Metabolism of porphyrins (Homo sapiens)

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4, 18, 26, 289, 1451, 222, 25123311, 1513, 15, 17, 23, 3412, 3021610, 24, 328313, 27199, 1416, 297, 20endoplasmic reticulum lumenmitochondrial matrixcytosolSUCC-CoACOO28xALAD:Pb2+:Zn2+H2OALAD CPOX(132-454) Pb2+ HMBLCO2CO2H+PRIN9UDP-GlcABMGHMOX1,2BILUDPUGT1A1tetramer,UGT1A4H2OH2OPXLP-ALAS2 NADP+PXLP-ALAS1 HMBS:DIPYCOX15Pb2+Fe2+FPPCOX10(?-443)BIL8x(ALAD:Zn2+)UGT1A1 BVUGT1A4 heme2x(FECH:2Fe-2Scluster)H2OFe2+FAD Pb2+HMOX1 H2O2heme AUGT1A1,4HMBS CoA-SHCOPRO1COPRO32xPPOX:FADUGT1A1 NADPHZn2+PBGhemeBLVRB UGT1A4 H2OZn2+ O2PPOX BDGPPGEN9GlyO2UROD Zn2+ FECH CO22Iron-2Sulfur Cluster H2OdALA2xCPOHMOX2 URO1dALAURO3Zn2+ ALAS1,2PPiDIPY 2xURODheme OALAD UROSPRIN9COPRO3H2O2NH3BLVRA Biliverdin reductase


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>


Pathway is converted from Reactome ID: 189445
Reactome version: 66

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  1. 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
  2. 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
  3. Mitchell LW, Volin M, Martins J, Jaffe EK.; ''Mechanistic implications of mutations to the active site lysine of porphobilinogen synthase.''; PubMed Europe PMC
  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
  5. Dailey TA, Dailey HA.; ''Human protoporphyrinogen oxidase: expression, purification, and characterization of the cloned enzyme.''; PubMed Europe PMC
  6. 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
  7. Anderson PM, Desnick RJ.; ''Purification and properties of uroporphyrinogen I synthase from human erythrocytes. Identification of stable enzyme-substrate intermediates.''; PubMed Europe PMC
  8. Jaffe EK, Martins J, Li J, Kervinen J, Dunbrack RL.; ''The molecular mechanism of lead inhibition of human porphobilinogen synthase.''; PubMed Europe PMC
  9. 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
  10. Cooper CL, Lash TD, Jones MA.; ''Kinetic evaluation of human cloned coproporphyrinogen oxidase using a ring isomer of the natural substrate.''; PubMed Europe PMC
  11. 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
  12. Tsai SF, Bishop DF, Desnick RJ.; ''Purification and properties of uroporphyrinogen III synthase from human erythrocytes.''; PubMed Europe PMC
  13. Gordon ER, Sommerer U, Goresky CA.; ''The hepatic microsomal formation of bilirubin diglucuronide.''; PubMed Europe PMC
  14. 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
  15. 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
  16. 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
  17. Peters WH, Jansen PL.; ''Microsomal UDP-glucuronyltransferase-catalyzed bilirubin diglucuronide formation in human liver.''; PubMed Europe PMC
  18. 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
  19. Salim M, Brown-Kipphut BA, Maines MD.; ''Human biliverdin reductase is autophosphorylated, and phosphorylation is required for bilirubin formation.''; PubMed Europe PMC
  20. 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
  21. 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
  22. Glerum DM, Tzagoloff A.; ''Isolation of a human cDNA for heme A:farnesyltransferase by functional complementation of a yeast cox10 mutant.''; PubMed Europe PMC
  23. 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
  24. Lee DS, Flachsová E, Bodnárová M, Demeler B, Martásek P, Raman CS.; ''Structural basis of hereditary coproporphyria.''; PubMed Europe PMC
  25. Murakami T, Reiter LT, Lupski JR.; ''Genomic structure and expression of the human heme A:farnesyltransferase (COX10) gene.''; PubMed Europe PMC
  26. 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
  27. 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
  28. 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
  29. Qiu W, Liesa M, Carpenter EP, Shirihai OS.; ''ATP Binding and Hydrolysis Properties of ABCB10 and Their Regulation by Glutathione.''; PubMed Europe PMC
  30. Shoolingin-Jordan PM.; ''Porphobilinogen deaminase and uroporphyrinogen III synthase: structure, molecular biology, and mechanism.''; PubMed Europe PMC
  31. 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
  32. Elder GH, Evans JO.; ''Evidence that the coproporphyrinogen oxidase activity of rat liver is situated in the intermembrane space of mitochondria.''; PubMed Europe PMC
  33. Grandchamp B, Phung N, Nordmann Y.; ''The mitochondrial localization of coproporphyrinogen III oxidase.''; PubMed Europe PMC
  34. 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


