Metabolism of porphyrins (Homo sapiens)

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2, 101765, 167, 23, 25, 272014, 2012, 265, 161, 8, 113, 415, 18229, 2113, 19, 24, 26mitochondrial matrixHMBSDIPY 2x2xCPO endoplasmic reticulum lumen2xUROD cytosol8xALADPb2+Zn2+ 2xPPOFAD 8x4xUGT1A1 PPOX BMGH2ONH3O2NADP+UDPCO2DIPY CoA-SHFPPGlyBDGALAD H2OBiliverdin reductase2xURODUROD HMBSDIPYheme ABILPPiCO2Fe2+COX102xH2O2UGT1A1COPRO3FAD Pb2+hemeHMOX1/28xALADPb2+Zn2+COALAD COPRO3Pb2+ H2O8xBVALAS1,2CO2dALAPb2+COX15hemeUROSSUCC-CoACOPRO1heme OH2O2NADPHUDP-GlcAH2OFECH PPGEN9Fe2+PRIN94xUGT1A1UGT1A1 Zn2+ URO1O2H+HMBLHMBS URO3dALACPOX2xCPO2xPPOFADPRIN9H2OO2PBGH2OZn2+ Zn2+BIL


Description

Porphyrins are heterocyclic macrocycles, consisting of four pyrrole subunits (tetrapyrrole) linked by four methine (=CH-) bridges. The extensive conjugated porphyrin macrocycle is chromatic and the name itself, porphyrin, is derived from the Greek word for purple. The aromatic character of porphyrins can be seen by NMR spectroscopy.
Porphyrins readily combine with metals by coordinating them in the central cavity. Iron (heme) and magnesium (chlorophyll) are two well known examples although zinc, copper, nickel and cobalt form other known metal-containing phorphyrins. A porphyrin which has no metal in the cavity is called a free base.
Some iron-containing porphyrins are called hemes (heme-containing proteins or hemoproteins) and these are found extensively in nature ie. hemoglobin. Hemoglobin is quantitatively the most important hemoprotein. The hemoglobin iron is the transfer site of oxygen and carries it in the blood all round the body for cell respiration. Other examples are cytochromes present in mitochondria and endoplasmic reticulum which takes part in electron transfer events, catalase and peroxidase whic protect the body against the oxidant hydrogen peroxide and tryptophan oxygenase which is present in intermediary metabolism. Hemoproteins are synthesized in all mammalian cells and the major sites are erythropoietic tissue and the liver.

The processes by which heme is synthesized, transported, and metabolized are a critical part of human iron metabolism (Severance and Hamze 2009); here the core processes of heme biosynthesis and catabolism have been annotated. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=189445</div>

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Bibliography

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  1. Erlinger S, Arias IM, Dhumeaux D.; ''Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences.''; PubMed Europe PMC Scholia
  2. Tsai SF, Bishop DF, Desnick RJ.; ''Purification and properties of uroporphyrinogen III synthase from human erythrocytes.''; PubMed Europe PMC Scholia
  3. Grandchamp B, Phung N, Nordmann Y.; ''The mitochondrial localization of coproporphyrinogen III oxidase.''; PubMed Europe PMC Scholia
  4. Oquendo CE, Antonicka H, Shoubridge EA, Reardon W, Brown GK.; ''Functional and genetic studies demonstrate that mutation in the COX15 gene can cause Leigh syndrome.''; PubMed Europe PMC Scholia
  5. Kamisako T, Kobayashi Y, Takeuchi K, Ishihara T, Higuchi K, Tanaka Y, Gabazza EC, Adachi Y.; ''Recent advances in bilirubin metabolism research: the molecular mechanism of hepatocyte bilirubin transport and its clinical relevance.''; PubMed Europe PMC Scholia
  6. Xu J, Liu Y, Yang Y, Bates S, Zhang JT.; ''Characterization of oligomeric human half-ABC transporter ATP-binding cassette G2.''; PubMed Europe PMC Scholia
  7. Anderson PM, Desnick RJ.; ''Purification and properties of uroporphyrinogen I synthase from human erythrocytes. Identification of stable enzyme-substrate intermediates.''; PubMed Europe PMC Scholia
