Metabolism of porphyrins (Homo sapiens)

From WikiPathways

Revision as of 11:54, 2 November 2020 by ReactomeTeam (Talk | contribs)
Jump to: navigation, search
37253, 726, 406, 386916, 36, 475130, 55504410, 12, 358, 652, 22, 56, 57, 61145343, 6826, 4062, 634621, 414, 324552, 666418, 5829, 42, 49, 6019, 24, 31, 5323, 27, 28, 486318, 5813, 3420, 6715, 3911, 56601, 56817, 33INTESTINECIRCULATIONmitochondrial intermembrane spacemitochondrial matrixERYTHROID CELLcytosolHEPATOCYTEBILE CANALICULUSendoplasmic reticulum lumencytosolADPPb2+FPP8xALAD:Pb2+:Zn2+H2OURO3FABP1 HMOX1 H2OCO2a reduced electronacceptorBMG BIL Pb2+BGETGSTA1 COX10(?-443)O2URO1CO2H+BDG H2OH2OHC-ABCG2 ALBALAD ALB BILNADPHBIL 2x(FECH:2Fe-2Scluster)an oxidized electronacceptorZn2+O2HMBS:DIPYFe2+BILheme H+UGT1A4GlySTBNUROD NADPHBILhemeSLCO1B1HMBS BVHC-ABCG2 H2O2FABP1 COX15SUCC-CoAPBGABCC1Pb2+ BMG,BDG2xCPONH4+8x(ALAD:Zn2+)BLVRA UDP-GlcAADPH2OH2O2UDPZn2+ BILPPiD-UBGNan oxidized electronacceptorFe2+NADP+UBGNO2Iron-2Sulfur Cluster BDG PPGEN9HMBLH2OBLVRA:Zn2+,BLVRBFAD hemeATPCOPRO3ABCC2GSTA1 NADP+BMG,BDGBILABCG2 tetramerBLVRB NADP+NADPHBMG an oxidized electronacceptorCO2PPOX COPRO1FLVCR1-1CPOX(132-454) H2OCOPRO3SLCO1B3heme O2xURODBIL:GSTA1, FABP1Zn2+ hemeFECH BMGDIPY SLCO2B1-3PiBILdALAPRIN9UBGNRBDG GUSBUBNGSTA1, FABP1PXLP-K391-ALAS2 BDGBMG a reduced electronacceptorH+ALB:hemeUDP-GlcAheme APXLP-ALAS1 HMOX2 a reduced electronacceptorH2OBDGFLVCR1-22xPPOX:FADZn2+ HMOX1,2COH2OPRIN9BIL:ALBUROSABCG2 tetramerALBALAD ATPALAS1,2ALB UDPBILRGlcAdALACoA-SHO2PiBMG,BDGBIL54, 59954, 59


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. View original pathway at Reactome.</div>

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 189445
Reactome-version 
Reactome version: 73

Try the New WikiPathways

View approved pathways at the new wikipathways.org.

Quality Tags

Ontology Terms

 

Bibliography

View all...
  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

View all...
