Action of uroporphyrinogen decarboxylase on uroporphyrinogen-III: a reassessment of the clockwise decarboxylation hypothesis

Purification and properties of the uroporphyrinogen decarboxylase from Rhodobacter sphaeroides

“…There is substantial evidence that changes in this ratio can affect the decarboxylation route (de Verneuil et al, 1983a;Kawanishi et al, 1983;Lash, 1991;Luo and Lim, 1993). Under the conditions used in our study, the high substrate:enzyme ratio may reduce the selectivity of the enzyme for the individual rings of the 0 eight negatively charged groups it is highly likely that several arginine residues may be involved (see also Figure 4).…”

Normal and abnormal heme biosynthesis. Part 7. Synthesis and metabolism of coproporphyrinogen-III analogues with acetate or butyrate side chains on rings C and D. Development of a modified model for the active site of coproporphyrinogen oxidase

“…3,[5][6][7] Interestingly, in enzyme incubation studies using uro'gen-III or specific hepta-or hexacarboxylate porphyrinogens, the process appears to be random and all of the possible porphyrinogen intermediates can be identified. [5][6][7][8] Moreover, all 14 possible type III intermediates are metabolized by URO-D and the type I, type II and type IV isomers of uro'gen are also substrates for this enzyme. [9][10][11] However, the clockwise decarboxylation pathway does appear to be dominant at very low substrate concentrations.…”

“…3 Under physiological conditions, this process occurs regioselectively starting with the acetate group on ring D and then proceeding to ring A, then B and finally ring C (the 'clockwise' decarboxylation pathway). 3,[5][6][7] However, there are four possible hepta-, six hexa-and four pentacarboxylate porphyrinogens that could be formed from uro'gen-III, and overall there are 24 possible pathways between uro'gen-III and copro'gen-III. 3,[5][6][7] Interestingly, in enzyme incubation studies using uro'gen-III or specific hepta-or hexacarboxylate porphyrinogens, the process appears to be random and all of the possible porphyrinogen intermediates can be identified.…”

“…3,[5][6][7] However, there are four possible hepta-, six hexa-and four pentacarboxylate porphyrinogens that could be formed from uro'gen-III, and overall there are 24 possible pathways between uro'gen-III and copro'gen-III. 3,[5][6][7] Interestingly, in enzyme incubation studies using uro'gen-III or specific hepta-or hexacarboxylate porphyrinogens, the process appears to be random and all of the possible porphyrinogen intermediates can be identified. [5][6][7][8] Moreover, all 14 possible type III intermediates are metabolized by URO-D and the type I, type II and type IV isomers of uro'gen are also substrates for this enzyme.…”

“…[9][10][11] However, the clockwise decarboxylation pathway does appear to be dominant at very low substrate concentrations. 5 Copro'gen-III is transferred into the mitochondria and undergoes two oxidative decarboxylations, promoted by coproporphyrinogen oxidase (CPO, EC 1.3.3.3) to produce proto'gen-IX (Scheme 1). 4b, 12,13 Subsequent dehydrogenation by protoporphyrinogen oxidase affords the corresponding porphyrin and iron(II) insertion by ferrochelatase then gives heme b (Scheme 1).…”