  8. Weisiger RA, Ostrow JD, Koehler RK, Webster CC, Mukerjee P, Pascolo L, Tiribelli C.; ''Affinity of human serum albumin for bilirubin varies with albumin concentration and buffer composition: results of a novel ultrafiltration method.''; PubMed Europe PMC Scholia
  9. Murakami T, Reiter LT, Lupski JR.; ''Genomic structure and expression of the human heme A:farnesyltransferase (COX10) gene.''; PubMed Europe PMC Scholia
  10. Krishnamurthy P, Ross DD, Nakanishi T, Bailey-Dell K, Zhou S, Mercer KE, Sarkadi B, Sorrentino BP, Schuetz JD.; ''The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme.''; PubMed Europe PMC Scholia
  11. Ritter JK, Chen F, Sheen YY, Tran HM, Kimura S, Yeatman MT, Owens IS.; ''A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini.''; PubMed Europe PMC Scholia
  12. Quigley JG, Yang Z, Worthington MT, Phillips JD, Sabo KM, Sabath DE, Berg CL, Sassa S, Wood BL, Abkowitz JL.; ''Identification of a human heme exporter that is essential for erythropoiesis.''; PubMed Europe PMC Scholia
  13. Rey MA, Duffy SP, Brown JK, Kennedy JA, Dick JE, Dror Y, Tailor CS.; ''Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis.''; PubMed Europe PMC Scholia
  14. Seyfried H, Klicpera M, Leithner C, Penner E.; ''[Bilirubin metabolism (author's transl)].''; PubMed Europe PMC Scholia
  15. Troxler RF, Dawber NH, Lester R.; ''Synthesis of urobilinogen by broken cell preparations of intestinal bacteria.''; PubMed Europe PMC Scholia
  16. Leung JW, Liu YL, Leung PS, Chan RC, Inciardi JF, Cheng AF.; ''Expression of bacterial beta-glucuronidase in human bile: an in vitro study.''; PubMed Europe PMC Scholia
  17. Antonicka H, Mattman A, Carlson CG, Glerum DM, Hoffbuhr KC, Leary SC, Kennaway NG, Shoubridge EA.; ''Mutations in COX15 produce a defect in the mitochondrial heme biosynthetic pathway, causing early-onset fatal hypertrophic cardiomyopathy.''; PubMed Europe PMC Scholia
  18. WATSON CJ, CAMPBELL M, LOWRY PT.; ''Preferential reduction of conjugated bilirubin to urobilinogen by normal fecal flora.''; PubMed Europe PMC Scholia
  19. Cui Y, König J, Leier I, Buchholz U, Keppler D.; ''Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6.''; PubMed Europe PMC Scholia
  20. Cunningham O, Gore MG, Mantle TJ.; ''Initial-rate kinetics of the flavin reductase reaction catalysed by human biliverdin-IXbeta reductase (BVR-B).''; PubMed Europe PMC Scholia
  21. Rigato I, Pascolo L, Fernetti C, Ostrow JD, Tiribelli C.; ''The human multidrug-resistance-associated protein MRP1 mediates ATP-dependent transport of unconjugated bilirubin.''; PubMed Europe PMC Scholia
  22. Rupe CO, Fetter MC.; ''Urinary urobilinogen determined by a mercuric chloride procedure.''; PubMed Europe PMC Scholia
  23. Astner I, Schulze JO, van den Heuvel J, Jahn D, Schubert WD, Heinz DW.; ''Crystal structure of 5-aminolevulinate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans.''; PubMed Europe PMC Scholia
  24. Mitchell LW, Volin M, Martins J, Jaffe EK.; ''Mechanistic implications of mutations to the active site lysine of porphobilinogen synthase.''; PubMed Europe PMC Scholia
  25. Schröter W.; ''[Intracellular bilirubin transport and the membrane of the hepatic endoplasmic reticulum: new aspects in the development of transitory bilirubinemia of the newborn].''; PubMed Europe PMC Scholia
  26. Bayeva M, Khechaduri A, Wu R, Burke MA, Wasserstrom JA, Singh N, Liesa M, Shirihai OS, Langer NB, Paw BH, Ardehali H.; ''ATP-binding cassette B10 regulates early steps of heme synthesis.''; PubMed Europe PMC Scholia