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
2Iron-2Sulfur Cluster R-ALL-189408 (Reactome)
2x(FECH:2Fe-2S cluster)ComplexR-HSA-189402 (Reactome)
2xCPOComplexR-HSA-189485 (Reactome)
2xPPOX:FADComplexR-HSA-189469 (Reactome)
2xURODComplexR-HSA-189454 (Reactome)
8x(ALAD:Zn2+)ComplexR-HSA-189400 (Reactome)
8xALAD:Pb2+:Zn2+ComplexR-HSA-190145 (Reactome)
ABCC1ProteinP33527 (Uniprot-TrEMBL)
ABCC2ProteinQ92887 (Uniprot-TrEMBL)
ABCG2 tetramerComplexR-HSA-917863 (Reactome)
ABCG2 tetramerComplexR-HSA-9661431 (Reactome)
ADPMetaboliteCHEBI:456216 (ChEBI)
ALAD ProteinP13716 (Uniprot-TrEMBL)
ALAS1,2ComplexR-HSA-189429 (Reactome)
ALB ProteinP02768 (Uniprot-TrEMBL)
ALB:hemeComplexR-HSA-9661451 (Reactome)
ALBProteinP02768 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:30616 (ChEBI)
BDG MetaboliteCHEBI:18392 (ChEBI)
BDGMetaboliteCHEBI:18392 (ChEBI)
BGETR-HSA-9663470 (Reactome)
BIL MetaboliteCHEBI:16990 (ChEBI)
BIL:ALBComplexR-HSA-9661438 (Reactome)
BIL:GSTA1, FABP1ComplexR-HSA-9663490 (Reactome)
BILMetaboliteCHEBI:16990 (ChEBI)
BILRR-CPE-9661715 (Reactome)
BLVRA ProteinP53004 (Uniprot-TrEMBL)
BLVRA:Zn2+,BLVRBComplexR-HSA-189387 (Reactome)
BLVRB ProteinP30043 (Uniprot-TrEMBL)
BMG MetaboliteCHEBI:16427 (ChEBI)
BMG,BDGComplexR-ALL-5679034 (Reactome)
BMG,BDGComplexR-ALL-5679042 (Reactome)
BMG,BDGComplexR-ALL-9661424 (Reactome)
BMGMetaboliteCHEBI:16427 (ChEBI)
BVMetaboliteCHEBI:17033 (ChEBI)
CO2MetaboliteCHEBI:16526 (ChEBI)
COMetaboliteCHEBI:17245 (ChEBI)
COPRO1MetaboliteCHEBI:28607 (ChEBI)
COPRO3MetaboliteCHEBI:15439 (ChEBI)
COX10(?-443)ProteinQ12887 (Uniprot-TrEMBL)
COX15ProteinQ7KZN9 (Uniprot-TrEMBL)
CPOX(132-454) ProteinP36551 (Uniprot-TrEMBL)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
D-UBGNMetaboliteCHEBI:4260 (ChEBI)
DIPY MetaboliteCHEBI:36319 (ChEBI)
FABP1 ProteinP07148 (Uniprot-TrEMBL) As inferred from mouse, FABP1 localizes to the nucleus where it may deliver lipids to PPARA.
FAD MetaboliteCHEBI:16238 (ChEBI)
FECH ProteinP22830 (Uniprot-TrEMBL)
FLVCR1-1ProteinQ9Y5Y0-1 (Uniprot-TrEMBL)
FLVCR1-2ProteinQ9Y5Y0-2 (Uniprot-TrEMBL)
FPPMetaboliteCHEBI:17407 (ChEBI)
Fe2+MetaboliteCHEBI:29033 (ChEBI)
GSTA1 ProteinP08263 (Uniprot-TrEMBL)
GSTA1, FABP1ComplexR-HSA-9663507 (Reactome)
GUSBProteinQ8VNV4 (Uniprot-TrEMBL)
GlcAMetaboliteCHEBI:15748 (ChEBI)
GlyMetaboliteCHEBI:57305 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2O2MetaboliteCHEBI:16240 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HC-ABCG2 ProteinQ9UNQ0 (Uniprot-TrEMBL)
HMBLMetaboliteCHEBI:57845 (ChEBI)
HMBS ProteinP08397 (Uniprot-TrEMBL)
HMBS:DIPYComplexR-HSA-189426 (Reactome)
HMOX1 ProteinP09601 (Uniprot-TrEMBL)
HMOX1,2ComplexR-HSA-189382 (Reactome)
HMOX2 ProteinP30519 (Uniprot-TrEMBL)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NH4+MetaboliteCHEBI:28938 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
PBGMetaboliteCHEBI:58126 (ChEBI)
PPGEN9MetaboliteCHEBI:15435 (ChEBI)
