Heme Synthesis
Heme Proteins

Author: Gianpiero Pescarmona
Date: 31/03/2007


Kegg Pathways



Heme A and CytC additional steps

Heme A differs from heme B in that a methyl side chain at ring position 8 is oxidized to a formyl group and a hydroxyethylfarnesyl group, an isoprenoid chain,, synthesized by mevalonate pathway

Cytochrome c-type heme lyase Links covalently the heme group to the apoprotein of cytochrome c


Genes and Environment


SuccinylCoA availability

Erythropoiesis and iron sulfur cluster biogenesis., 2010
ISCA and C1orf69 are thought to assemble Fe-S clusters for mitochondrial aconitase and for lipoate synthase, the enzyme producing lipoate for *pyruvate dehydrogenase complex (PDC). PDC and aconitase are involved in the production of succinyl-CoA, a substrate for heme biosynthesis.*Thus, many steps of heme synthesis depend on Fe-S cluster assembly.

Catene lineari coinvolte nella sintesi eme:
ossigeno aria -> ossigeno sangue -> emoglobina ->
• flusso locale rene-> ossigeno disponibile -> sintesi eritropoietina, eme e 1,25(OH)2VitD3
• flusso locale cervello -> ossigeno disponibile -> sintesi eme
• flusso locale fegato -> ossigeno disponibile -> sintesi eme, albumina e 25(OH)2VitD3
• flusso locale tiroide -> ossigeno disponibile -> sintesi eme e ormone tiroideo
• flusso locale surrene -> ossigeno disponibile -> sintesi eme e DHEA e cortisolo
• flusso locale ovaio -> ossigeno disponibile -> sintesi estrogeni da DHEA -> attivazione sintesi eme in tutti gli altri tessuti

Iron reduction depends on Endosomes or mitochondrial O2-?

Acquisition of iron from transferrin regulates reticulocyte heme synthesis 1985

Heme binding to albuminoid proteins is the result of recent evolution. 2007

Phosphatidylinositol 3-kinase and Ras/mitogen-activated protein kinase signaling pathways are required for the regulation of 5-aminolevulinate synthase gene expression by insulin.2001
Scassa ME, Guberman AS, Varone CL, Cánepa ET.
Exp Cell Res. 2001 Dec 10;271(2):201-13.

Heme transport

Heme synthesis inhibitors

voce bibliografica

Ponka P., 2001:Cell biology of heme.

Inhibition by Succinylacetone from tyrosine catabolism

Hepatocellular carcinoma despite long-term survival in chronic tyrosinaemia I.

J Bioenerg Biomembr. 2009 Oct;41(5):457-64.
Amino acids variations in amyloid-beta peptides, mitochondrial dysfunction, and new therapies for Alzheimer's disease. 2009
Atamna H.

Department of Basic Sciences, Neuroscience, The Commonwealth Medical College, 501 Madison Avenue, Scranton, PA 18510, USA. hatamna@tcmedc.org
Soluble oligomers and/or aggregates of Amyloid-beta (Abeta) are viewed by many as the principal cause for neurodegeneration in Alzheimer's disease (AD). However, the mechanism by which Abeta and its aggregates cause neurodegeneration is not clear. The toxicity of Abeta has been attributed to its hydrophobicity. However, many specific mitochondrial cytopathologies e.g., loss of complex IV, loss of iron homeostasis, or oxidative damage cannot be explained by Abeta's hydrophobicity. In order to understand the role of Abeta in these cytopathologies we hypothesized that Abeta impairs specific metabolic pathways. We focused on heme metabolism because it links iron, mitochondria, and Abeta. We generated experimental evidence showing that Abeta alters heme metabolism in neuronal cells. Furthermore, we demonstrated that Abeta binds to and depletes intracellular regulatory heme (forming an Abeta-heme complex), which provides a strong molecular connection between Abeta and heme metabolism. We showed that heme depletion leads to key cytopathologies identical to those seen in AD including loss of iron homeostasis and loss of mitochondrial complex IV. Abeta-heme exhibits a peroxidase-like catalytic activity, which catalytically accelerates oxidative damage. Interestingly, the amino acids sequence of rodent Abeta (roAbeta) and human Abeta (huAbeta) is identical except for three amino acids within the hydrophilic region, which is also the heme-binding motif that we identified. We found that huAbeta, unlike roAbeta, binds heme tightly and forms a peroxidase. Although, roAbeta and huAbeta equally form fibrils and aggregates, rodents do not develop AD-like neuropathology. These findings led us to propose a new mechanism for mitochondrial dysfunction and huAbeta's neurotoxicity. This mechanism prompted the development of methylene blue (MB), which increased heme synthesis, complex IV, and mitochondrial function. Thus, MB may delay the onset and progression of AD and serve as a lead to develop novel drugs to treat AD.

Atamna H, Heme, iron, and the mitochondrial decay of ageing. 2004

2016-08-09T17:34:29 - Gianpiero Pescarmona

Heme, iron, and the mitochondrial decay of ageing., 2004

written by Atamna H

2009-12-03T16:44:39 - Gianpiero Pescarmona

HCV and porphyrins

Abnormal Urinary Coproporphyrin Levels in Patients Infected by Hepatitis C Virus With or Without Human Immunodeficiency Virus: A Study of 177 Patients.

February 3rd, 1997

According to the authors' abstract of an article published in Archives of Dermatology, "Objective: Many cases of porphyria cutanea tarda have been described in association with human immunodeficiency virus (HIV) infection in young individuals. The link between hepatitis C virus (HCV) and porphyria cutanea tarda is even stronger as more than 50% of patients who have this diagnosis in Italy, France, or Spain are also infected by HCV. To study the role of viral infections on the metabolism of porphyrins, we measured the urinary porphyrin levels in patients with HIV and HCV infections. Design: Survey; prospective study. Setting: University Hospital of Strasbourg,...

Influence of hepatitis C virus (HCV) infection on porphyrin and iron metabolism in porphyria cutanea tarda (PCT) patients. 2001

Bloomer JP, expert on heme synthesis

Hormone-stimulated heme synthesis by isolated mitochondria 1978



thrombocytopenia and high serum alpha-fetoprotein.

Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. 1992

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