uroporphyrinogens

Summary

Summary: Porphyrinogens which are intermediates in heme biosynthesis. They have four acetic acid and four propionic acid side chains attached to the pyrrole rings. Uroporphyrinogen I and III are formed from polypyrryl methane in the presence of uroporphyrinogen III cosynthetase and uroporphyrin I synthetase, respectively. They can yield uroporphyrins by autooxidation or coproporphyrinogens by decarboxylation.

Top Publications

  1. Fumagalli S, Kotler M, Rossetti M, Batlle A. Studies on uroporphyrinogen biosynthesis in pig liver. Z Naturforsch C. 1991;46:1101-8 pubmed
    ..The differential action of some of these chemicals on PBG-D and PBG-D-I system would suggest that PBG-D and isomerase may not be only physically adjacent but actually associated. ..
  2. Lannfelt L, Wetterberg L, Gellerfors P, Lilius L, Floderus Y, Thunell S. Mutations in acute intermittent porphyria detected by ELISA measurement of porphobilinogen deaminase. J Clin Chem Clin Biochem. 1989;27:857-62 pubmed
  3. Miller D, Woods J. Redox activities of mercury-thiol complexes: implications for mercury-induced porphyria and toxicity. Chem Biol Interact. 1993;88:23-35 pubmed
    ..These findings suggest that mercury-thiol complexes possess redox activity in biological systems, which promotes the oxidation of porphyrinogens and possibly other biomolecules. ..
  4. Jahn D, Hungerer C, Troup B. [Unusual pathways and environmentally regulated genes of bacterial heme biosynthesis]. Naturwissenschaften. 1996;83:389-400 pubmed
    ..The current knowledge on the various enzymatic reactions and gene regulatory mechanisms is reviewed. ..
  5. Warren M, Raux E, Schubert H, Escalante Semerena J. The biosynthesis of adenosylcobalamin (vitamin B12). Nat Prod Rep. 2002;19:390-412 pubmed
    ..This review covers some of the most important findings that have been made and provides the reader with a complete description of the transformation of uroporphyrinogen III into adenosylcobalamin (AdoCbl). 183 references are cited. ..
  6. Spencer J, Stolowich N, Roessner C, Scott A. The Escherichia coli cysG gene encodes the multifunctional protein, siroheme synthase. FEBS Lett. 1993;335:57-60 pubmed
    ..Thus CysG is a multifunctional protein solely responsible for siroheme synthesis from uro'gen III in E. coli, and accordingly is renamed siroheme synthase. ..
  7. Heldt D, Lawrence A, Lindenmeyer M, Deery E, Heathcote P, Rigby S, et al. Aerobic synthesis of vitamin B12: ring contraction and cobalt chelation. Biochem Soc Trans. 2005;33:815-9 pubmed
    ..The genetic requirements of cobalt chelation and the subsequent reduction of the metal ion are discussed. ..
  8. Shoolingin Jordan P, Warren M, Awan S. Discovery that the assembly of the dipyrromethane cofactor of porphobilinogen deaminase holoenzyme proceeds initially by the reaction of preuroporphyrinogen with the apoenzyme. Biochem J. 1996;316 ( Pt 2):373-6 pubmed
  9. Feliciano J, Liu Y, Daunert S. Novel reporter gene in a fluorescent-based whole cell sensing system. Biotechnol Bioeng. 2006;93:989-97 pubmed
    ..Advantages and limitations of using the cobA gene in whole-cell sensing applications are presented. ..

More Information

Publications62

  1. Lambrecht R, Jacobs J, Sinclair P, Sinclair J. Inhibition of uroporphyrinogen decarboxylase activity. The role of cytochrome P-450-mediated uroporphyrinogen oxidation. Biochem J. 1990;269:437-41 pubmed
    ..The latter finding suggested that a labile inhibitor was formed during the oxidation. These results suggest uroporphyrinogen oxidation may be important in the mechanism of chemically induced uroporphyria. ..
