Metabolism of porphyrins (Homo sapiens)

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3, 4, 23, 242, 10, 2215, 185, 202119, 215, 201, 176, 9, 13, 16147, 263, 2711812, 25cytosol4xUGT1A1 2xUROD 2x8xmitochondrial matrix2xPPOFAD HMBSDIPY 2xCPO 8xALADPb2+Zn2+ endoplasmic reticulum lumenFAD UGT1A1Biliverdin reductase2xPPOFADHMBSDIPYH2OBMGhemeHMBS SUCC-CoAH2O2x4xUGT1A1HMOX1/2O2H2OhemeUROD PBGDIPY COX15Fe2+heme OH2O2H+heme AFECH FPPBDGURO3Pb2+NADPHPb2+Fe2+NADP+Zn2+ BIL8xALADPb2+Zn2+CO2ALAD UDP-GlcAZn2+ BILNH3dALAPPGEN92xCPOCOHMBLPRIN9UROSCOX10H2OUDPH2OCOPRO1ALAS1,2BVCOPRO3UGT1A1 O2ALAD GlyH2O2dALA2xURODCO2PRIN9CO28xCPOXPPOX Zn2+H2OCoA-SHCOPRO3PPiPb2+ URO1O2


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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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
2xCPOREACT_9421 (Reactome)
2xPPO FADREACT_9418 (Reactome)
2xREACT_9461 (Reactome)
2xURODREACT_9422 (Reactome)
2xURODREACT_9436 (Reactome)
4xUGT1A1REACT_22319 (Reactome)
8xALAD

Pb2+

Zn2+		ArrowREACT_9437 (Reactome)
8xREACT_9430 (Reactome)
8xREACT_9437 (Reactome)
ALAS1,2REACT_9463 (Reactome)
BDGArrowREACT_22319 (Reactome)
BILArrowREACT_22177 (Reactome)
BILREACT_22274 (Reactome)
BMGArrowREACT_22274 (Reactome)
BMGREACT_22319 (Reactome)
BVArrowREACT_22100 (Reactome)
BVREACT_22177 (Reactome)
Biliverdin reductaseREACT_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)
COX10REACT_163705 (Reactome)
COX15REACT_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 DIPYREACT_9446 (Reactome)
HMOX1/2REACT_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)
UGT1A1REACT_22274 (Reactome)
URO1ArrowREACT_9408 (Reactome)
URO3ArrowREACT_9526 (Reactome)
UROSREACT_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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