Myo-Inositol Catabolism in Human Pentosurics: The Predominant Role of the Glucuronate-Xylulose-Pentose Phosphate Pathway

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

doi:10.1111/j.1749-6632.1970.tb55938.x

Cited by 18 publications

(24 citation statements)

References 22 publications

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“…A possible route for the further catabolism of L-galactonic acid would be the route which was suggested for the catabolism of myoinositol (25). In this route, L-galactonic acid is metabolized through the intermediates 3-ketogulanate, L-xylulose, xylitol, D-xylulose, and xylulose 5-phosphate.…”

Section: Discussionmentioning

confidence: 98%

Identification in the Mold Hypocrea jecorina of the First Fungal d-Galacturonic Acid Reductase

et al. 2005

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A d-galacturonic acid reductase and the corresponding gene were identified from the mold Hypocrea jecorina (Trichoderma reesei). We hypothesize that the enzyme is part of a fungal d-galacturonic acid catabolic pathway which has not been described previously and which is distinctly different from the bacterial pathway. H. jecorina grown on d-galacturonic acid exhibits an NADPH-dependent d-galacturonic acid reductase activity. This activity is absent when the mold is grown on other carbon sources. The d-galacturonic acid reductase was purified, and tryptic digests of the purified protein were sequenced. The open reading frame of the corresponding gene was then cloned from a cDNA library. The open reading frame was functionally expressed in the yeast Saccharomyces cerevisiae. A histidine-tagged protein was purified, and the enzyme kinetics were characterized. The enzyme converts in a reversible reaction from d-galacturonic acid and NADPH to l-galactonic acid and NADP. The enzyme also exhibits activity with d-glucuronic acid and dl-glyceraldehyde.

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Section: Discussionmentioning

confidence: 98%

Identification in the Mold Hypocrea jecorina of the First Fungal d-Galacturonic Acid Reductase

et al. 2005

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“…lonate, which through a series of reactions is converted into xylulose and ribulose, which finally enter into the glycolytic pathway (38). Thus, it seems that RSOR/MIOX and MI are apparently vital to the homeostasis of the kidney, especially in the hyperglycemic state.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional and Post-translational Modulation of myo-Inositol Oxygenase by High Glucose and Related Pathobiological Stresses

Nayak

Kondeti

Xie

et al. 2011

Journal of Biological Chemistry

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These findings suggest that phosphorylation of RSOR/MIOX enhances its activity, which is augmented by HG via transcriptional/translational events that are also modulated by diabetes-related pathobiological stresses.Diabetic nephropathy in man is characterized by thickening of basement membranes, mesangial expansion with progression to glomerulosclerosis, tubular atrophy, and interstitial fibrosis, resulting ultimately in renal failure (1-3). A number of mechanisms, involving a complex array of glucose-metabolizing enzymes and various signaling molecules, have been proposed for the pathogenesis of diabetic nephropathy (4 -12). One of the molecules whose homeostasis is well known to be adversely affected in diabetic neuropathy is myo-inositol (MI) 2 (13, 14); however, its pathogenetic role in diabetic nephropathy is unclear. MI is an essential molecule distributed ubiquitously, and it plays a vital role in signal transduction and osmoregulation, the latter process due to MI having been endowed with unique properties as an organic osmolyte or polyol (15, 16). As MI is also responsible for phosphoinositide signaling, it would be critical for cellular activity and is likely to have a high turnover rate, and thus its regular supplementation would be necessary to maintain various normal physiological processes (17, 18). The major sources by which it could be derived include dietary uptake, cyclic turnover from phosphoinositide signaling pathway, and de novo synthesis from glucose (19,20), the latter process confined mainly to kidney, brain, liver, and testis. Overall, it seems that MI homeostasis is maintained by a combination of transport, synthesis, and its catabolism. In diabetes, excessive urinary excretion of MI suggests its deranged homeostasis, which in part may be due to the fact that high extracellular glucose inhibits the cellular uptake of MI by compromising its tubular reabsorption (21,22). On the other hand, high glucose generates excessive intracellular sorbitol via the polyol pathway, which also interferes in the uptake of MI and causes its depletion (15,21,22). Besides sorbitol-induced MI depletion and inhibition of cellular MI uptake, there may be further accentuation of MI deficiency related to its catabolism, which is regulated by an enzyme known as myo-inositol oxygenase (MIOX) (23,24). It catabolizes MI to D-glucuronate, which enters into the pentose phosphate pathway following the interconversion of glucuronate to xylulose (25). Conceivably, this catabolic pathway is extensively utilized by the kidney because