  2. Billi de Catabbi S, Rios de Molina M, San Martin de Viale L. Studies on the active centre of rat liver porphyrinogen carboxylase in vivo effect of hexachlorobenzene. Int J Biochem. 1991;23:675-9 pubmed
    ..This treatment seems to partially protect the active site of the porphyrinogen carboxylase from the modification reactions. ..
  3. Sinclair P, Gorman N, Dalton T, Walton H, Bement W, Sinclair J, et al. Uroporphyria produced in mice by iron and 5-aminolaevulinic acid does not occur in Cyp1a2(-/-) null mutant mice. Biochem J. 1998;330 ( Pt 1):149-53 pubmed
    ..These results indicate the absolute requirement for hepatic CYP1A2 in causing experimental uroporphyria under the conditions used. ..
  4. Johansson P, Hederstedt L. Organization of genes for tetrapyrrole biosynthesis in gram--positive bacteria. Microbiology. 1999;145 ( Pt 3):529-38 pubmed
    ..It is shown that YInF is required for sirohaem synthesis and probably catalyses the precorrin-2 to sirohaem conversion. YInD probably catalyses precorrin-2 synthesis from UroIII and NasF seems to be specific for nitrite reduction. ..
  5. Sasarman A, Chartrand P, Proschek R, Desrochers M, Tardif D, Lapointe C. Uroporphyrin-accumulating mutant of Escherichia coli K-12. J Bacteriol. 1975;124:1205-12 pubmed
    ..The results of the genetic analysis suggest the gene order rif, hemE, thiA, metA; however, they do not totally exclude the gene order rif, thiA, hemE, metA. ..
  6. Jacobs J, Nichols C, Marek D, Gorman N, Walton H, Sinclair P, et al. Effect of arsenite on the induction of CYP1A4 and CYP1A5 in cultured chick embryo hepatocytes. Toxicol Appl Pharmacol. 2000;168:177-82 pubmed
    ..These results indicate the induction of CYP1A4 and 1A5 is inhibited by sodium arsenite at the level of transcription, suggesting that the Ah receptor complex may be involved. ..
  7. Sinclair P, Gorman N, Walton H, Bement W, Dalton T, Sinclair J, et al. CYP1A2 is essential in murine uroporphyria caused by hexachlorobenzene and iron. Toxicol Appl Pharmacol. 2000;162:60-7 pubmed
    ..These results indicate that, in mice, CYP1A2 is essential in the process leading to HCBZ-induced uroporphyria. Contributions by other CYP forms induced by HCBZ appear to be minimal. ..
  8. Gorman N, Walton H, Sinclair J, Sinclair P. CYP1A-catalyzed uroporphyrinogen oxidation in hepatic microsomes from non-mammalian vertebrates (chick and duck embryos, scup and alligator). Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1998;121:405-12 pubmed
    ..The differences in PHAH stimulation of UROX among the non-mammalian species have implications in the evolutionary changes in CYP1A, as well as the mechanism of development of PHAH-stimulated uroporphyria in different species. ..
  9. Warren M, Bolt E, Roessner C, Scott A, Spencer J, Woodcock S. Gene dissection demonstrates that the Escherichia coli cysG gene encodes a multifunctional protein. Biochem J. 1994;302 ( Pt 3):837-44 pubmed
    ..The evidence presented in this paper suggests that the CysG protein is a multifunctional protein involved in SAM-dependent methylation, pyridine dinucleotide dependent dehydrogenation and ferrochelation. ..
  10. Pichon C, Atshaves B, Danso Danquah R, Stolowich N, Scott A. 19-Bromo-1-hydroxymethylbilane, a novel inhibitor of uro'gen III synthase. Bioorg Med Chem. 1994;2:267-77 pubmed
    ..A novel hydroxymethylbilane analog, 19-Br-HMB (11), has been synthesized. Its activity with the enzyme Uro'gen III synthase shows competitive inhibition. ..
