Hemesynthesis defects and porphyrias (WP5169)

Homo sapiens

Defects in the heme biosynthesis in a hepatocyte can result in specific metabolic disorders called porphyrias. These diseases can be split into two categories, namely acute porphyrias and non-acute porphyrias. Acute hepatic porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and Doss porphyria (ALADP) are all part of the acute-hepatic porphyrias. This type is often associated with an overproduction of neurotoxic porphyrins and porphyrin precursors. The non-acute porphyrias include, porphyria cutanea tarda, erythropoietic porphyria, and congenital erythropoietic porphyria. These diseases are instead characterised by photosensitivity of the skin and in severe cases liver damage, caused by porphyrins. Another type of porphyria are the X-linked protoporphyria diseases, which are a result of a gain of function mutation in the 5-aminolevulinic acid synthase 2 gene. This causes an accumulation of protoporphyrin IX. The disease present in the patient is determined by what enzyme is affected in the heme biosynthesis pathway. This pathway has been constructed using chapter 33 of the book; Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases (first edition), by N.Blau et al (ISBN 3642403360 (978-3642403361)).


Julia Johnsson , Denise Slenter , and Eric Weitz


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Homo sapiens


Inherited Metabolic Disorders (IMD) Pathways Rare Diseases


Disease Ontology

sideroblastic anemia 1 acute porphyria erythropoietic protoporphyria inherited metabolic disorder cutaneous porphyria porphyria cutanea tarda porphyria hepatoerythropoietic porphyria acute intermittent porphyria

Pathway Ontology

inborn error of metabolism pathway erythropoietic porphyria pathway pathway porphyria pathway acute intermittent porphyria pathway hepatic porphyria pathway disease pathway heme biosynthetic pathway

Cell Type Ontology



Label Type Compact URI Comment
Pentacarboxyl porphyrinogen III Metabolite hmdb:HMDB0001957 Alternative name: Pentacarboxyporphyrinogen III
Protoporphyrin IX Metabolite chebi:57306
Uroporphyrinogen III Metabolite chebi:15437
Coproporphyrinogen I Metabolite chebi:28607
Protoporphyrinogen IX Metabolite chebi:15435
Protoheme Metabolite chebi:26355 Alternative name: Heme
delta-aminolevulinic acid Metabolite chebi:17549
Glycine Metabolite hmdb:HMDB0000123 Alternative name: Glycine
Porphobilinogen Metabolite chebi:17381
hydroxymethylbilane Metabolite chebi:57845
Uroporphyrinogen I Metabolite chebi:28766
succinyl-CoA Metabolite chebi:15380
Heptacarboxylporphyrin III Metabolite hmdb:HMDB0001956 Alternative name: Heptacarboxyporphyrinogen III
Pentacarboxylporphyrin I Metabolite hmdb:HMDB0000789 Alternative name: Pentacarboxyporphyrinogen I
Hexacarboxylporphyrin III Metabolite hmdb:HMDB0001952 Alternative name: Hexacarboxyporphyrinogen III
Hexacarboxylporphyrin I Metabolite hmdb:HMDB0000743 Alternative name: Hexacarboxyporphyrinogen I
Heptaporphyrin Metabolite chebi:89912 Alternative name: Heptacarboxyporphyrinogen I
Coproporphyrinogen III Metabolite chebi:15439
PPOX GeneProduct ncbigene:5498 Alternative name:Proto-Oxidase
HMBS GeneProduct ncbigene:3145 Alternative name: PBG-Deaminase
ALAS1 GeneProduct ncbigene:211 Alternative name: ALA-Synthase
ALAD GeneProduct ncbigene:210 Alternative name: ALA-Dehydratase
ALAS2 GeneProduct ncbigene:212 Alternative name: ALA-Synthase
UROS GeneProduct ncbigene:7390 Alternative name: UR0-111-synthase
UROD GeneProduct ncbigene:7389 Alternative name: URO-Decarboxylase
CPOX GeneProduct ncbigene:1371 Alternative name: Copro-Oxidase
FECH GeneProduct ncbigene:2235 Alternative name: Ferrocnelatase