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“…First described in the late 1950s by Charalampous,25–27 the MIOX reaction initiates the only known pathway in humans for catabolism of MI, the sugar backbone of the array of cellular ‘second messengers’ known collectively as inositol (poly)phosphates and phosphoinositides 32. Subsequent transformations convert DG to xylitol.…”

Section: Discovery and Physiology Of Mioxmentioning

confidence: 99%

myo-Inositol oxygenase: a radical new pathway for O₂and C–H activation at a nonheme diiron cluster

et al. 2009

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The enzyme myo-inositol oxygenase (MIOX) catalyzes conversion of myo-inositol (cyclohexan-1,2,3,5/4,6-hexa-ol or MI) to D-glucuronate (DG), initiating the only known pathway in humans for catabolism of the carbon skeleton of cell-signaling inositol (poly)phosphates and phosphoinositides. Recent kinetic, spectroscopic, and crystallographic studies have shown that the enzyme activates its substrates, MI and O 2 , at a carboxylate-bridged nonheme diiron(II/III) cluster, making it the first of many known nonheme diiron oxygenases to employ the mixed-valent form of its cofactor. Evidence suggests that (1) the Fe(III) site coordinates MI via its C1 and C6 hydroxyl groups, (2) the Fe(II) site reversibly coordinates O 2 to produce a superoxo-diiron(III/III) intermediate, and (3) the pendant oxygen atom of the superoxide ligand abstracts hydrogen from C1 to initiate the unique C-C-bond-cleaving, four-electron oxidation reaction. This review recounts the studies leading to the recognition of the novel cofactor requirement and catalytic mechanism of MIOX and forecasts how remaining gaps in our understanding might be filled by additional experiments.Bacterial multi-component monooxygenases [BMMs; e.g., soluble methane monooxygenase (sMMO), toluene/o-xylene monooxygenase (ToMO), and phenol hydroxylase], plant fatty acyl desaturases (e.g., stearoyl acyl carrier protein Δ 9 -desaturase) and the R2 subunits of conventional class I ribonucleotide reductases (RNR-R2s) all use carboxylate-bridged dinuclear iron clusters to activate O 2 for cleavage of strong C-H or O-H bonds. 1-5 Each of these reaction begins with the reduction of O 2 to the peroxide oxidation state by the diiron(II/ II) form of the cofactor. In several cases, peroxide-bridged diiron(III/III) intermediates have been directly characterized. 6-11 Several of the peroxide complexes are known or believed to undergo O-O-bond cleavage to generate high-valent iron complexes that cleave the target C/ O-H bonds. 1-5 For example, the diiron(III/IV) complex, X, in the RNR-R2 reaction oxidizes a tyrosine residue by one electron, cleaving the phenolic O-H bond and activating the protein for participation in nucleotide reduction with its partner subunit, RNR-R1. [12][13][14][15][16][17][18][19][20][21] Similarly, the diiron(IV/IV) complex, Q, in the sMMO reaction cleaves a C-H bond of methane to initiate its hydroxylation. 1,3,7,[22][23][24] In each of these reactions, a diiron(III/III) form of the cluster is generated at the end of the oxidation sequence. For the reactions that are catalytic, a complete "turnover" therefore requires reduction of the cluster back to the O 2 -reactive diiron(II/II) state by additional proteins, with electrons provided ultimately by NAD(P)H. 1,3,4 Although this Please send correspondence to: J.

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Myo-Inositol Catabolism in Human Pentosurics: The Predominant Role of the Glucuronate-Xylulose-Pentose Phosphate Pathway

Cited by 18 publications

References 22 publications

Identification in the Mold Hypocrea jecorina of the First Fungal d-Galacturonic Acid Reductase

Identification in the Mold Hypocrea jecorina of the First Fungal d-Galacturonic Acid Reductase

Transcriptional and Post-translational Modulation of myo-Inositol Oxygenase by High Glucose and Related Pathobiological Stresses

myo-Inositol oxygenase: a radical new pathway for O₂and C–H activation at a nonheme diiron cluster

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Myo-Inositol Catabolism in Human Pentosurics: The Predominant Role of the Glucuronate-Xylulose-Pentose Phosphate Pathway

Cited by 18 publications

References 22 publications

Identification in the Mold Hypocrea jecorina of the First Fungal d-Galacturonic Acid Reductase

Identification in the Mold Hypocrea jecorina of the First Fungal d-Galacturonic Acid Reductase

Transcriptional and Post-translational Modulation of myo-Inositol Oxygenase by High Glucose and Related Pathobiological Stresses

myo-Inositol oxygenase: a radical new pathway for O2and C–H activation at a nonheme diiron cluster

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myo-Inositol oxygenase: a radical new pathway for O₂and C–H activation at a nonheme diiron cluster