Structural Isomerism and chirality of <i>N</i>‐monosubstituted protoporphyrins

Matteis, Federico De; Jackson, Anthony H.; Gibbs, Anthony H.; Rao, K.R.S. Sambasiva; Atton, Jennifer G.; Weerasinghe, S.; Hollands, C.

doi:10.1016/0014-5793(82)80216-0

Cited by 24 publications

(6 citation statements)

References 21 publications

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“…These findings suggest that both size and position of the Nalkyl group are important for the inhibitory activity of a N-alkylated dicarboxylic porphyrin (see also De Matteis et al, 1980c;Ortiz de Montellano et al, 1981a). They are compatible with the concept (De Matteis et al, 1982b) that when one of the propionic acid-substituted rings is alkylated (as is the case in the Nc and ND isomers) then, because the N-alkylated ring is significantly tilted out of the porphyrin plane, the alignment of the two propionic acid chains with respect to each other may be altered. As a consequence, the binding of the modified porphyrin by the chelatase may be impaired, particularly when the N-alkyl group is large in size or a metal is present in the centre of the porphyrin macrocycle, as in both cases the distortion of the N-alkylated ring would be expected to be greater.…”

Section: Resultssupporting

confidence: 79%

“…Where two main isomeric fractions were obtained (Fl and F2 in order of elution, see Table 1), both were collected and, after hydrolysis of the methyl esters, the N-substituted porphyrins were tested for inhibitory activity on ferrochelatase in vitro (Tephly et al, 1979) as the free porphyrins (A) or, in some cases, as the zinc chelate derivatives (B). Inhibitory activity is expressed as units (De Matteis et al, 1980b) per nmol of pigment calculated from the Soret absorption by using the published E value (De Matteis et al, 1982b) for N-methylprotoporphyrin and its zinc complex. Results given are averages + S.E.M.…”

Section: Resultsmentioning

confidence: 99%

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Studies on the inhibition of ferrochelatase by N-alkylated dicarboxylic porphyrins. Steric factors involved and evidence that the inhibition is reversible

Matteis¹,

Gibbs²,

Harvey³

1985

Biochemical Journal

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The structural requirements for the inhibition of ferrochelatase by N-alkylated porphyrins were investigated and experiments carried out to explore the mechanism of enzyme inhibition. Three dicarboxylic porphyrins, all substrates of the enzyme, are strongly inhibitory when N-alkylated; in contrast, uroporphyrin and coproporphyrin (which are not substrates) do not inhibit after N-alkylation. Free carboxylic acid functions are required for inhibition, as the methyl ester derivatives are not themselves inhibitory. Porphyrins bearing the alkyl group on the pyrrole nitrogen of rings C and D are less effective inhibitors, particularly when zinc is chelated in the centre of the tetrapyrrole or the N-alkyl group is relatively large in size. The substituents at the 2- and 4-positions of the porphyrin system may also affect the inhibitory activity, particularly for the isomers with ring C and D alkylated. The zinc chelates of several N-alkylprotoporphyrins are inhibitory towards haem oxygenase, another haem-binding enzyme, and also in this case increasing the size of the alkyl group decreased the inhibitory activity, particularly for isomers with ring C or D alkylated. The inhibition could be reversed by prolonged incubation with excess porphyrin substrate, but dealkylation of the N-alkylporphyrin during enzyme inhibition could not be demonstrated. It is concluded (a) that N-alkylated dicarboxylic porphyrins compete reversibly with the porphyrin substrate for the enzyme active site and (b) that the structural and steric factors discussed above affect the inhibitory activity by modifying the affinity of the N-alkylporphyrin inhibitor for the enzyme.

