The metabolism of coproporphyrinogen-III into protoporphyrin-IX

Jackson, Anthony H.; Elder, George H.; Smith, S.G.

doi:10.1016/0020-711x(78)90063-0

Cited by 20 publications

(7 citation statements)

References 36 publications

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“…The hemes and chlorophylls all derive from the type-III skeleton, but type-I isomers may arise particularly under abnormal conditions (e.g., in the porphyrias) 10 and type-II and -IV coproporphyrins have been detected in porphyric human urine and feces ) are not substrates for copro'gen oxidase, but copro'gen-IV has been shown to be a good substrate for this enzyme (Scheme ). − In kinetic studies using chicken red cell hemolysates as an enzyme source, copro'gen-III is converted into proto'gen-IX via hardero'gen (Scheme ), although very little of the tricarboxylate intermediate accumulates at intermediary times . In contrast, while copro'gen-IV appears to be an equally good substrate for this enzyme and is eventually converted into proto'gen-XIII, the type IV “hardero'gen” accumulates to approximately 40% of total porphyrinogen content part way through the metabolism .…”

Section: Substrate Recognition: a Model For The Active Site Of Copro...mentioning

confidence: 99%

“…Copro'gens I and II (Chart ) are not substrates for copro'gen oxidase, but copro'gen-IV has been shown to be a good substrate for this enzyme (Scheme ). − In kinetic studies using chicken red cell hemolysates as an enzyme source, copro'gen-III is converted into proto'gen-IX via hardero'gen (Scheme ), although very little of the tricarboxylate intermediate accumulates at intermediary times . In contrast, while copro'gen-IV appears to be an equally good substrate for this enzyme and is eventually converted into proto'gen-XIII, the type IV “hardero'gen” accumulates to approximately 40% of total porphyrinogen content part way through the metabolism . Other substrates have been reported (Table ), − and these suggest that a specific sequence of peripheral substituents are necessary for enzyme−substrate recognition.…”

Section: Substrate Recognition: a Model For The Active Site Of Copro...mentioning

confidence: 99%

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Normal and Abnormal Heme Biosynthesis. 1. Synthesis and Metabolism of Di- and Monocarboxylic Porphyrinogens Related to Coproporphyrinogen-III and Harderoporphyrinogen: A Model for the Active Site of Coproporphyrinogen Oxidase

et al. 1998

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Coproporphyrinogen oxidase (copro'gen oxidase), which catalyses the conversion of coproporphyrinogen-III via a monovinylic intermediate to protoporphyrinogen-IX, is one of the least well understood enzymes in the heme biosynthetic pathway. To develop a model for the substrate recognition and binding recognition for this enzyme, a series of substrate analogues were prepared with two alkyl substituents on positions 13 and 17 in place of the usual propionate residues. Although the required substrate probes are porphyrinogens (hexahydroporphyrins), the corresponding porphyrin methyl esters were initialy synthesized via a,c-biladiene intermediates. These were hydrolyzed and reduced with 3% sodium amalgam to give the unstable porphyrinogens needed for the biochemical investigations. These modified structures were metabolized by avian preparations of copro'gen oxidase to give monovinylic products, but the second propionate residue was not further metabolized. In three cases, the metabolites were isolated and further characterized by proton NMR spectroscopy and mass spectrometry. When methyl or ethyl groups were placed at the 13 and 17 positions, the resulting porphyrinogens were very good substrates (although the ethyl version, mesoporphyrinogen-VI, gave slightly better results), but when propyl units were introduced metabolism was significantly inhibited and the butyl-substituted structure was only slightly transformed after long incubation periods. These results suggest the presence of an active-site lipophobic region near the catalytic site for copro'gen oxidase. The observation that the related 3-vinyl- and 3-ethylporphyrinogens with 13,17-diethyl substituents were not substrates for this enzyme confirmed the need for a second propionate residue to hold the substrate in place at the catalytic site.

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Section: Substrate Recognition: a Model For The Active Site Of Copro...mentioning

confidence: 99%

Section: Substrate Recognition: a Model For The Active Site Of Copro...mentioning

confidence: 99%

Normal and Abnormal Heme Biosynthesis. 1. Synthesis and Metabolism of Di- and Monocarboxylic Porphyrinogens Related to Coproporphyrinogen-III and Harderoporphyrinogen: A Model for the Active Site of Coproporphyrinogen Oxidase

et al. 1998

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“…Through studies with porphyrinogen analogs using chicken red cell hemolysates as the enzyme source, it has been shown that modifications of B and C ring propionates reduce catalytic ability of CPO (Elder et al 1978; Jackson et al 1978, Yoshinaga and Sano 1980; Lash et al 1999; Jones et al 2002). This led to a model in which a binding site was necessary for the B ring propionate, which positioned the A ring propionate correctly for the first oxidative decarboxylation.…”

