Coproporphyrin synthesis

Methods using condensations of two dipyrrolic units suffer from inherent symmetry restrictions, though these are of course less serious than those involved in the use of monopyrrole tetramerization. Thus the routes through dipyrroles are limited to synthesis of porphyrins which are centrosymmetrically substituted (by way of self-condensation of a suitably activated dipyrrole), or to porphyrins which possess subunit symmetry in one or both halves of the molecule. It is very fortunate that this latter restriction is not serious for the synthesis of porphyrins from natural materials because rings c and d of uroporphyrin-III, coproporphyrin-III and protoporphyrin-IX (Table 1), for example, are symmetrically substituted about the C-15 atom. 

Copper-sulfide cluster 884s Coproporphyrin III 843,845s Comified cell envelope 439 Corrin in transmethylation 592 Corrin ring 867, 868 Corrinoid-dependent synthesis of acetyl-CoA 876, 877 Cosmarium 22 COSY-NOESY diagram 143 Cotransport (symport) process 411,416,417 Coulomb 283... 

For porphyrins of C4 symmetry, e.g. coproporphyrin I12 and etioporphyrin I,13 cyclotetrameriza-tion of a-(functionalized methyl)pyrrole is suitable, though the pyrrole synthesis is not always facile (Scheme 2). Drastic conditions or prolonged reaction occasionally cause isomeric by-product formation.2... 

Coproporphyrin I synthesis, 816 Coronands classification, 919 metal ion complexes, 928,938 Corphins, 855 Coninoids, 983 Corrins, 871-888 demetallation, 882 deuteration, 879 electrophilic reactions, 879 metallation, 882 NMR, 878 nucleophilicity, 886 nucleophilic reactions, 879 oxidation, 879 oxidative lactamization, 880 oxidative lactonization, 880 photochemistry, 887 reactions, 879 at metal, 885 rearrangements, 879 redox chemistry, 888 spectra, 877 synthesis, 878 Corroles, 871-888 demetallation, 874 deuteration, 872 hydrogenation, 872 metallation, 874 reactions, 872 at metal, 875 redox chemistry, 876 synthesis, 871 Corticotropin zinc complexes medical use, 966 Cotton effect anils, 717... 

The use of metal ions as templates for macrocycle synthesis has an obvious relevance to the understanding of how biological molecules are formed in vivo. The early synthesis of phthalocyanins from phthalonitrile in the presence of metal salts (89) has been followed by the use of Cu(II) salts as templates in the synthesis of copper complexes of etioporphyrin-I (32), tetraethoxycarbonylporphyrin (26), etioporphyrin-II (78), and coproporphyrin-II (81). Metal ions have also been used as templates in the synthesis of corrins, e.g., nickel and cobalt ions in the synthesis of tetradehydrocorrin complexes (64) and nickel ions to hold the two halves of a corrin ring system while cycliza-tion was effected (51), and other biological molecules (67, 76, 77). 

Porphyrias are inherited or acquired disorders caused by a deficiency of enzymes in the heme biosynthetic pathway. Porphyrin is synthesized in both the erythroblasts and the liver, and either one may be the site of a disorder. Congenital erythropoietic pOTjdtyria, for example, prematurely destroys eythrocytes. This disease results from insufficient cosynthase. In this porphyria, the synthesis of the required amount of uroporphyrinogen III is accompanied by the formation of very large quantities of uroporphyrinogen I, the useless symmetric isomer. Uroporphyrin I, coproporphyrin I, and other symmetric derivatives also accumulate. The urine of... 

When a P. aeruginosa mutant (PALS 128) was grown under iron rich conditions, the specific activity of the SA-forming enzymes was below the limits of detection [79]. Liu et al. [88], suggest that entC gene expression may be limited at the translational level as well, even when the operon is induced under iron deficiency. This may be understandable because chorismic acid is an essential metabolite for Phe, Trp, Tyr, folate and ubiquinone synthesis. In B. subtilis it was shown that the accumulation of 2,3-DHBA(Glycine) was influenced by the levels of aromatic amino acids and anthranilic acid. Anthranilic acid inhibited the synthesis of DHBA from chorismic acid [117]. It seemed that the reduction in phenolic acid accumulation caused by aromatic amino acids is a consequence of enzyme repression [121]. The synthesis of 2,3-DHBA in B. subtilis is also reduced by other phenolic acids, such as m-substimted benzoic acids. Inhibition of accumulation of phenolic acid by other phenolic acids, would indicate a fairly specific effect on phenolic acid synthesis, but not on the accumulation of coproporphyrin that also accumulates in iron-deficient cultures oiB. subtilis [121]. 