  11. Urquhart A, Elder G, Roberts A, Lambrecht R, Sinclair P, Bement W, et al. Uroporphyria produced in mice by 20-methylcholanthrene and 5-aminolaevulinic acid. Biochem J. 1988;253:357-62 pubmed
  12. De Matteis F, Harvey C, Reed C, Hempenius R. Increased oxidation of uroporphyrinogen by an inducible liver microsomal system. Possible relevance to drug-induced uroporphyria. Biochem J. 1988;250:161-9 pubmed
  13. Jacobs J, Sinclair P, Lambrecht R, Sinclair J. Effects of iron-EDTA on uroporphyrinogen oxidation by liver microsomes. FEBS Lett. 1989;250:349-52 pubmed
    ..These data suggest that the oxidations of uroporphyrinogen in the presence and absence of added iron occur by different mechanisms. ..
  14. Urata G. [The chemistry of porphyrins and their precursors on the heme biosynthetic chain]. Nihon Rinsho. 1995;53:1319-28 pubmed
  15. Jordan P. The biosynthesis of uroporphyrinogen III: mechanism of action of porphobilinogen deaminase. Ciba Found Symp. 1994;180:70-89; discussion 89-96 pubmed
    ..9A resolution and gives important insight into the enzymic mechanism. Aspartate 84 plays a key role in catalysis and its substitution by glutamate reduces kcat by two orders of magnitude. ..
  16. Mercer Smith J, Raudino A, Mauzerall D. A model for the origin of photosynthesis--III. The ultraviolet photochemistry of uroporphyrinogen. Photochem Photobiol. 1985;42:239-44 pubmed
    ..This research shows how the oxidation of uroporphyrinogen to uroporphyrin, the first biogenetic porphyrin, could have occurred anaerobically and abiotically on the primordial earth. ..
  17. Pichon C, Atshaves B, Stolowich N, Scott A. Evidence for an intermediate in the enzymatic formation of uroporphyrinogen III. Bioorg Med Chem. 1994;2:153-68 pubmed
    ..Using conditions to slow down the enzyme activity (high pH, low temperature), the transient species was trapped with ammonium ions as aminomethylbilane and with sodium borohydride as methylbilane, and observed by 13C-NMR. ..
  18. Lambrecht R, Sinclair P, Gorman N, Sinclair J. Uroporphyrinogen oxidation catalyzed by reconstituted cytochrome P450IA2. Arch Biochem Biophys. 1992;294:504-10 pubmed
  19. Kurlandzka A, Zoladek T, Rytka J, Labbe Bois R, Urban Grimal D. The effects in vivo of mutationally modified uroporphyrinogen decarboxylase in different hem12 mutants of baker's yeast (Saccharomyces cerevisiae). Biochem J. 1988;253:109-16 pubmed
    ..The biochemical phenotypes of both the haploid and the heterozygous diploid resembles closely the situation encountered in porphyria cutanea tarda, the most common human form of porphyria. ..
  20. Woods J, Calas C. Iron stimulation of free radical-mediated porphyrinogen oxidation by hepatic and renal mitochondria. Biochem Biophys Res Commun. 1989;160:101-8 pubmed
    ..These observations suggest a mechanism by which iron could contribute to excess porphyrin excretion in various inherited or chemically-induced porphyrias. ..
  21. Daïkha Dahmane F, Dommergues M, Narcy F, Gubler M, Dumez Y, Gauthier E, et al. Congenital erythropoietic porphyria: prenatal diagnosis and autopsy findings in two sibling fetuses. Pediatr Dev Pathol. 2001;4:180-4 pubmed
    ..The autopsy showed brown skin, and at histological examination, porphyrin pigment was deposited in many tissues. Retrospectively, similar deposits were found in the tissues of the first fetus. ..
  22. Raux E, Lanois A, Rambach A, Warren M, Thermes C. Cobalamin (vitamin B12) biosynthesis: functional characterization of the Bacillus megaterium cbi genes required to convert uroporphyrinogen III into cobyrinic acid a,c-diamide. Biochem J. 1998;335 ( Pt 1):167-73 pubmed
    ..These strains were used to demonstrate that, whereas B. megaterium cbiD, -G and -X are essential for cobyric acid synthesis, the cbiW and -Y genes could be deleted without detriment to cobyric acid production in E. coli. ..