PPOX ProteinP50336 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRIN9MetaboliteCHEBI:15430 (ChEBI)
PXLP-ALAS1 ProteinP13196 (Uniprot-TrEMBL)
PXLP-K391-ALAS2 ProteinP22557 (Uniprot-TrEMBL)
Pb2+ MetaboliteCHEBI:27889 (ChEBI)
Pb2+MetaboliteCHEBI:27889 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
SLCO1B1ProteinQ9Y6L6 (Uniprot-TrEMBL)
SLCO1B3ProteinQ9NPD5 (Uniprot-TrEMBL)
SLCO2B1-3ProteinO94956-3 (Uniprot-TrEMBL)
STBNMetaboliteCHEBI:26756 (ChEBI)
SUCC-CoAMetaboliteCHEBI:57292 (ChEBI)
UBGNOR-HSA-9661701 (Reactome)
UBGNRR-CPE-9661737 (Reactome)
UBNMetaboliteCHEBI:36378 (ChEBI)
UDP-GlcAMetaboliteCHEBI:17200 (ChEBI)
UDPMetaboliteCHEBI:17659 (ChEBI)
UGT1A4ProteinP22310 (Uniprot-TrEMBL)
URO1MetaboliteCHEBI:28766 (ChEBI)
URO3MetaboliteCHEBI:15437 (ChEBI)
UROD ProteinP06132 (Uniprot-TrEMBL)
UROSProteinP10746 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
Zn2+MetaboliteCHEBI:29105 (ChEBI)
a reduced electron acceptorMetaboliteCHEBI:17654 (ChEBI)
an oxidized electron acceptorMetaboliteCHEBI:17654 (ChEBI)
dALAMetaboliteCHEBI:356416 (ChEBI)
heme AMetaboliteCHEBI:24479 (ChEBI)
heme MetaboliteCHEBI:17627 (ChEBI)
heme OMetaboliteCHEBI:24480 (ChEBI)
hemeMetaboliteCHEBI:17627 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2x(FECH:2Fe-2S cluster)mim-catalysisR-HSA-189465 (Reactome)
2xCPOmim-catalysisR-HSA-189421 (Reactome)
2xPPOX:FADmim-catalysisR-HSA-189423 (Reactome)
2xURODmim-catalysisR-HSA-189425 (Reactome)
2xURODmim-catalysisR-HSA-190182 (Reactome)
8x(ALAD:Zn2+)R-HSA-190141 (Reactome)
8x(ALAD:Zn2+)mim-catalysisR-HSA-189439 (Reactome)
8xALAD:Pb2+:Zn2+ArrowR-HSA-190141 (Reactome)
ABCC1mim-catalysisR-HSA-9661405 (Reactome)
ABCC2mim-catalysisR-HSA-5679041 (Reactome)
ABCG2 tetramermim-catalysisR-HSA-917979 (Reactome)
ABCG2 tetramermim-catalysisR-HSA-9661417 (Reactome)
ADPArrowR-HSA-5679041 (Reactome)
ADPArrowR-HSA-917979 (Reactome)
ADPArrowR-HSA-9661417 (Reactome)
ALAS1,2mim-catalysisR-HSA-189442 (Reactome)
ALB:hemeArrowR-HSA-9661419 (Reactome)
ALBArrowR-HSA-9661425 (Reactome)
ALBR-HSA-9661419 (Reactome)
ALBR-HSA-9661432 (Reactome)
ATPR-HSA-5679041 (Reactome)
ATPR-HSA-917979 (Reactome)
ATPR-HSA-9661417 (Reactome)
BDGArrowR-HSA-159179 (Reactome)
BDGR-HSA-9661820 (Reactome)
BGETmim-catalysisR-HSA-9661446 (Reactome)
BIL:ALBArrowR-HSA-9661432 (Reactome)
BIL:ALBR-HSA-9661425 (Reactome)
BIL:GSTA1, FABP1ArrowR-HSA-9663511 (Reactome)
BIL:GSTA1, FABP1R-HSA-9663492 (Reactome)
BILArrowR-HSA-189381 (Reactome)
BILArrowR-HSA-189384 (Reactome)
BILArrowR-HSA-9661397 (Reactome)
BILArrowR-HSA-9661405 (Reactome)
BILArrowR-HSA-9661425 (Reactome)
BILArrowR-HSA-9661723 (Reactome)
BILArrowR-HSA-9661799 (Reactome)
BILArrowR-HSA-9661820 (Reactome)
BILArrowR-HSA-9663492 (Reactome)
BILR-HSA-159194 (Reactome)
BILR-HSA-189381 (Reactome)
BILR-HSA-9661397 (Reactome)
BILR-HSA-9661405 (Reactome)
BILR-HSA-9661432 (Reactome)
BILR-HSA-9661723 (Reactome)