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Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Studies on the inhibition of ferrochelatase by N-alkylated dicarboxylic porphyrins. Steric factors involved and evidence that the inhibition is reversible

Matteis¹,

Gibbs²,

Harvey³

1985

Biochemical Journal

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“…liver after treatment with DDC and 4-ethyl-DDC have both been shown to be a mixture of all four structural isomers (Ortiz de Montellano & Kunze, 1981;). In the case of N-methylprotoporphyrin produced by treatment with DDC, two different structural isomers have both been found to be optically active (De Matteis et al, 1982b), suggesting that they are both produced on an enzymic template. However, it is not yet known whether all four isomers are produced on the same enzymic site, or whether alkylation of haem may take place on more than one site, each giving rise preferentially to one isomer of N-alkylprotoporphyrin.…”

mentioning

confidence: 99%

N-alkylation of the haem moiety of cytochrome P-450 caused by substituted dihydropyridines. Preferential attack of different pyrrole nitrogen atoms after induction of various cytochrome P-450 isoenzymes

Matteis¹,

Gibbs²,

Hollands³

1983

Biochemical Journal

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1. 3,5-Diethoxycarbonyl-4-ethyl-1,4-dihydro-2,6-dimethylpyridine (4-ethyl-DDC) gives rise to N-ethylprotoporphyrin in the liver of rats by donating its 4-ethyl group to one of the pyrrole nitrogen atoms of haem. Four structural isomers are obtained, depending on which pyrrole nitrogen is alkylated. 2. When rats are pretreated with an inducer of cytochrome P-450, the production of N-ethylprotoporphyrin caused by 4-ethyl-DDC is greater, both in the whole animal and in hepatocytes incubated with the drug in vitro. 3. Pre-incubation of hepatocytes with 2-allyl-2-isopropylacetamide decreases the yield of N-ethylprotoporphyrin due to 4-ethyl-DDC, an effect largely reversed by adding exogenous haem. 4. The isomeric composition of N-ethylprotoporphyrin produced in vivo and in vitro depends on the cytochrome P-450 isoenzyme that predominates at the time of treatment, suggesting a role for the apo-cytochrome in directing alkylation on to one of the pyrrole nitrogens.

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“…Protoporphyrin dimethyl ester was heated at 95 °C with methyl iodide for 24 h . NMPD was purified by a thin layer chromatography, and identified spectrophotometrically (11). The content was estimated using a mM extinction coefficient of 135 at 419 nm.…”

Section: Methodsmentioning

confidence: 99%

Effects of 5-aminolevulinate and N-methyl-protoporphyrin dimethyl ester on bacteriochlorophyll synthesis in aerobic bacteria.

Shiba

1992

J. Gen. Appl. Microbiol.

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The aerobic bacteria, Erythrobacter longus and Roseobacter denitrificans, were examined for the effects of 5-aminolevulinate (ALA) and Nmethylprotoporphyrin dimethyl ester (NMPD) on bacteriochlorophyll (Bchl) synthesis. Although external ALA seemed to be incorporated into a tetrapyrrole synthetic pathway leading to Bchl synthesis, there was no increase of Bchl in either Ro. denitrificans or E. longus. With the addition of ALA, increased was protoporphyrin IX in Ro. denitrificans, or protoheme in E. longus. NMPD enhanced the Bchl synthesis in E. longus but not in Ro. denitrificans. It is likely that E. longus and Ro. denitrificans are different from each other in the regulatory mechanism of Bchl synthesis.

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Structural Isomerism and chirality of N‐monosubstituted protoporphyrins

Cited by 24 publications

References 21 publications

Studies on the inhibition of ferrochelatase by N-alkylated dicarboxylic porphyrins. Steric factors involved and evidence that the inhibition is reversible

Studies on the inhibition of ferrochelatase by N-alkylated dicarboxylic porphyrins. Steric factors involved and evidence that the inhibition is reversible

N-alkylation of the haem moiety of cytochrome P-450 caused by substituted dihydropyridines. Preferential attack of different pyrrole nitrogen atoms after induction of various cytochrome P-450 isoenzymes

Effects of 5-aminolevulinate and N-methyl-protoporphyrin dimethyl ester on bacteriochlorophyll synthesis in aerobic bacteria.

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