A useful synthesis of copropotphyrin III and related compounds has now been achieved by modification of protoporphyrin IX the key reaction in this process is the terminal oxidation of the vinyl residues by thaliium(UI) trifluoroacetate (Scheme 6) this has now been utilized for the preparation of a specifically C-labeled coproporphyrin III required for biosynthetic studies. Further adaptation of this process has allowed the preparation of a range of other intermediates and analogs between copro- and protoporphyrin, including hardero-, pempto-, and chlorocruoroporphyrin and their isomers, as well as dihydroprotoporphyrin. ... 

The other indirect measures which can be used to monitor lead exposure are changes in the levels of a range of enzymes and metabolites involved in the synthesis and operation of haem. Thus, increases in the levels of free erythrocyte protoporphyrin (FEP) or of zinc protoporphyrin (ZPP) in blood can be associated with increased levels of lead in blood, as can decreased levels of activity of the enzyme delta-aminolaevulinic acid ddiydratase (ALAD). Similarly increases in the levels of urinary coproporphyrin (CP) and urinary aminolaevulinic acid (ALAU) also reflect increased lead exposure. These measures are not, however, always reliable since they can be affected by other factors, for exattqrle ZPP may be increased by iron deficiency. Measurements of these parameters tend, therefore, to be us only in conjunction with, and to provide supplementary data to, blood lead measurements. 

Fig. 3. Stages of porphyrin synthesis which occur in the iiver cytopiasm. Coproporphyrin I is excreted in constant but smail amounts in the urine (40-190 mg/day) and feces (300-1,100 mg/day) its rate of excretion increases during hemoiytic disorders. The further conversion of coproporphyrinogen III occurs in the mitochondria.

A second mechanism is by heme acting as repressor for the synthesis of ALA-synthetase (2). Data that suggested this mechanism were obtained from mutant 2-33 which formed heme in traces but possessed a level of ALA-synthetase 2.5 times that of the wild type that is, without heme repression more ALA-synthetase was made [Lascelles and Hatch, 145]. The following experiments suggested either repression or feedback inhibition by heme, (a) When a mutant that could not form heme was used, coproporphyrin accumulated that is, without heme there was no limitation of ALA production, (b) Decreasing the O2 of the medium resulted in an increase in ALA-synthetase or its activity one may interpret this result as a shunting of porphyrins into the Mg branch, thus decreasing the availability of porphyrins for heme... 

Methionine deficiency leads to coproporphyrin accumulation. Lascelles and Hatch [145] suggested that heme formation may be inhibited under these conditions, perhaps at the iron insertion step because methionine is required for the synthesis of phosphatidyl choline and the latter appears to be needed for ferrochelatase activity. Tait [147a] reported that under anaerobic conditions the conversion of coproporphyrinogen to protoporphyrinogen required methionine, ATP, and ferrous ions. 

Under normal conditions, the main pathway for porphobilinogen is its conversion to protoporphyrin IX and heme. Heme is used for heme protein synthesis in the liver (cytochromes, and such enzymes as catalase). An alternative pathway for porphobilinogen is its transformation to uro- and coproporphyrin I, which are not further used by cellular metabolism. A block in porphobilinogen use for heme synthesis is likely to divert the porphobilinogen into the alternative pathway, and then uroporphyrin I accumulates. This does not occur in acute intermittent porphyria. 

Illumination of suspensions of P. shermanii by light (2000-2500 lux) for 48-72 h sharply decreases the production of vitamin B and its corrinoid precursors, cobyrinic acid and its amides, and is accompanied by a considerable increase in porphyrin synthesis (mainly coproporphyrins III) (Yeliseev and Bykhovsky, 1990). The amidation of cobyrinic acids is an important regulatory step of the vitamin Bn biosynthesis (Yeliseev et al., 1988). When methylation is impaired, polycarboxylic corrinoids accumulate, inhibiting steps that precede the synthesis of corrinoids, including the methylation of UPB III (Bykhovsky and Zaitseva, 1989). 

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