BILR-HSA-9661745 (Reactome)
BILR-HSA-9661799 (Reactome)
BILR-HSA-9663511 (Reactome)
BILRmim-catalysisR-HSA-9661745 (Reactome)
BLVRA:Zn2+,BLVRBmim-catalysisR-HSA-189384 (Reactome)
BMG,BDGArrowR-HSA-5679041 (Reactome)
BMG,BDGArrowR-HSA-9661417 (Reactome)
BMG,BDGArrowR-HSA-9661446 (Reactome)
BMG,BDGR-HSA-5679041 (Reactome)
BMG,BDGR-HSA-9661417 (Reactome)
BMG,BDGR-HSA-9661446 (Reactome)
BMGArrowR-HSA-159194 (Reactome)
BMGR-HSA-159179 (Reactome)
BVArrowR-HSA-189398 (Reactome)
BVR-HSA-189384 (Reactome)
CO2ArrowR-HSA-189421 (Reactome)
CO2ArrowR-HSA-189425 (Reactome)
CO2ArrowR-HSA-189442 (Reactome)
CO2ArrowR-HSA-190182 (Reactome)
COArrowR-HSA-189398 (Reactome)
COPRO1ArrowR-HSA-190182 (Reactome)
COPRO3ArrowR-HSA-189425 (Reactome)
COPRO3ArrowR-HSA-189467 (Reactome)
COPRO3R-HSA-189421 (Reactome)
COPRO3R-HSA-189467 (Reactome)
COX10(?-443)mim-catalysisR-HSA-2995330 (Reactome)
COX15mim-catalysisR-HSA-2995334 (Reactome)
CoA-SHArrowR-HSA-189442 (Reactome)
D-UBGNArrowR-HSA-9661745 (Reactome)
D-UBGNR-HSA-9661710 (Reactome)
D-UBGNR-HSA-9661726 (Reactome)
FLVCR1-1mim-catalysisR-HSA-917892 (Reactome)
FLVCR1-2mim-catalysisR-HSA-9661408 (Reactome)
FPPR-HSA-2995330 (Reactome)
Fe2+ArrowR-HSA-189398 (Reactome)
Fe2+R-HSA-189465 (Reactome)
GSTA1, FABP1ArrowR-HSA-9663492 (Reactome)
GSTA1, FABP1R-HSA-9663511 (Reactome)
GUSBmim-catalysisR-HSA-9661820 (Reactome)
GlcAArrowR-HSA-9661820 (Reactome)
GlyR-HSA-189442 (Reactome)
H+ArrowR-HSA-189439 (Reactome)
H+ArrowR-HSA-189465 (Reactome)
H+R-HSA-189442 (Reactome)
H2O2ArrowR-HSA-189421 (Reactome)
H2O2ArrowR-HSA-189423 (Reactome)
H2OArrowR-HSA-189398 (Reactome)
H2OArrowR-HSA-189439 (Reactome)
H2OArrowR-HSA-189488 (Reactome)
H2OArrowR-HSA-190168 (Reactome)
H2OR-HSA-189406 (Reactome)
H2OR-HSA-2995330 (Reactome)
H2OR-HSA-5679041 (Reactome)
H2OR-HSA-917979 (Reactome)
H2OR-HSA-9661417 (Reactome)
H2OR-HSA-9661820 (Reactome)
HMBLArrowR-HSA-189406 (Reactome)
HMBLR-HSA-189488 (Reactome)
HMBLR-HSA-190168 (Reactome)
HMBS:DIPYmim-catalysisR-HSA-189406 (Reactome)
HMOX1,2mim-catalysisR-HSA-189398 (Reactome)
NADP+ArrowR-HSA-189384 (Reactome)
NADP+ArrowR-HSA-189398 (Reactome)
NADP+ArrowR-HSA-9661820 (Reactome)
NADPHR-HSA-189384 (Reactome)
NADPHR-HSA-189398 (Reactome)
NADPHR-HSA-9661820 (Reactome)
NH4+ArrowR-HSA-189406 (Reactome)
O2R-HSA-189398 (Reactome)
O2R-HSA-189421 (Reactome)
O2R-HSA-189423 (Reactome)
PBGArrowR-HSA-189439 (Reactome)
PBGR-HSA-189406 (Reactome)
PPGEN9ArrowR-HSA-189421 (Reactome)
PPGEN9R-HSA-189423 (Reactome)
PPiArrowR-HSA-2995330 (Reactome)
PRIN9ArrowR-HSA-189423 (Reactome)
PRIN9ArrowR-HSA-189457 (Reactome)
PRIN9R-HSA-189457 (Reactome)
PRIN9R-HSA-189465 (Reactome)
Pb2+R-HSA-190141 (Reactome)
Pb2+TBarR-HSA-189465 (Reactome)
PiArrowR-HSA-5679041 (Reactome)
PiArrowR-HSA-917979 (Reactome)
PiArrowR-HSA-9661417 (Reactome)