  27. Kamisako T, Leier I, Cui Y, König J, Buchholz U, Hummel-Eisenbeiss J, Keppler D.; ''Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2.''; PubMed Europe PMC Scholia
  28. Vítek L, Majer F, Muchová L, Zelenka J, Jirásková A, Branný P, Malina J, Ubik K.; ''Identification of bilirubin reduction products formed by Clostridium perfringens isolated from human neonatal fecal flora.''; PubMed Europe PMC Scholia
  29. Wakabayashi K, Nakagawa H, Tamura A, Koshiba S, Hoshijima K, Komada M, Ishikawa T.; ''Intramolecular disulfide bond is a critical check point determining degradative fates of ATP-binding cassette (ABC) transporter ABCG2 protein.''; PubMed Europe PMC Scholia
  30. Fu G, Liu H, Doerksen RJ.; ''Molecular modeling to provide insight into the substrate binding and catalytic mechanism of human biliverdin-IXα reductase.''; PubMed Europe PMC Scholia
  31. Kim DH, Jin YH, Jung EA, Han MJ, Kobashi K.; ''Purification and characterization of beta-glucuronidase from Escherichia coli HGU-3, a human intestinal bacterium.''; PubMed Europe PMC Scholia
  32. Desuzinges-Mandon E, Arnaud O, Martinez L, Huché F, Di Pietro A, Falson P.; ''ABCG2 transports and transfers heme to albumin through its large extracellular loop.''; PubMed Europe PMC Scholia
  33. Krishnamurthy PC, Du G, Fukuda Y, Sun D, Sampath J, Mercer KE, Wang J, Sosa-Pineda B, Murti KG, Schuetz JD.; ''Identification of a mammalian mitochondrial porphyrin transporter.''; PubMed Europe PMC Scholia
  34. Akagi R, Shimizu R, Furuyama K, Doss MO, Sassa S.; ''Novel molecular defects of the delta-aminolevulinate dehydratase gene in a patient with inherited acute hepatic porphyria.''; PubMed Europe PMC Scholia
  35. Kullak-Ublick GA, Ismair MG, Stieger B, Landmann L, Huber R, Pizzagalli F, Fattinger K, Meier PJ, Hagenbuch B.; ''Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver.''; PubMed Europe PMC Scholia
  36. Cooper CL, Lash TD, Jones MA.; ''Kinetic evaluation of human cloned coproporphyrinogen oxidase using a ring isomer of the natural substrate.''; PubMed Europe PMC Scholia
  37. Simons PC, Jagt DL.; ''Bilirubin binding to human liver ligandin (glutathione S-transferase).''; PubMed Europe PMC Scholia
  38. Koníčková R, Jirásková A, Zelenka J, Lešetický L, Štícha M, Vítek L.; ''Reduction of bilirubin ditaurate by the intestinal bacterium Clostridium perfringens.''; PubMed Europe PMC Scholia
  39. Qiu W, Liesa M, Carpenter EP, Shirihai OS.; ''ATP Binding and Hydrolysis Properties of ABCB10 and Their Regulation by Glutathione.''; PubMed Europe PMC Scholia
  40. Peters WH, Jansen PL.; ''Microsomal UDP-glucuronyltransferase-catalyzed bilirubin diglucuronide formation in human liver.''; PubMed Europe PMC Scholia
  41. de Verneuil H, Sassa S, Kappas A.; ''Purification and properties of uroporphyrinogen decarboxylase from human erythrocytes. A single enzyme catalyzing the four sequential decarboxylations of uroporphyrinogens I and III.''; PubMed Europe PMC Scholia
  42. Jaffe EK, Martins J, Li J, Kervinen J, Dunbrack RL.; ''The molecular mechanism of lead inhibition of human porphobilinogen synthase.''; PubMed Europe PMC Scholia
  43. Wu CK, Dailey HA, Rose JP, Burden A, Sellers VM, Wang BC.; ''The 2.0 A structure of human ferrochelatase, the terminal enzyme of heme biosynthesis.''; PubMed Europe PMC Scholia
  44. Zhang W, Mojsilovic-Petrovic J, Andrade MF, Zhang H, Ball M, Stanimirovic DB.; ''The expression and functional characterization of ABCG2 in brain endothelial cells and vessels.''; PubMed Europe PMC Scholia
  45. Knauer MJ, Girdwood AJ, Kim RB, Tirona RG.; ''Transport function and transcriptional regulation of a liver-enriched human organic anion transporting polypeptide 2B1 transcriptional start site variant.''; PubMed Europe PMC Scholia