  23. Li N, Chu X, Wu L, Liu X, Li D. Functional studies of rat hydroxymethylbilane synthase. Bioorg Chem. 2008;36:241-51 pubmed publisher
    ..Three analogs were found to be weak substrates of the enzyme. All four analogs can be used for the preparation of uroporphyrin I analogs. ..
  24. Christenson W, Bestervelt L, Piper W. Evidence for pteridine regulation of lead-mediated inhibition of uroporphyrinogen and heme formation in rat bone marrow. Toxicol Appl Pharmacol. 1992;113:138-43 pubmed
  25. Hibino A, Petri R, Buchs J, Ohtake H. Production of uroporphyrinogen III, which is the common precursor of all tetrapyrrole cofactors, from 5-aminolevulinic acid by Escherichia coli expressing thermostable enzymes. Appl Microbiol Biotechnol. 2013;97:7337-44 pubmed publisher
    ..1 mM (990 mg/l) urogen III was produced from 10 mM ALA. The present technology has great potential to supply urogen III for the biocatalytic production of vitamin B??. ..
  26. Arch D, Bergeron M, Hathaway L, Kushner J, Phillips J, Franklin M. Longitudinal study of a mouse model of familial porphyria cutanea tarda. Cell Mol Biol (Noisy-le-grand). 2009;55:46-54 pubmed
    ..This murine model of familial PCT affords the opportunity to study changes in porphyrinogen and porphyrin accumulation and transport in the absence of exogenous factors that alter P450 activity and transmembrane transporters. ..
  27. Silva P, Ramos M. Density-functional study of mechanisms for the cofactor-free decarboxylation performed by uroporphyrinogen III decarboxylase. J Phys Chem B. 2005;109:18195-200 pubmed
    ..5 kcal.mol(-1). The central positioning of this residue in close proximity to all four pyrrole rings in the substrate may play a key role in the sequential activation of each of these moieties. ..
  28. Phillips J, Jackson L, Bunting M, Franklin M, Thomas K, Levy J, et al. A mouse model of familial porphyria cutanea tarda. Proc Natl Acad Sci U S A. 2001;98:259-64 pubmed
    ..The URO-D(+/-) mouse serves as an excellent model of familial PCT and affords the opportunity to define the mechanism by which iron influences URO-D activity. ..
  29. Sinclair P, Gorman N, Walton H, Bement W, Szakacs J, Gonzalez F, et al. Relative roles of CYP2E1 and CYP1A2 in mouse uroporphyria caused by acetone. Arch Biochem Biophys. 2000;384:383-90 pubmed
    ..Acetone was not an inducer of hepatic CYP1A2 in the wild-type mice. Although acetone is an inducer of CYP2E1, CYP1A2 appears to have the essential role in acetone-enhancement of uroporphyria. ..
  30. Di Pierro E, Brancaleoni V, Cappellini M. Gene symbol: HMBS. Disease: Porphyria, acute intermittent. Hum Genet. 2005;116:537 pubmed
  31. Jacobs J, Sinclair P, Bement W, Lambrecht R, Sinclair J, Goldstein J. Oxidation of uroporphyrinogen by methylcholanthrene-induced cytochrome P-450. Essential role of cytochrome P-450d. Biochem J. 1989;258:247-53 pubmed
    ..These data indicate that hepatic P-450d catalyses uroporphyrinogen oxidation. We suggest that the P-450d-catalysed oxidation of uroporphyrinogen has a role in the uroporphyria caused by hexachlorobenzene and other compounds...
  32. Hansson M, Rutberg L, Schröder I, Hederstedt L. The Bacillus subtilis hemAXCDBL gene cluster, which encodes enzymes of the biosynthetic pathway from glutamate to uroporphyrinogen III. J Bacteriol. 1991;173:2590-9 pubmed
    ..An analysis of B. subtilis carrying integrated plasmids or deletions-substitutions in or downstream of hemL indicates that no further genes in heme synthesis are part of the proposed hem operon. ..