R-HSA-159179 (Reactome) The principal conjugate of bilirubin in bile is bilirubin diglucuronide (BDG). The monomeric forms of UGT1A1 (Bilirubin UDP-glucuronyltransferase 1) only conjugates the first step of bilirubin conjugation to form the monoglucuronide. A tetrameric form of UGT1A1 can transfer glucuronic acid (GlcA) to bilirubin (BIL) and bilirubin monoglucuronide (BMG) to form both the monoglucuronide and the diglucuronide (BDG) conjugates respectively (Peters & Jansen 1986, Gorden et al. 1983, Choudhury et al. 1981, Fevery et al. 1971). UGT1A4 is also able to catalyse the formation of BDG (Ritter et al. 1992).
R-HSA-159194 (Reactome) Bilirubin (BIL) is a breakdown product of heme. Its accumulation in the blood can be fatal. It is highly lipophilic and thus requires conjugation to become more water soluble to aid excretion. Both UGT1A1 and 4 can transfer glucuronic acid (GlcA) to bilirubin to form either its monoglucuronide (BMG) or diglucuronide (BDG) conjugates (Bosma et al. 1994, Ritter et al. 1992). Mutations of the UGT1A1 gene cause complete loss or partial activity for bilirubin glucuronidation.
R-HSA-189381 (Reactome) The enzyme which catalyzes the conjugation of bilirubin (UGT1A1) is found in the ER. Bilirubin translocates to the ER, probably by simple diffusion, to be glucuronylated (Schröter 1972). To date, no transporter has been identified for this process (Fujiwara & Itoh 2014).
R-HSA-189384 (Reactome) Bilirubin (BIL) is the breakdown product of heme, causing death if allowed to accumulate in the blood. It is highly lipophilic and requires conjugation to become more water soluble to aid excretion. BIL is formed from the reduction of biliverdin (BV) by bilverdin reductases BLVRA and BLVRB (Cunningham et al. 2000, Fu et al. 2012, O'Brien et al. 2015).
R-HSA-189398 (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.
R-HSA-189406 (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.
R-HSA-189421 (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.
R-HSA-189423 (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.
R-HSA-189425 (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).
R-HSA-189439 (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).
R-HSA-189442 (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.
R-HSA-189456 (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 (Bayeva et al.2013).
R-HSA-189457 (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 (Krishnamurthy et al. 2006).
R-HSA-189465 (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).
R-HSA-189467 (Reactome) Coproporpyrinogen III (COPRO3) enters the mitochondrial intermembrane space from the cytosol. It is not known whether this process is facilitated by a transporter (Grandchamp et al. 1978).
R-HSA-189488 (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.
R-HSA-190141 (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).
R-HSA-190168 (Reactome) Hydroxymethybilane (HMBL) can spontaneously cyclize and rearrange to form uroporphyrinogen I (URO1).