  46. Doyle L, Ross DD.; ''Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2).''; PubMed Europe PMC Scholia
  47. Lee DS, Flachsová E, Bodnárová M, Demeler B, Martásek P, Raman CS.; ''Structural basis of hereditary coproporphyria.''; PubMed Europe PMC Scholia
  48. Hostetler HA, McIntosh AL, Atshaves BP, Storey SM, Payne HR, Kier AB, Schroeder F.; ''L-FABP directly interacts with PPARalpha in cultured primary hepatocytes.''; PubMed Europe PMC Scholia
  49. Shoolingin-Jordan PM.; ''Porphobilinogen deaminase and uroporphyrinogen III synthase: structure, molecular biology, and mechanism.''; PubMed Europe PMC Scholia
  50. Moran-Jimenez MJ, Ged C, Romana M, Enriquez De Salamanca R, Taïeb A, Topi G, D'Alessandro L, de Verneuil H.; ''Uroporphyrinogen decarboxylase: complete human gene sequence and molecular study of three families with hepatoerythropoietic porphyria.''; PubMed Europe PMC Scholia
  51. Fujiwara R, Itoh T.; ''Extensive protein-protein interactions involving UDP-glucuronosyltransferase (UGT) 2B7 in human liver microsomes.''; PubMed Europe PMC Scholia
  52. König J, Cui Y, Nies AT, Keppler D.; ''A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane.''; PubMed Europe PMC Scholia
  53. Rowland A, Miners JO, Mackenzie PI.; ''The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification.''; PubMed Europe PMC Scholia
  54. Griffiths WC, Diamond I, Dextraze P.; ''The albumin binding of unconjugated bilirubin in serum.''; PubMed Europe PMC Scholia
  55. Bugiani M, Tiranti V, Farina L, Uziel G, Zeviani M.; ''Novel mutations in COX15 in a long surviving Leigh syndrome patient with cytochrome c oxidase deficiency.''; PubMed Europe PMC Scholia
  56. Gardner LC, Smith SJ, Cox TM.; ''Biosynthesis of delta-aminolevulinic acid and the regulation of heme formation by immature erythroid cells in man.''; PubMed Europe PMC Scholia
  57. Shoolingin-Jordan PM, Al-Dbass A, McNeill LA, Sarwar M, Butler D.; ''Human porphobilinogen deaminase mutations in the investigation of the mechanism of dipyrromethane cofactor assembly and tetrapyrrole formation.''; PubMed Europe PMC Scholia
  58. Petruzzella V, Tiranti V, Fernandez P, Ianna P, Carrozzo R, Zeviani M.; ''Identification and characterization of human cDNAs specific to BCS1, PET112, SCO1, COX15, and COX11, five genes involved in the formation and function of the mitochondrial respiratory chain.''; PubMed Europe PMC Scholia
  59. Dailey TA, Dailey HA.; ''Human protoporphyrinogen oxidase: expression, purification, and characterization of the cloned enzyme.''; PubMed Europe PMC Scholia
  60. van de Steeg E, Stránecký V, Hartmannová H, Nosková L, Hřebíček M, Wagenaar E, van Esch A, de Waart DR, Oude Elferink RP, Kenworthy KE, Sticová E, al-Edreesi M, Knisely AS, Kmoch S, Jirsa M, Schinkel AH.; ''Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver.''; PubMed Europe PMC Scholia
  61. Wolfrum C, Borrmann CM, Borchers T, Spener F.; ''Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha - and gamma-mediated gene expression via liver fatty acid binding protein: a signaling path to the nucleus.''; PubMed Europe PMC Scholia
  62. Gordon ER, Sommerer U, Goresky CA.; ''The hepatic microsomal formation of bilirubin diglucuronide.''; PubMed Europe PMC Scholia
  63. Fevery J, Van Damme B, Michiels R, De Groote J, Heirwegh KP.; ''Bilirubin conjugates in bile of man and rat in the normal state and in liver disease.''; PubMed Europe PMC Scholia
  64. Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Oude Elferink RP, Chowdhury JR, Chowdhury NR, Jansen PL.; ''Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man.''; PubMed Europe PMC Scholia
