacerbates Cellular Injury following High Glucose Ambience

myo-Inositol Oxygenase Overexpression Accentuates Generation of Reactive Oxygen Species and Exacerbates Cellular Injury following High Glucose Ambience

Pathobiology of renal-specific oxidoreductase/myo-inositol oxygenase in diabetic nephropathy: its implications in tubulointerstitial fibrosis

NADPH‐dependent 5‐keto‐D‐gluconate reductase is a part of the fungal pathway for D‐glucuronate catabolism

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MYO‐INOSITOL CATABOLISM IN HUMAN PENTOSURICS: THE PREDOMINANT ROLE OF THE GLUCURONATE‐XYLULOSE‐PENTOSE PHOSPHATE PATHWAY *

Cited by 30 publications

References 22 publications

myo-Inositol Oxygenase Overexpression Accentuates Generation of Reactive Oxygen Species and Exacerbates Cellular Injury following High Glucose Ambience

myo-Inositol Oxygenase Overexpression Accentuates Generation of Reactive Oxygen Species and Exacerbates Cellular Injury following High Glucose Ambience

Pathobiology of renal-specific oxidoreductase/myo-inositol oxygenase in diabetic nephropathy: its implications in tubulointerstitial fibrosis

NADPH‐dependent 5‐keto‐D‐gluconate reductase is a part of the fungal pathway for D‐glucuronate catabolism

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MYO‐INOSITOL CATABOLISM IN HUMAN PENTOSURICS: THE PREDOMINANT ROLE OF THE GLUCURONATE‐XYLULOSE‐PENTOSE PHOSPHATE PATHWAY ^*