Biosynthesis of porphyries and related macrocycles. Part 17. Chemical and enzymic transformation of isomeric aminomethylbilanes into uroporphyrinogens: proof that unrearranged bilane is the preferred enzymic substrate and detection of a transient intermediate

Abstract

Six isomeric aminomethylbilanes have been built by unambiguous synthesis. One bilane has the unrearranged structure corresponding to straightforward head-to-tail assembly of four units of porphobilinogen ; the other five bilanes have one or more of the pyrrole rings reversed relative to the unrearranged bilane. The action of deaminasecosynthetase on these bilanes has been studied and the results showed that (a) the enzyme system ring closes the unrearranged bilane far more efficiently than it closes any of the five isomeric bilanes, (b) under the best conditions the product formed enzymically from the unrearranged bilane is almost pure uroporphyrinogen-Ill, and (c) a transient intermediate is formed enzymically from the unrearranged bilane which can be detected kinetically. Further support is thereby given to the earlier conclusion that the intramolecular rearrangement which produces the natural type-Ill porphyrins occurs at the unrearranged tetrapyrrole level.The enzymic results for the other bilanes are also described together with an improved method for analytical separation of the four isomeric esters of coproporphyrin. t Similar preparations of deaminase-cosynthetase were also used in Part 16 and Part 15 1 4 of this Series. * This solution was freshly prepared from sodium metabisulphite; 0.1 ml contained just sufficient reagent t o decolourise 0.4 ml of the iodine solution.* The non-systematic name ' tripyrrene ' has been retained in order to ensure consistency with earlier parts of the Series. Such compounds should be named according to the IUPAC rules as ' trip yrrins . '

Congenital erythropoietic porphyria: advances in pathogenesis and treatment

“…URO‐synthase normally catalyses the conversion of the linear tetrapyrrole hydroxymethylbilane by inversion of the pyrrole D ring and cyclization to uroporphyrinogen III, the physiological cyclic isomer which is metabolized in subsequent enzymatic steps to haem (Fig 1) (Jordan & Berry, 1980; Battersby et al , 1982a,b; Shoolingin‐Jordan, 1995). In patients with CEP, URO‐synthase activity is markedly deficient, but not absent.…”

Congenital erythropoietic porphyria: identification and expression of 10 mutations in the uroporphyrinogen III synthase gene.

“…URO-synthase normally catalyzes the conversion of the linear tetrapyrrole, hydroxymethylbilane, to uroporphyrinogen III, the physiologic cyclic isomer which is metabolized in subsequent enzymatic steps to heme (9,10). The markedly deficient activity of URO-synthase results in the nonenzymatic conversion of hydroxymethylbilane to the uroporphyrinogen I isomer, which is then oxidized to the nonphysiologic and pathogenic compound, URO I.…”

Congenital erythropoietic porphyria: identification and expression of exonic mutations in the uroporphyrinogen III synthase gene.

“…This enzyme normally catalyzes the rapid cyclization of the linear tetrapyrrole, hydroxymethylbilane (HMB), to form the uroporphyrinogen III isomer, the physiologic precursor of heme (3,4). In patients with this autosomal recessive disorder, the enzymatic defect leads to the accumulation ofHMB which is nonenzymatically cyclized to the uroporphyrinogen I isomer and then oxidized to uroporphyrin I (URO I), a nonphysiologic and pathogenic compound (1).…”