Uroporphyrinogen III synthase: Studies on its mechanism of action, molecular biology and biochemistry

Crockett, Nigel; Alefounder, Peter R.; Battersby, Alan R.; Abell, Chris

doi:10.1016/s0040-4020(01)86492-9

Cited by 27 publications

(1 citation statement)

References 29 publications

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“…Hydroxymethylbilane, being unstable in solution, can nonenzymatically cyclize to form UROgen I, which is a physiologically redundant end product. However, hydroxymethylbilane is normally rapidly converted to UROgen III by the action of UROgen III synthase (39). Both I and III forms of UROgens have the potential to be oxidized to their respective porphyrin forms in the cytosol, although this apparently does not occur to a large extent under the physiological conditions studied here.…”

Section: Figmentioning

confidence: 82%

Export of a Heterologous Cytochrome P450 (CYP105D1) in Escherichia coli Is Associated with Periplasmic Accumulation of Uroporphyrin

Akhtar

Kaderbhai

Hopper

et al. 2003

Journal of Biological Chemistry

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This report suggests an important physiological role of a CYP in the accumulation of uroporphyrin I arising from catalytic oxidative conversion of uroporphyrinogen I to uroporphyrin I in the periplasm of Escherichia coli cultured in the presence of 5-aminolevulinic acid. A structurally competent Streptomyces griseus CYP105D1 was expressed as an engineered, exportable form in aerobically grown E. coli. Its progressive induction in the presence of 5-aminolevulinic acid-supplemented medium was accompanied by an accumulation of a greater than 100-fold higher amount of uroporphyrin I in the periplasm relative to cells lacking CYP105D1. Expression of a cytoplasm-resident engineered CYP105D1 at a comparative level to the secreted form was far less effective in promoting porphyrin accumulation in the periplasm. Expression at a 10-fold molar excess over the exported CYP105D1 of another periplasmically exported hemoprotein, the globular core of cytochrome b 5 , did not substitute the role of the periplasmically localized CYP105D1 in promoting porphyrin production. This, therefore, eliminated the possibility that uroporphyrin accumulation is merely a result of increased hemoprotein synthesis. Moreover, in the strain that secreted CYP105D1, uroporphyrin production was considerably reduced by azole-based P450 inhibitors. Production of both holo-CYP105D1 and uroporphyrin was dependent upon 5-aminolevulinic acid, except that at higher concentrations this resulted in a decrease in uroporphyrin. This study suggests that the exported CYP105D1 oxidatively catalyzes periplasmic conversion of uroporphyrinogen I to uroporphyrin I in E. coli. The findings have significant implications in the ontogenesis of human uroporphyria-related diseases.

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Section: Figmentioning

confidence: 82%

Export of a Heterologous Cytochrome P450 (CYP105D1) in Escherichia coli Is Associated with Periplasmic Accumulation of Uroporphyrin

Akhtar

Kaderbhai

Hopper

et al. 2003

Journal of Biological Chemistry

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The Evidence for a Spirocyclic Intermediate in the Formation of Uroporphyrinogen III by Cosynthase

Leeper

2007

Ciba Foundation Symposium 180 ‐ the Biosynthesis of the Tetrapyrrole Pigments

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Warum ist Porphobilinogen das biologische Substrat für die Bildung der Porphyrine? Rechnungen zur Konformation acyclischer Tetrapyrrole sowie säurekatalysierte Cyclisierung von Hydroxymethylpyrrolen

Tietze

Geissler

1993

Angewandte Chemie

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Das Substitutionsmuster am Pyrrol ist entscheidend für die hohe Tendenz zur Umwandlung von Porphobilinogen 1 in Uroporphyrinogen III 6. Dies ergaben Modellreaktionen mit den Hydroxymethylpyrrolen 2‐5 sowie semiempirische Rechnungen, deren Ergebnisse zeigen, daß das als Intermediate zu formulieren‐de acyclische Tetramer aus 3 aufgrund von 1,3‐Allylspannung bevorzugt in einer cyclischen Konformation vorliegt, aus der heraus die Cyclisierung sehr leicht erfolgen kann. P = (CH2) 2CO2H, A = CH2CO2H.

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Uroporphyrinogen III synthase: Studies on its mechanism of action, molecular biology and biochemistry

Cited by 27 publications

References 29 publications

Export of a Heterologous Cytochrome P450 (CYP105D1) in Escherichia coli Is Associated with Periplasmic Accumulation of Uroporphyrin

Export of a Heterologous Cytochrome P450 (CYP105D1) in Escherichia coli Is Associated with Periplasmic Accumulation of Uroporphyrin

The Evidence for a Spirocyclic Intermediate in the Formation of Uroporphyrinogen III by Cosynthase

Warum ist Porphobilinogen das biologische Substrat für die Bildung der Porphyrine? Rechnungen zur Konformation acyclischer Tetrapyrrole sowie säurekatalysierte Cyclisierung von Hydroxymethylpyrrolen

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