  1. Lead poisoning in inherited delta-aminolevulinic acid dehydratase deficiency. Doss M, Laubenthal F, Stoeppler M. Int Arch Occup Environ Health. 1984;54(1):55–63. PubMed Europe PMC Scholia
  2. Hereditary tyrosinemia and the heme biosynthetic pathway. Profound inhibition of delta-aminolevulinic acid dehydratase activity by succinylacetone. Sassa S, Kappas A. J Clin Invest. 1983 Mar;71(3):625–34. PubMed Europe PMC Scholia
  3. Molecular aspects of the inherited porphyrias. Sassa S, Kappas A. J Intern Med. 2000 Feb;247(2):169–78. PubMed Europe PMC Scholia
  4. Lead, chemical porphyria, and heme as a biological mediator. Fujita H, Nishitani C, Ogawa K. Tohoku J Exp Med. 2002 Feb;196(2):53–64. PubMed Europe PMC Scholia
  5. The porphyrias. Dombeck TA, Satonik RC. Emerg Med Clin North Am. 2005 Aug;23(3):885–99, x. PubMed Europe PMC Scholia
  6. A critical review of biomarkers used for monitoring human exposure to lead: advantages, limitations, and future needs. Barbosa F Jr, Tanus-Santos JE, Gerlach RF, Parsons PJ. Environ Health Perspect. 2005 Dec;113(12):1669–74. PubMed Europe PMC Scholia
  7. Lead and delta-aminolevulinic acid dehydratase polymorphism: where does it lead? A meta-analysis. Scinicariello F, Murray HE, Moffett DB, Abadin HG, Sexton MJ, Fowler BA. Environ Health Perspect. 2007 Jan;115(1):35–41. PubMed Europe PMC Scholia
  8. Structure and function of enzymes in heme biosynthesis. Layer G, Reichelt J, Jahn D, Heinz DW. Protein Sci. 2010 Jun;19(6):1137–61. PubMed Europe PMC Scholia
  9. Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327R. Hasanoglu A, Balwani M, Kasapkara CS, Ezgü FS, Okur I, Tümer L, et al. J Inherit Metab Dis. 2011 Feb;34(1):225–31. PubMed Europe PMC Scholia
  10. Porphyrin and heme metabolism and the porphyrias. Bonkovsky HL, Guo JT, Hou W, Li T, Narang T, Thapar M. Compr Physiol. 2013 Jan;3(1):365–401. PubMed Europe PMC Scholia
  11. Porphyria Diagnostics-Part 1: A Brief Overview of the Porphyrias. Ramanujam VMS, Anderson KE. Curr Protoc Hum Genet. 2015 Jul 1;86:17.20.1-17.20.26. PubMed Europe PMC Scholia
  12. Diagnosis and treatment of sideroblastic anemias: from defective heme synthesis to abnormal RNA splicing. Cazzola M, Malcovati L. Hematology Am Soc Hematol Educ Program. 2015;2015:19–25. PubMed Europe PMC Scholia
  13. Novel Mechanisms for Heme-dependent Degradation of ALAS1 Protein as a Component of Negative Feedback Regulation of Heme Biosynthesis. Kubota Y, Nomura K, Katoh Y, Yamashita R, Kaneko K, Furuyama K. J Biol Chem. 2016 Sep 23;291(39):20516–29. PubMed Europe PMC Scholia
  14. Update review of the acute porphyrias. Stein PE, Badminton MN, Rees DC. Br J Haematol. 2017 Feb;176(4):527–38. PubMed Europe PMC Scholia
  15. Status of Serum Calcium, Vitamin D and Parathyroid Hormone and Hematological Indices Among Lead Exposed Jewelry Workers in Dhaka, Bangladesh. Mazumdar I, Goswami K, Ali MS. Indian J Clin Biochem. 2017 Mar;32(1):110–6. PubMed Europe PMC Scholia
  16. Molecular pathophysiology and genetic mutations in congenital sideroblastic anemia. Fujiwara T, Harigae H. Free Radic Biol Med. 2019 Mar;133:179–85. PubMed Europe PMC Scholia
  17. Recent advances on porphyria genetics: Inheritance, penetrance & molecular heterogeneity, including new modifying/causative genes. Yasuda M, Chen B, Desnick RJ. Mol Genet Metab. 2019 Nov;128(3):320–31. PubMed Europe PMC Scholia
  18. Erythropoietic Protoporphyria and X-Linked Protoporphyria: pathophysiology, genetics, clinical manifestations, and management. Balwani M. Mol Genet Metab. 2019 Nov;128(3):298–303. PubMed Europe PMC Scholia
  19. Harderoporphyria: Case of lifelong photosensitivity associated with compound heterozygous coproporphyrinogen oxidase (CPOX) mutations. Moghe A, Ramanujam VMS, Phillips JD, Desnick RJ, Anderson KE. Mol Genet Metab Rep. 2019 Feb 19;19:100457. PubMed Europe PMC Scholia
  20. Clinical Guide and Update on Porphyrias. Stölzel U, Doss MO, Schuppan D. Gastroenterology. 2019 Aug;157(2):365-381.e4. PubMed Europe PMC Scholia
  21. Ecogenetics of lead toxicity and its influence on risk assessment. Mani MS, Kabekkodu SP, Joshi MB, Dsouza HS. Hum Exp Toxicol. 2019 Sep;38(9):1031–59. PubMed Europe PMC Scholia
  22. Heme biosynthesis and the porphyrias. Phillips JD. Mol Genet Metab. 2019 Nov;128(3):164–77. PubMed Europe PMC Scholia
  23. 5-Aminolevulinate dehydratase porphyria: Update on hepatic 5-aminolevulinic acid synthase induction and long-term response to hemin. Lahiji AP, Anderson KE, Chan A, Simon A, Desnick RJ, Ramanujam VMS. Mol Genet Metab. 2020 Dec;131(4):418–23. PubMed Europe PMC Scholia