  65. Chowdhury JR, Chowdhury NR, Wu G, Shouval R, Arias IM.; ''Bilirubin mono- and diglucuronide formation by human liver in vitro: assay by high-pressure liquid chromatography.''; PubMed Europe PMC Scholia
  66. Levi AJ, Gatmaitan Z, Arias IM.; ''Two hepatic cytoplasmic protein fractions, Y and Z, and their possible role in the hepatic uptake of bilirubin, sulfobromophthalein, and other anions.''; PubMed Europe PMC Scholia
  67. Elder GH, Evans JO.; ''Evidence that the coproporphyrinogen oxidase activity of rat liver is situated in the intermembrane space of mitochondria.''; PubMed Europe PMC Scholia
  68. Glerum DM, Tzagoloff A.; ''Isolation of a human cDNA for heme A:farnesyltransferase by functional complementation of a yeast cox10 mutant.''; PubMed Europe PMC Scholia
  69. Chiabrando D, Marro S, Mercurio S, Giorgi C, Petrillo S, Vinchi F, Fiorito V, Fagoonee S, Camporeale A, Turco E, Merlo GR, Silengo L, Altruda F, Pinton P, Tolosano E.; ''The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
115020view16:55, 25 January 2021ReactomeTeamReactome version 75
113465view11:54, 2 November 2020ReactomeTeamReactome version 74
112665view16:05, 9 October 2020ReactomeTeamReactome version 73
101581view11:44, 1 November 2018ReactomeTeamreactome version 66
101117view21:28, 31 October 2018ReactomeTeamreactome version 65
100645view20:02, 31 October 2018ReactomeTeamreactome version 64
100195view16:47, 31 October 2018ReactomeTeamreactome version 63
99746view15:13, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99311view12:46, 31 October 2018ReactomeTeamreactome version 62
96915view14:08, 19 April 2018EgonwCorrected the ChEBI identifier
93806view13:37, 16 August 2017ReactomeTeamreactome version 61
93347view11:21, 9 August 2017ReactomeTeamreactome version 61
86431view09:18, 11 July 2016ReactomeTeamreactome version 56
83091view09:57, 18 November 2015ReactomeTeamVersion54
81415view12:56, 21 August 2015ReactomeTeamVersion53
76884view08:15, 17 July 2014ReactomeTeamFixed remaining interactions
76589view11:57, 16 July 2014ReactomeTeamFixed remaining interactions
75922view09:57, 11 June 2014ReactomeTeamRe-fixing comment source
75623view10:49, 10 June 2014ReactomeTeamReactome 48 Update
74978view13:50, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74622view08:40, 30 April 2014ReactomeTeamReactome46
68998view17:45, 8 July 2013MaintBotUpdated to 2013 gpml schema
44899view10:20, 6 October 2011MartijnVanIerselOntology Term : 'porphyrin and chlorophyll metabolic pathway' added !
42168view23:34, 4 March 2011MaintBotModified categories
42070view21:54, 4 March 2011MaintBotAutomatic update
39878view05:54, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2xCPOComplexREACT_9811 (Reactome)
2xPPO FADComplexREACT_9681 (Reactome)
2xComplexREACT_9592 (Reactome)
2xURODComplexREACT_9830 (Reactome)
4xUGT1A1ComplexREACT_22998 (Reactome)
8xALAD

Pb2+

Zn2+		ComplexREACT_9852 (Reactome)
8xComplexREACT_9587 (Reactome)
ALAD ProteinP13716 (Uniprot-TrEMBL)
ALAS1,2REACT_9546 (Reactome)
BDGMetaboliteCHEBI:18392 (ChEBI)
BILMetaboliteCHEBI:16990 (ChEBI)
BMGMetaboliteCHEBI:16427 (ChEBI)
BVMetaboliteCHEBI:17033 (ChEBI)
Biliverdin reductaseREACT_22833 (Reactome)
CO2MetaboliteCHEBI:16526 (ChEBI)
COMetaboliteCHEBI:17245 (ChEBI)
COPRO1MetaboliteCHEBI:28607 (ChEBI)
COPRO3MetaboliteCHEBI:15439 (ChEBI)
COX10ProteinQ12887 (Uniprot-TrEMBL)
COX15ProteinQ7KZN9 (Uniprot-TrEMBL)
CPOXProteinP36551 (Uniprot-TrEMBL)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
DIPY MetaboliteCHEBI:36319 (ChEBI)
FAD MetaboliteCHEBI:16238 (ChEBI)
FECH ProteinP22830 (Uniprot-TrEMBL)
FPPMetaboliteCHEBI:17407 (ChEBI)