R-HSA-190182 (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).
R-HSA-2995330 (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).
R-HSA-2995334 (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).
R-HSA-5679041 (Reactome) Canalicular multispecific organic anion transporter 1 (ABCC2 aka multidrug resistance-associated protein 2, MRP2), in addition to transporting many organic anions, mediates the ATP-dependent transport of glutathione and glucuronate conjugates from hepatocytes into bile. In the reaction annotated here, ABCC2 specifically transports, with high affinity and efficiency, mono- and di-glucuronated bilirubin (BMG, BDG respectively) into bile (Kamisako et al. 1999). ABCC2 is located on the canalicular membrane of hepatocytes. Bilirubin, the end product of heme breakdown, is an important constituent of bile and is responsible for its characteristic colour.
R-HSA-917892 (Reactome) Heme is utilised as a prosthetic group in the production of hemoproteins inside cells. However, when intracellular heme accumulation occurs, heme is able to exert its pro-oxidant and cytotoxic action. The amount of free heme must be tightly controlled to maintain cellular homeostasis and avoid pathological conditions (Chiabrando et al. 2014). The heme transporter FLVCR is expressed in intestine and liver tissue, but also in developing erythroid cells where it is required to protect them from heme toxicity (Quigley et al, 2004; Rey et al, 2008). Two different isoforms have been described. FLVCR1-1 (FLVCR1a) resides in the plasma membrane and is responsible for heme detoxification in several cell types, such as erythroid progenitors, endothelial cells, hepatocytes, lymphocytes and intestinal cells.
R-HSA-917979 (Reactome) Heme is utilised as a prosthetic group in the production of hemoproteins inside cells. However, when intracellular heme accumulation occurs, heme is able to exert its pro-oxidant and cytotoxic action. The amount of free heme must be tightly controlled to maintain cellular homeostasis and avoid pathological conditions (Chiabrando et al. 2014). The tetrameric efflux pump ATP-binding cassette sub-family G member 2 (ABCG2) (Xu et al. 2004) can relieve cells from toxic heme concentrations even against a concentration gradient. It is expressed in placenta, liver, and small intestine (Krishnamurthy et al. 2004, Doyle & Ross 2003, Zhang et al. 2003).
R-HSA-9661397 (Reactome) Bilirubin (BIL), the end product of heme catabolism, is taken up from the blood circulation into the liver. The organic anion transporting polypeptide SLCO1B1 (OATP, OATP2, OATPC, SLC21A6), localised on the basolateral (sinusoidal side) hepatocyte membrane, can mediate the uptake of BIL and various other lipophilic anions into the human liver (Konig et al. 2000, Cui et al. 2001).
R-HSA-9661405 (Reactome) Bilirubin (BIL), formed in erythroid cells, exits the cell to be transported to the liver for conjugation and ultimately, excretion. BIL possibly leaves the cell by simple diffusion as it is highly lipophilic (Kamisako et al. 2000). However, the multidrug resistance-associated protein 1 (ABCC1 aka MRP1) is known to mediate the ATP-dependent export of organic anions and drugs from cells. Unconjugated bilirubin (BIL) may also be exported from cells by ABCC1 (Rigato et al. 2004).
R-HSA-9661408 (Reactome) Feline leukemia virus subgroup C receptor-related protein 1 isoform 2 (FLVCR1-2), located on the mitochondrial membrane of all hematopoietic tissues, is a heme transporter that mediates heme efflux from the mitochondrion to the cytosol (Chiabrando et al. 2012). Silencing of FLVCR1-2 causes mitochondrial heme accumulation and termination of erythroid differentiation.
R-HSA-9661417 (Reactome) Bilirubin glucuronides (BMG and BDG) are transported out of hepatocytes through their apical surfaces into the bile ducts, mainly by ABCC2 (MRP2) but also by the tetrameric efflux pump ATP-binding cassette sub-family G member 2 (ABCG2) (Xu et al. 2004).
R-HSA-9661419 (Reactome) Circulating free heme is cytotoxic. Binding of albumin (ALB) to heme protects cells from this potential toxicity (Desuzinges-Mandon et al. 2010).