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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


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)
ALAD ProteinP13716 (Uniprot-TrEMBL)
ALAS1,2ComplexR-HSA-189429 (Reactome)
BDGMetaboliteCHEBI:18392 (ChEBI)
BILMetaboliteCHEBI:16990 (ChEBI)
BLVRA ProteinP53004 (Uniprot-TrEMBL)
BLVRB ProteinP30043 (Uniprot-TrEMBL)
BMGMetaboliteCHEBI:16427 (ChEBI)
BVMetaboliteCHEBI:17033 (ChEBI)
Biliverdin reductaseComplexR-HSA-189387 (Reactome)
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)
DIPY MetaboliteCHEBI:36319 (ChEBI)
FAD MetaboliteCHEBI:16238 (ChEBI)
FECH ProteinP22830 (Uniprot-TrEMBL)
FPPMetaboliteCHEBI:17407 (ChEBI)
Fe2+MetaboliteCHEBI:18248 (ChEBI)
GlyMetaboliteCHEBI:57305 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2O2MetaboliteCHEBI:16240 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HMBLMetaboliteCHEBI:16645 (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)
NH3MetaboliteCHEBI:16134 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
PBGMetaboliteCHEBI:17381 (ChEBI)
PPGEN9MetaboliteCHEBI:15435 (ChEBI)
PPOX ProteinP50336 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRIN9MetaboliteCHEBI:15430 (ChEBI)
PXLP-ALAS1 ProteinP13196 (Uniprot-TrEMBL)
PXLP-ALAS2 ProteinP22557 (Uniprot-TrEMBL)
Pb2+ MetaboliteCHEBI:27889 (ChEBI)
Pb2+MetaboliteCHEBI:27889 (ChEBI)
SUCC-CoAMetaboliteCHEBI:15380 (ChEBI)
UDP-GlcAMetaboliteCHEBI:17200 (ChEBI)
UDPMetaboliteCHEBI:17659 (ChEBI)
UGT1A1 tetramer,UGT1A4ComplexR-HSA-5604991 (Reactome)
UGT1A1 ProteinP22309 (Uniprot-TrEMBL)
UGT1A1,4ComplexR-HSA-5605002 (Reactome)
UGT1A4 ProteinP22310 (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
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)
ALAS1,2mim-catalysisR-HSA-189442 (Reactome)
BDGArrowR-HSA-159179 (Reactome)
BILArrowR-HSA-189381 (Reactome)
BILArrowR-HSA-189384 (Reactome)
BILR-HSA-159194 (Reactome)
BILR-HSA-189381 (Reactome)
BMGArrowR-HSA-159194 (Reactome)
BMGR-HSA-159179 (Reactome)
BVArrowR-HSA-189398 (Reactome)
BVR-HSA-189384 (Reactome)
Biliverdin reductasemim-catalysisR-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)
FPPR-HSA-2995330 (Reactome)
Fe2+ArrowR-HSA-189398 (Reactome)
Fe2+R-HSA-189465 (Reactome)
GlyR-HSA-189442 (Reactome)
H+ArrowR-HSA-189465 (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)
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)
NADPHR-HSA-189384 (Reactome)
NADPHR-HSA-189398 (Reactome)
NH3ArrowR-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)
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 here to be eliminated from the body.
R-HSA-189384 (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.
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).
SUCC-CoAR-HSA-189442 (Reactome)
UDP-GlcAR-HSA-159179 (Reactome)
UDP-GlcAR-HSA-159194 (Reactome)
UDPArrowR-HSA-159179 (Reactome)
UDPArrowR-HSA-159194 (Reactome)
UGT1A1 tetramer,UGT1A4mim-catalysisR-HSA-159179 (Reactome)
UGT1A1,4mim-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)
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)
hemeR-HSA-189398 (Reactome)
hemeR-HSA-2995330 (Reactome)
hemeTBarR-HSA-189442 (Reactome)

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