Fe2+MetaboliteCHEBI:18248 (ChEBI)
GlyMetaboliteCHEBI:15428 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2O2MetaboliteCHEBI:16240 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HMBLMetaboliteCHEBI:16645 (ChEBI)
HMBS DIPYComplexREACT_9578 (Reactome)
HMBS ProteinP08397 (Uniprot-TrEMBL)
HMOX1/2REACT_22577 (Reactome)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NH3MetaboliteCHEBI:16134 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
PBGMetaboliteCHEBI:17381 (ChEBI)
PPGEN9MetaboliteCHEBI:15435 (ChEBI)
PPOX ProteinP50336 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRIN9MetaboliteCHEBI:15430 (ChEBI)
Pb2+ MetaboliteCHEBI:27889 (ChEBI)
Pb2+MetaboliteCHEBI:27889 (ChEBI)
SUCC-CoAMetaboliteCHEBI:15380 (ChEBI)
UDP-GlcAMetaboliteCHEBI:17200 (ChEBI)
UDPMetaboliteCHEBI:17659 (ChEBI)
UGT1A1 ProteinP22309 (Uniprot-TrEMBL)
UGT1A1ProteinP22309 (Uniprot-TrEMBL)
URO1MetaboliteCHEBI:28766 (ChEBI)
URO3MetaboliteCHEBI:15437 (ChEBI)
UROD ProteinP06132 (Uniprot-TrEMBL)
UROSProteinP10746 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
Zn2+MetaboliteCHEBI:29105 (ChEBI)
dALAMetaboliteCHEBI:17549 (ChEBI)
heme AMetaboliteCHEBI:24479 (ChEBI)
heme OMetaboliteCHEBI:24480 (ChEBI)
hemeMetaboliteCHEBI:17627 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2xCPOmim-catalysisREACT_9421 (Reactome)
2xPPO FADmim-catalysisREACT_9418 (Reactome)
2xURODmim-catalysisREACT_9422 (Reactome)
2xURODmim-catalysisREACT_9436 (Reactome)
2xmim-catalysisREACT_9461 (Reactome)
4xUGT1A1mim-catalysisREACT_22319 (Reactome)
8xALAD

Pb2+

Zn2+		ArrowREACT_9437 (Reactome)
8xREACT_9437 (Reactome)
8xmim-catalysisREACT_9430 (Reactome)
ALAS1,2mim-catalysisREACT_9463 (Reactome)
BDGArrowREACT_22319 (Reactome)
BILArrowREACT_22177 (Reactome)
BILREACT_22274 (Reactome)
BMGArrowREACT_22274 (Reactome)
BMGREACT_22319 (Reactome)
BVArrowREACT_22100 (Reactome)
BVREACT_22177 (Reactome)
Biliverdin reductasemim-catalysisREACT_22177 (Reactome)
CO2ArrowREACT_9421 (Reactome)
CO2ArrowREACT_9422 (Reactome)
CO2ArrowREACT_9436 (Reactome)
CO2ArrowREACT_9463 (Reactome)
COArrowREACT_22100 (Reactome)
COPRO1ArrowREACT_9436 (Reactome)
COPRO3ArrowREACT_9422 (Reactome)
COPRO3REACT_9421 (Reactome)
COX10mim-catalysisREACT_163705 (Reactome)
COX15mim-catalysisREACT_163781 (Reactome)
CoA-SHArrowREACT_9463 (Reactome)
FPPREACT_163705 (Reactome)
Fe2+ArrowREACT_22100 (Reactome)
Fe2+REACT_9461 (Reactome)
GlyREACT_9463 (Reactome)
H+ArrowREACT_9461 (Reactome)
H2O2ArrowREACT_9418 (Reactome)
H2O2ArrowREACT_9421 (Reactome)
H2OArrowREACT_22100 (Reactome)
H2OArrowREACT_9408 (Reactome)
H2OArrowREACT_9430 (Reactome)
H2OArrowREACT_9526 (Reactome)
H2OREACT_163705 (Reactome)
H2OREACT_9446 (Reactome)
HMBLArrowREACT_9446 (Reactome)
HMBS DIPYmim-catalysisREACT_9446 (Reactome)
HMOX1/2mim-catalysisREACT_22100 (Reactome)
NADP+ArrowREACT_22100 (Reactome)
NADP+ArrowREACT_22177 (Reactome)
NADPHREACT_22100 (Reactome)
NADPHREACT_22177 (Reactome)
NH3ArrowREACT_9446 (Reactome)
O2REACT_22100 (Reactome)
O2REACT_9418 (Reactome)
O2REACT_9421 (Reactome)
PBGArrowREACT_9430 (Reactome)
PBGREACT_9446 (Reactome)
PPGEN9ArrowREACT_9421 (Reactome)
PPGEN9REACT_9418 (Reactome)
PPiArrowREACT_163705 (Reactome)
PRIN9ArrowREACT_9418 (Reactome)
PRIN9REACT_9461 (Reactome)
Pb2+REACT_9437 (Reactome)
Pb2+TBarREACT_9461 (Reactome)
REACT_163705 (Reactome) Heme O and heme A are specifically synthesised for the heme-copper respiratory oxidases. Mitochondrial protoheme IX farnesyltransferase (COX10) mediates the transformation of protoheme IX (heme) and farnesyl diphosphate (FAPP) to heme O (Glerum & Tzagoloff 1994). COX10 is highly expressed in muscle, heart and brain (Murakami et al. 1997).