  33. Warren M, Scott A. Tetrapyrrole assembly and modification into the ligands of biologically functional cofactors. Trends Biochem Sci. 1990;15:486-91 pubmed
  34. Beukeveld G, Wolthers B, Nordmann Y, Deybach J, Grandchamp B, Wadman S. A retrospective study of a patient with homozygous form of acute intermittent porphyria. J Inherit Metab Dis. 1990;13:673-83 pubmed
    ..Due to the early onset in the index patient, its persistent character, and the fact that both parents are affected we postulate retrospectively to have diagnosed a case of homozygous or a double heterozygous AIP, hitherto undescribed. ..
  35. Leeper F. The evidence for a spirocyclic intermediate in the formation of uroporphyrinogen III by cosynthase. Ciba Found Symp. 1994;180:111-23; discussion 124-30 pubmed
  36. Sinclair P, Gorman N, Walton H, Sinclair J, Lee C, Rifkind A. Identification of CYP1A5 as the CYP1A enzyme mainly responsible for uroporphyrinogen oxidation induced by AH receptor ligands in chicken liver and kidney. Drug Metab Dispos. 1997;25:779-83 pubmed
  37. Sattler I, Roessner C, Stolowich N, Hardin S, Harris Haller L, Yokubaitis N, et al. Cloning, sequencing, and expression of the uroporphyrinogen III methyltransferase cobA gene of Propionibacterium freudenreichii (shermanii). J Bacteriol. 1995;177:1564-9 pubmed
    ..These two genes do not appear to constitute part of an extensive cobalamin operon. ..
  38. De Matteis F, Dawson S, Pons N, Pipino S. Bilirubin and uroporphyrinogen oxidation by induced cytochrome P4501A and cytochrome P4502B. Role of polyhalogenated biphenyls of different configuration. Biochem Pharmacol. 2002;63:615-24 pubmed
  39. Luo J, Lim C. Order of uroporphyrinogen III decarboxylation on incubation of porphobilinogen and uroporphyrinogen III with erythrocyte uroporphyrinogen decarboxylase. Biochem J. 1993;289 ( Pt 2):529-32 pubmed
  40. Pons N, Pipino S, De Matteis F. Interaction of polyhalogenated compounds of appropriate configuration with mammalian or bacterial CYP enzymes. Increased bilirubin and uroporphyrinogen oxidation in vitro. Biochem Pharmacol. 2003;66:405-14 pubmed
    ..A role of the ferryl-oxygen intermediate is suggested in the oxidation of biologically important molecules, with possible implications for the therapy of jaundice and for toxic oxidative reactions, such as uroporphyria and cancer. ..
  41. Ivanova V, Zimonjic D, Popescu N, Bonner W. Chromosomal localization of the human histone H2A.X gene to 11q23.2-q23.3 by fluorescence in situ hybridization. Hum Genet. 1994;94:303-6 pubmed
    ..In addition the HMB-synthase gene contains constitutive and erythroid specific promoters. K562, an erythroid cell line, was found to contain a high concentration of the 1.6-kb polyadenylated H2A.X mRNA. ..
  42. Silva P, Schulz C, Jahn D, Jahn M, Ramos M. A tale of two acids: when arginine is a more appropriate acid than H3O+. J Phys Chem B. 2010;114:8994-9001 pubmed publisher
  43. Ku W, Piper W. Pteridine modulation of lead inhibition of uroporphyrinogen synthesis in erythroid precursor cells. Toxicol Lett. 1990;51:91-7 pubmed
    ..MELC are expected to be a useful in vitro model for studying the role of endogenous folates on uroporphyrinogen synthesis and heme formation in erythroid precursor cells following lead exposure. ..
  44. Jacobs J, Sinclair P, Lambrecht R, Sinclair J, Jacobs N. Role of inducer binding in cytochrome P-450 IA2-mediated uroporphyrinogen oxidation. J Biochem Toxicol. 1990;5:193-9 pubmed
    ..We conclude that uroporphyrinogen oxidation is catalyzed by cytochrome P-450 that is free of inducer. ..