R-HSA-9661425 (Reactome) When the bilirubin-albumin complex (BIL:ALB) reaches the liver, the highly permeable hepatic circulation facilitates the complex to reach the sinusoidal side of the hepatocyte. The exact mechanism of unbound BIL uptake is unclear but may proceed like this. BIL in complex with ALB is reversible and a tiny fraction of of free BIL is present in plasma in equilibrium with BIL:ALB. Hence this free BIL may be taken up at a rate determined by its plasma concentration. As free BIL is taken up, more BIL is released from ALB and becomes available for uptake (Bhagavan & Ha 2015).
R-HSA-9661432 (Reactome) The serum protein albumin (ALB) binds unconjugated bilirubin (BIL), preventing BIL toxicity (Griffiths et al. 1975, Weisiger et al. 2001). ALB-bound BIL is a water-soluble complex and is transported to the liver where it is selectively absorbed by hepatocytes.
R-HSA-9661446 (Reactome) To be excreted from the cell, mono- and di-glucuronated bilirubin (BMG, BDG respectively) translocate from the ER lumen to the cytosol. Glucuronated bilirubin is a much more hydrophilic substance than bilirubin so the assumption is some form of active transport is required for this translocation. No transporter has been identified yet but tentatively, we assign the name bilirubin glucuronide efflux transporter (BGET) (Erlinger et al. 2014, Rowland et al. 2013).
R-HSA-9661710 (Reactome) The D urobilinogen (D UBGN) that remains in the intestine is directly reduced to stercobilin (STBN) or oxidised to urobilin (UBN), a yellow pigment seen in urine (Rupe & Fetter 1981). How this oxidation is mediated is unknown (Hamoud et al. 2018).
R-HSA-9661723 (Reactome) Bilirubin (BIL), the end product of heme catabolism, is taken up from the blood circulation into the liver. The solute carrier organic anion transporter family member 2B1 (SLCO2B1, aka OATPRP2, OATPB, SLC21A9), localised on the basolateral (sinusoidal side) hepatocyte membrane, can mediate the uptake of BIL and various other lipophilic anions into the human liver (Kullak-Ublick et al. 2001). The predominant isoform in the liver is SLCO2B1 isoform 3 (Knauer et al. 2013).
R-HSA-9661726 (Reactome) The D-urobilinogen (D-UBGN) that remains in the intestine is directly reduced to stercobilin (STBN) by unknown bacterial reductases. Stercobilins oxidize to form brownish pigments which lead to the characteristic brown colour found in normal feces (Vitek et al. 2006). STBN can also be reduced to stercobilinogen (L-urobilinogen), which can then be further oxidized to STBN. This constitutes the "enterohepatic urobilinogen cycle."
R-HSA-9661745 (Reactome) Microbes present in the large intestine reduce bilirubin (BIL) to D-urobilinogen (D-UBGN) (Troxler et al. 1968, Watson et al. 1958, Vitek et al. 2006). The identity of the bilirubin reductase (BILR) is unknown (Koní�ková et al. 2012). Some D-UBGN can be reabsorbed into the portal circulation and delivered to the liver where it is recycled back into the biliary flow.
R-HSA-9661799 (Reactome) Bilirubin (BIL), the end product of heme catabolism, is taken up from the blood circulation into the liver. The organic anion transporting polypeptide (SLCO1B3, aka OATP-8, LST2, SLC21A8), localised on the basolateral (sinusoidal side) hepatocyte membrane, can mediate the uptake of BIL and various other lipophilic anions into the human liver (van de Steeg et al. 2012).
R-HSA-9661820 (Reactome) Bilirubin diglucuronide (BDG) is a substrate for microbial β-glucuronidase, which can cleave the glucuronosyl moieties and liberate bilirubin for reabsorption through the basolateral surfaces of the intestines where it can undergo further metabolism or pass directly back into the circulation. This process, known as enterohepatic circulation, can extend the half-life of bilirubin while adding to the total serum bilirubin load (Seyfried et al. 1976). Conjugated bilirubin is excreted in bile through the duodenum, where it can be unconjugated by enteric bacteria (Kim et al. 1995). Many bacterial β-glucuronidases can cleave the glucuronosyl moieties from conjugated bilirubins in the human gut. In vitro assays reveal the C. perfringens species produce beta-glucuronidase enzyme activity that is at least 30-fold higher than other bacterial species (Leung et al. 2001).