REACT_163781 (Reactome) Heme A is the prosthetic group of cytochrome c oxidase, the terminal enzyme in the respiratory chain. It is formed by the action of cytochrome c oxidase assembly protein COX15 homolog (COX15) on heme O (Petruzzella et al. 1998, Antonicka et al. 2003). Defects in COX15 cause of mitochondrial complex IV deficiency (MT-C4D; MIM:220110), also called cytochrome c oxidase deficiency resulting in a disorder of the mitochondrial respiratory chain seen as heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs (Antonicka et al. 2003). Defects in COX15 also cause Leigh syndrome (LS; MIM:256000), an early-onset progressive neurodegenerative disorder characterised by the presence of focal, bilateral lesions in one or more areas of the central nervous system (Oquendo et al. 2004, Bugiani et al. 2005).
REACT_22100 (Reactome) Heme oxygenase (HO) cleaves the heme ring at the alpha-methene bridge to form bilverdin. This reaction forms the only endogenous source of carbon monoxide. HO-1 is inducible and is thought to have an antioxidant role as it's activated in virtually all cell types and by many types of "oxidative stress" (Poss and Tonegawa, 1997). HO-2 is non-inducible.
REACT_22177 (Reactome) Bilirubin is the breakdown product of heme, causing death if allowed to accumulate in the blood. It is highly lipophilic thus requires conjugation to become more water soluble to aid excretion.
REACT_22274 (Reactome) Bilirubin is a breakdown product of heme, causing death if allowed to accumulate in the blood. It is highly lipophilic and thus requires conjugation to become more water soluble to aid excretion. UGT1A1 is the only enzyme that converts bilirubin to either a monoglucuronide or diglucuronide. Mutations of the UGT1A1 gene cause complete loss or partial activity for bilirubin glucuronidation.
REACT_22319 (Reactome) The principal conjugate of bilirubin in bile is bilirubin diglucuronide. The monmeric form of UGT1A1 (Bilirubin UDP-glucuronyltransferase) only conjugates the first step of bilirubin conjugation to form the monoglucuronide. A tetrameric form of UGT1A1 can convert bilirubin to both the monoglucuronide and the diglucuronide.
REACT_22403 (Reactome) The enzyme which catalyzes the conjugation of bilirubin (UGT1A1) is found in the ER. Bilirubin translocates here to be eliminated from the body.
REACT_9393 (Reactome) Protoporphyrin IX (PRIN9) is transported into the mitochondrial matrix where it becomes available for the last step in the heme biosynthetic pathway. The transporter that mediates this event is unknown.
REACT_9408 (Reactome) Hydroxymethybilane (HMBL) can spontaneously cyclize and rearrange to form uroporphyrinogen I (URO1).
REACT_9418 (Reactome) Six electrons are oxidized in protophorphyrinogen IX (PPGEN9) to form the planar macrocycle protoporphyrin IX (PRIN9). This reaction is performed by the enzyme protoporphyrinogen oxidase (PPO). PPO functions as a homodimer containing one non-covalently-bound FAD. The protein resides on the outer surface of the inner mitochondrial membrane. PPO deficiency is associated with variegate porphyria in vivo.
REACT_9421 (Reactome) O2-dependent coproporpyrinogen oxidase (CPO) catalyzes the conversion of coproporphyrinogen III (COPRO3) to protoporphyrinogen IX (PPGEN9). The localization of the human enzyme to the mitochondrial intermembrane space is inferred from studies of the homologous rat enzyme (Elder and Evans 1978). The human enzyme functions as a homodimer (Lee et al. 2005). Enzyme deficiency is associated with hereditary coproporphyria in vivo.
REACT_9422 (Reactome) Cytosolic uroporphyrinogen decarboxylase (UROD) catalyzes the sequntial removal of four carboxylic groups from the acetic acid side chains of uroporphyrinogen III (URO3) to form coproporphyrinogen III (COPRO3) (de Verneuil et al. 1983). Human UROD is a dimer (Whitby et al. 1998). Heterogenous and homogenous deficiencies of UROD are associated with porphyria cutanea tarda and hepatoerythropoietic porphyria respectively in vivo (Moran-Jiminez et al. 1996).
REACT_9430 (Reactome) 5-Aminolevulinic acid dehydratase (ALAD aka porphobilinogen synthase, PBGS), catalyzes the asymmetric condensation of two molecules of ALA to form porphobilinogen (PBG). The substrate that becomes the acetyl side chain-containing half of PBG is called A-side ALA; the half that becomes the propionyl side chains and the pyrrole nitrogen is called P-ALA (Jaffe 2004). PBG is the first pyrrole formed, the precursor to all tetrapyrrole pigments such as heme and chlorophyll. There are at least eight bonds that are made or broken during this reaction. The active form of the ALAD enzyme is an octamer complexed with eight Zn2+ ions, four that are strongly bound and four that are weakly bound. The four weakly bound ones are dispensible for enzyme activity in vitro (Bevan et al. 1980; Mitchell et al. 2001).