Section: Discussionmentioning

confidence: 99%

Role of aspartate 400, arginine 262, and arginine 401 in the catalytic mechanism of human coproporphyrinogen oxidase

Stephenson¹,

Stacey²,

Morgenthaler³

et al. 2007

Protein Science

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Coproporphyrinogen oxidase (CPO) is the sixth enzyme in the heme biosynthetic pathway, catalyzing two sequential oxidative decarboxylations of propionate moieties on coproporphyrinogen-III forming protoporphyrinogen-IX through a monovinyl intermediate, harderoporphyrinogen. Site-directed mutagenesis studies were carried out on three invariant amino acids, aspartate 400, arginine 262, and arginine 401, to determine residue contribution to substrate binding and/or catalysis by human recombinant CPO. Kinetic analyses were performed on mutant enzymes incubated with three substrates, coproporphyrinogen-III, harderoporphyrinogen, or mesoporphyrinogen-VI, in order to determine catalytic ability to perform the first and/or second oxidative decarboxylation. When Asp400 was mutated to alanine no divinyl product was detected, but the production of a small amount of monovinyl product suggested the K m value for coproporphyrinogen-III did not change significantly compared to the wild-type enzyme. Upon mutation of Arg262 to alanine, CPO was again a poor catalyst for the production of a divinyl product, with a catalytic efficiency <0.01% compared to wild-type, including a 15-fold higher K m for coproporphyrinogen-III. The efficiency of divinyl product formation for mutant enzyme Arg401Ala was ;3% compared to wild-type CPO, with a threefold increase in the K m value for coproporphyrinogen-III. These data suggest Asp400, Arg262, and Arg401 are active site amino acids critical for substrate binding and/or catalysis. Possible roles for arginine 262 and 401 include coordination of carboxylate groups of coproporphyrinogen-III, while aspartate 400 may initiate deprotonation of substrate, resulting in an oxidative decarboxylation.

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“…Όπως έδειξαν οι Sano and Granick (1961) το ένζυμο αυτό απαιτεί την παρουσία μοριακού οξυγόνου. Τελικό προϊ όν της αντίδρασης είναι το πρωτοπορφυρινογόνο IX, επειδή το έν ζυμο δρα μονό πάνω στο ισομερές III και όχι στο ισομερές Ι. Λε πτομέρειες για τον μηχανισμό της αντίδρασης αυτής αναφέρονται σε άρθρο των Jakson, Elder and Smith (1978).…”

Section: πέμπτο ενζυμικό στάδιοunclassified

“…Οι μελέτες των Poulson and Polglase (1975) and Poulson (1976) σε παρασκευάσμα τα από βακτηρίδια έδωσαν ενδείξεις ότι πρόκειται για ένζυμο ε ξαρτώμενο από το οξυγόνο (μιτοχονδριακό ένζυμο) μ.β. 180.000" το ένζυμο έχει μεγάλη ειδικότητα ως προς το υπόστρωμα και γι'αυ τό δεν αντιδρά με ουροπορφυρίνες ή κοπροπορφυρίνες και είναι πιο δραστικό σε υποστρώματα που φέρουν λιπόφιλες ομάδες στους δακτυ-λίουςΑ και Β του πορφυρινογόνου (Jakson, Elder and Smith, 1978 Διαταραχή της σύνθεσης της αίμης. Μέχρι σήμερα ο τομέας που έχει ερευνηθεί πιο πολύ είναι εκείνος που αφορά στην επίδρα ση του μολύβδου στην μεταβολική οδό βιοσύνθεσης της αίμης.…”

Section: έκτο ενζυμιχό στάδιοunclassified

Εφαρμογη Νεωτερων Μεθοδων Στην Μετρηση Του Μολυβδου Και Μερικων Παραμετρων Του Μεταβολισμου Των Πορφυρινων

Χορδοβατζη¹

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The metabolism of coproporphyrinogen-III into protoporphyrin-IX

Cited by 20 publications

References 36 publications

Normal and Abnormal Heme Biosynthesis. 1. Synthesis and Metabolism of Di- and Monocarboxylic Porphyrinogens Related to Coproporphyrinogen-III and Harderoporphyrinogen: A Model for the Active Site of Coproporphyrinogen Oxidase

Normal and Abnormal Heme Biosynthesis. 1. Synthesis and Metabolism of Di- and Monocarboxylic Porphyrinogens Related to Coproporphyrinogen-III and Harderoporphyrinogen: A Model for the Active Site of Coproporphyrinogen Oxidase

Role of aspartate 400, arginine 262, and arginine 401 in the catalytic mechanism of human coproporphyrinogen oxidase

Εφαρμογη Νεωτερων Μεθοδων Στην Μετρηση Του Μολυβδου Και Μερικων Παραμετρων Του Μεταβολισμου Των Πορφυρινων

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