  45. Phillips J, Bergonia H, Reilly C, Franklin M, Kushner J. A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda. Proc Natl Acad Sci U S A. 2007;104:5079-84 pubmed
    ..These studies define the mechanism underlying clinical expression of the PCT phenotype, namely oxidation of uroporphyrinogen to uroporphomethene, a competitive inhibitor of URO-D. The oxidation reaction is iron-dependent. ..
  46. Iida K, Nakamura M, Hanamitsu H, Kajiwara M. Identification of tetrapyrrole compounds excreted by Rhodobacter sphaeroides and sources of the methyl hydrogens of bacteriochlorophyll a biosynthesized by R. sphaeroides, based on 13C-NMR spectral analysis of coproporphyrin III tetramethyl ester. Chem Pharm Bull (Tokyo). 2007;55:1067-9 pubmed
  47. Schubert H, Phillips J, Heroux A, Hill C. Structure and mechanistic implications of a uroporphyrinogen III synthase-product complex. Biochemistry. 2008;47:8648-55 pubmed publisher
    ..A conserved tyrosine residue is potentially positioned to facilitate loss of a hydroxyl from the substrate to initiate the catalytic reaction. ..
  48. Correa Garcia S, Rossetti M, Bermudez Moretti M, Batlle A. Yeast porphobilinogen deaminase also forms enzyme-pyrrole intermediates. Enzyme Protein. 1994;48:275-81 pubmed
  49. Araya M, Tantaleán J, Perez J, Fuentes D, Calderón I, Saavedra C, et al. Cloning, purification and characterization of Geobacillus stearothermophilus V uroporphyrinogen-III C-methyltransferase: evaluation of its role in resistance to potassium tellurite in Escherichia coli. Res Microbiol. 2009;160:125-33 pubmed publisher
    ..coli, suggesting that the role of SUMT methyltransferase in tellurite(ate) detoxification is not related to tellurium volatilization. ..
  50. Jinno H, Hanioka N, Onodera S, Nishimura T, Ando M. Irgasan DP 300 (5-chloro-2-(2,4-dichlorophenoxy)-phenol) induces cytochrome P450s and inhibits haem biosynthesis in rat hepatocytes cultured on Matrigel. Xenobiotica. 1997;27:681-92 pubmed
    ..6. These results indicate that Irgasan DP 300 produced accumulation of hydroxymethylbilane in rat hepatocytes by inhibiting uroporphyrinogen III synthase, and consequently an accumulation of uroporphyrin I...
  51. Buchenau B, Kahnt J, Heinemann I, Jahn D, Thauer R. Heme biosynthesis in Methanosarcina barkeri via a pathway involving two methylation reactions. J Bacteriol. 2006;188:8666-8 pubmed
    ..The existence of this pathway, previously exclusively found in the sulfate-reducing delta-proteobacterium Desulfovibrio vulgaris, was demonstrated for M. barkeri via the incorporation of two methyl groups from methionine into protoheme...
  52. de Catabbi S, de Calmanovici R, Minutolo C, Aldonatti C, San Martin de Viale L. Porphyria-induced hepatic porphyrinogen carboxy-lyase inhibitor and its interaction with the active site(s) of the enzyme. Biochem Mol Biol Int. 1999;47:945-56 pubmed
    ..In addition an indirect effect of the inhibitor mediated through free radicals could be discarded. ..
  53. Rose S, Frydman R, de los Santos C, Sburlati A, Valasinas A, Frydman B. Spectroscopic evidence for a porphobilinogen deaminase-tetrapyrrole complex that is an intermediate in the biosynthesis of uroporphyrinogen III. Biochemistry. 1988;27:4871-9 pubmed
    ..It was found that while the HMB inhibited uro'gen III formation at higher concentrations and longer incubation times, uro'gen III formation from the complex did not decrease with time. ..