Deficiencies of ALAD enzyme in vivo are associated with 5-aminolevulinate dehydratase-deficient porphyria (e.g., Akagi et al. 2000).
REACT_9436 (Reactome) Cytosolic uroporphyrinogen decarboxylase (UROD) catalyzes the sequential removal of four carboxylic groups from the acetic acid side chains of uroporphyrinogen I (URO1) to form coproporphyrinogen I (COPRO1). UROD catalyzes this reaction less efficiently than the decarboxylation of uroporphyrinogen III (de Verneuil et al. 1983).
REACT_9437 (Reactome) Lead binds to ALAD enzyme displacing half the zinc ions essential for its catalytic activity and inactivating it. Lead is a major environmental toxin and this enzyme is one of its principal molecular targets (Jaffe et al. 2001).
REACT_9446 (Reactome) Cytosolic porphobilinogen deaminase catalyzes the polymerization of four molecules of porphobilinogen (PBG) to generate hydroxymethylbilane (HMB), an unstable tetrapyrrole. This reaction is the first step in the formation of the tetrapyrrole macrocycle. Two isoforms of porphobilinogen deaminase are generated by alternative splicing, one expresssed in erythroid tissues and one ubiquitously expressed in the body. Deficiencies of both forms of PBG deaminase are associated with acute intermittent porphyria.
REACT_9454 (Reactome) 5-aminolevulinate is transported from the mitochondrial matrix to the cytosol. The transporter that enables it to cross the inner mitochondrial membrane is unknown.
REACT_9461 (Reactome) Ferrochelatase (FECH) catalyzes the insertion of ferrous iron into protoporphyrin IX (PRIN9) to form heme. FECH is localized on the matrix surface of the inner mitochondrial membrane and this reaction takes place within the mitochondrial matrix. The enzyme functions as a homodimer with each monomer containing a nitric oxide-sensitive 2Fe-2S cluster. Enzyme deficiency is associated with erythropoietic protoporphyria in vivo, and inhibition of ferrochelatase activity is a clinically important consequence of lead poisoning (Piomelli et al. 1987).
REACT_9463 (Reactome) The committed step for porphyrin synthesis is the formation of 5-aminolevulinate (ALA) by condensation of glycine (from the general amino acid pool) and succinyl-CoA (from the TCA cycle), in the mitochondrial matrix. The reaction is catalyzed by two different ALA synthases, one expressed ubiquitously (ALAS1) and the other only expressed in erythroid precursors (ALAS2). Both enzymes are expressed as homodimers and require pyridoxal 5-phosphate as a cofactor.
No disease-causing mutations of ALAS1 have been recognised in humans. Mutations in ALAS2 cause X-linked sideroblastic anaemia (XLSA), characterised by a microcytic hypochromic anaemia.
REACT_9526 (Reactome) Cytosolic uroporphyrinogen III synthase (URO3S) catalyzes the conversion of HMB (hydroxymethylbilane) to uroporphyrinogen III, a reaction involving ring closure and intramolecular rearrangement. Uroporphyrinogen III represents a branch point for the pathways leading to formation of heme, chlorophyll and corrins. HMB is rapidly converted from a linear tetrapyrrole to the cyclic form. Deficiencies of URO3S in vivo are associated with congenital erythropoietic porphyria.
REACT_9945 (Reactome) Coproporpyrinogen III (COPRO3) enters the mitochondrial intermembrane space from the cytosol. It is not known whether this process is facilitated by a transporter.
SUCC-CoAREACT_9463 (Reactome)
UDP-GlcAREACT_22274 (Reactome)
UDP-GlcAREACT_22319 (Reactome)
UDPArrowREACT_22274 (Reactome)
UDPArrowREACT_22319 (Reactome)
UGT1A1mim-catalysisREACT_22274 (Reactome)
URO1ArrowREACT_9408 (Reactome)
URO3ArrowREACT_9526 (Reactome)
UROSmim-catalysisREACT_9526 (Reactome)
Zn2+ArrowREACT_9437 (Reactome)
dALAArrowREACT_9463 (Reactome)
heme OArrowREACT_163705 (Reactome)
hemeArrowREACT_9461 (Reactome)
hemeREACT_163705 (Reactome)
hemeREACT_22100 (Reactome)
hemeTBarREACT_9463 (Reactome)

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