Urobilinogen (D-urobilinogen) is closely related to two other compounds: mesobilirubinogen (I-urobilinogen) and stercobilinogen (L-urobilinogen). Somewhat confusingly, all three compounds are frequently collectively referred to as "urobilinogens".
R-HSA-9663492 (Reactome) Once GSTA1 and FABP1 proteins transport bilirubin to the ER, it is assumed they must dissociate from BIL ((Levi et al. 1969, Simons & Jagt 1980) to allow its translocation, most likely by simple diffusion, into the ER lumen.
R-HSA-9663511 (Reactome) Upon entry into the hepatocyte, bilirubin (BIL) can bind to one of two cytosolic binding proteins; glutathione S-transferase A1 (GSTA1 aka ligandin, Y-protein), a major cytosolic protein that has both transport and detoxification functions or fatty acid-binding protein (FABP1 aka Z-protein) (Levi et al. 1969, Simons & Jagt 1980, Arias 2012). It is assumed GSTA1 transports BIL to the ER where it is detoxified by conjugation with a glucuronosyl moiety.
SLCO1B1mim-catalysisR-HSA-9661397 (Reactome)
SLCO1B3mim-catalysisR-HSA-9661799 (Reactome)
SLCO2B1-3mim-catalysisR-HSA-9661723 (Reactome)
STBNArrowR-HSA-9661726 (Reactome)
SUCC-CoAR-HSA-189442 (Reactome)
UBGNOmim-catalysisR-HSA-9661710 (Reactome)
UBGNRmim-catalysisR-HSA-9661726 (Reactome)
UBNArrowR-HSA-9661710 (Reactome)
UDP-GlcAR-HSA-159179 (Reactome)
UDP-GlcAR-HSA-159194 (Reactome)
UDPArrowR-HSA-159179 (Reactome)
UDPArrowR-HSA-159194 (Reactome)
UGT1A4mim-catalysisR-HSA-159179 (Reactome)
UGT1A4mim-catalysisR-HSA-159194 (Reactome)
URO1ArrowR-HSA-190168 (Reactome)
URO1R-HSA-190182 (Reactome)
URO3ArrowR-HSA-189488 (Reactome)
URO3R-HSA-189425 (Reactome)
UROSmim-catalysisR-HSA-189488 (Reactome)
Zn2+ArrowR-HSA-190141 (Reactome)
a reduced electron acceptorArrowR-HSA-9661710 (Reactome)
a reduced electron acceptorR-HSA-9661726 (Reactome)
a reduced electron acceptorR-HSA-9661745 (Reactome)
an oxidized electron acceptorArrowR-HSA-9661726 (Reactome)
an oxidized electron acceptorArrowR-HSA-9661745 (Reactome)
an oxidized electron acceptorR-HSA-9661710 (Reactome)
dALAArrowR-HSA-189442 (Reactome)
dALAArrowR-HSA-189456 (Reactome)
dALAR-HSA-189439 (Reactome)
dALAR-HSA-189456 (Reactome)
heme AArrowR-HSA-2995334 (Reactome)
heme OArrowR-HSA-2995330 (Reactome)
heme OR-HSA-2995334 (Reactome)
hemeArrowR-HSA-189465 (Reactome)
hemeArrowR-HSA-917892 (Reactome)
hemeArrowR-HSA-917979 (Reactome)
hemeArrowR-HSA-9661408 (Reactome)
hemeR-HSA-189398 (Reactome)
hemeR-HSA-2995330 (Reactome)
hemeR-HSA-917892 (Reactome)
hemeR-HSA-917979 (Reactome)
hemeR-HSA-9661408 (Reactome)
hemeR-HSA-9661419 (Reactome)
hemeTBarR-HSA-189442 (Reactome)

Personal tools