Prolyl 4-hydroxylase activity in relation to the oxidation state of enzyme-bound iron

Jong, Luitzen de; Albracht, S.P.J.; Kemp, A.

doi:10.1016/0167-4838(82)90162-5

Cited by 101 publications

(81 citation statements)

References 14 publications

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“…S1D). This demonstrates that unlike C-P4H (27,28), there is no obligate requirement of ascorbate for TET activity.…”

Section: Resultsmentioning

confidence: 80%

“…The classic example of this is collagen prolyl 4-hydroxylase (C-P4H), which in the absence of substrate undergoes a partial reaction involving decarboxylation of oxoglutarate and oxidation of the iron center to the inactive Fe 3+ ion. Without ascorbate, this "uncoupled" reaction essentially destroys C-P4H activity in <1 min (27,28) and is thought to be responsible for many of the symptoms associated with vitamin C deficiency.…”

Section: Resultsmentioning

confidence: 99%

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Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms

Hore

Meyenn

Ravichandran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

151

139

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Epigenetic memory, in particular DNA methylation, is established during development in differentiating cells and must be erased to create naïve (induced) pluripotent stem cells. The ten-eleven translocation (TET) enzymes can catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives, thereby actively removing this memory. Nevertheless, the mechanism by which the TET enzymes are regulated, and the extent to which they can be manipulated, are poorly understood. Here we report that retinoic acid (RA) or retinol (vitamin A) and ascorbate (vitamin C) act as modulators of TET levels and activity. RA or retinol enhances 5hmC production in naïve embryonic stem cells by activation of TET2 and TET3 transcription, whereas ascorbate potentiates TET activity and 5hmC production through enhanced Fe 2+ recycling, and not as a cofactor as reported previously. We find that both ascorbate and RA or retinol promote the derivation of induced pluripotent stem cells synergistically and enhance the erasure of epigenetic memory. This mechanistic insight has significance for the development of cell treatments for regenenerative medicine, and enhances our understanding of how intrinsic and extrinsic signals shape the epigenome.

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“…S1D). This demonstrates that unlike C-P4H (27,28), there is no obligate requirement of ascorbate for TET activity.…”

Section: Resultsmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms

Hore

Meyenn

Ravichandran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

151

139

View full text Add to dashboard Cite

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“…However, the vitamin has other important, non-antioxidant biological functions [16,17], of which some are related to its ability to reduce ferric (Fe 3+ ) to ferrous (Fe 2+ ) iron. AA promotes intestinal absorption of dietary non-haem Fe 2+ iron through the divalent metal transporter 1 [18] and increases the activity of Fe 2+ -dependent prolyl hydroxylases that participate in the synthesis of collagen and carnitine [19,20]. The ability of AA to reduce ferric to ferrous iron may, Vitamin C, DNA damage and iron homeostasis 5 however, have deleterious consequences.…”

Section: Introductionmentioning

confidence: 99%

Vitamin C modulation of H2O2-induced damage and iron homeostasis in human cells

Duarte

Jones

2007

Free Radical Biology and Medicine

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Vitamin C (ascorbic acid, AA) is an important antioxidant in human plasma. It is clear, however, that AA has other important, non-antioxidant roles in cells. Of particular interest is its involvement in iron metabolism, since AA enhances dietary iron absorption, increases the activity of Fe 2+ -dependent cellular enzymes, promotes Fenton reactions in vitro and was reported to have deleterious effects in individuals with iron overload. Nevertheless, the ability of AA to modulate iron metabolism and enhance iron-dependent damage in cells, tissues and organisms has not been fully elucidated. Here we investigated the effect of AA on iron-mediated oxidative stress in normal human fibroblasts. Incubation with physiologically relevant concentrations of AA was not harmful but sensitised cells towards H 2 O 2 -induced, iron-dependent DNA strand breakage and cell death. We also report that AA increased the levels of intracellular catalytic iron and concomitantly modulated the expression of two wellestablished iron-regulated genes, ferritin and transferrin receptor. In summary, we present evidence of a novel, non-antioxidant role of AA in human cells, where it increases iron availability and enhances ROS-mediated, iron-dependent damage. We suggest that AA may exacerbate the deleterious effects of metals in vivo and promote normal tissue injury in situations associated with elevated ROS production.

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“…without subsequent hydroxylation (Tuderman et al, 1977;Rao & Adams, 1978;Counts et al, 1978). Ascorbate serves as a specific alternative oxygen acceptor in such cycles (Myllyla et al, 1984;De Jong & Kemp, 1984), and in its absence the enzyme is rapidly inactivated by self-oxidation (Myllyli et al, 1978;De Jong et al, 1982).…”

Section: Introductionmentioning

confidence: 99%

Time-dependent inactivation of chick-embryo prolyl 4-hydroxylase by coumalic acid. Evidence for a syncatalytic mechanism

Günzler¹,

Hanauske-Abel²,

Myllylä³

et al. 1987

Biochemical Journal

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From the structure-activity relationships of known competitive inhibitors, coumalic acid (2-oxo-1,2H-pyran-5-carboxylic acid) was deduced to be a potential syncatalytic inhibitor for chick-embryo prolyl 4-hydroxylase. The compound caused time-dependent inactivation, the reaction rate being first-order. The inactivation constant was 0.094 min-1, the Ki 17 mm and the bimolecular rate constant 0.09 M-1 -s-1. Human prolyl 4-hydroxylase and chick embryo lysyl hydroxylase were also inactivated, though to a lesser extent. Inactivation could be prevented by adding high concentrations of 2-oxoglutarate or its competitive analogues to the reaction mixture. In Lineweaver-Burk kinetics, coumalic acid displayed S-parabolic competitive inhibition with respect to 2-oxoglutarate. The inactivation reaction had cofactor requirements similar to those for the decarboxylation of 2-oxoglutarate. Enzymic activity was partially preserved in the absence of iron, but the rescue was incomplete, owing to decreased stability of the enzyme under this condition. Coumalic acid also decreased the electrophoretic mobility of the a-subunit, but the f-subunit was not affected. Prolonged incubation of coumalic acid above pH 6.8 led to loss of its inactivating potency, owing to hydrolysis. It is concluded that the inactivation of prolyl 4-hydroxylase by coumalic acid is due to a syncatalytic mechanism. The data also suggest that the 2-oxoglutarate-binding site of the enzyme is located within the a-subunit.

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Prolyl 4-hydroxylase activity in relation to the oxidation state of enzyme-bound iron

Cited by 101 publications

References 14 publications

Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms

Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms

Vitamin C modulation of H2O2-induced damage and iron homeostasis in human cells

Time-dependent inactivation of chick-embryo prolyl 4-hydroxylase by coumalic acid. Evidence for a syncatalytic mechanism

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