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Porphyrin and Heme Metabolism and the Porphyrias

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Abstract

Porphyrins and metalloporphyrins are the key pigments of life on earth as we know it, because they include chlorophyll (a magnesium‐containing metalloporphyrin) and heme (iron protoporphyrin). In eukaryotes, porphyrins and heme are synthesized by a multistep pathway that involves eight enzymes. The first and rate‐controlling step is the formation of delta‐aminolevulinic acid (ALA) from glycine plus succinyl CoA, catalyzed by ALA synthase. Intermediate steps occur in the cytoplasm, with formation of the monopyrrole porphobilinogen and the tetrapyrroles hydroxymethylbilane and a series of porphyrinogens, which are serially decarboxylated. Heme is utilized chiefly for the formation of hemoglobin in erythrocytes, myoglobin in muscle cells, cytochromes P‐450 and mitochondrial cytochromes, and other hemoproteins in hepatocytes. The rate‐controlling step of heme breakdown is catalyzed by heme oxygenase (HMOX), of which there are two isoforms, called HMOX1 and HMOX2. HMOX breaks down heme to form biliverdin, carbon monoxide, and iron. The porphyrias are a group of disorders, mainly inherited, in which there are defects in normal porphyrin and heme synthesis. The cardinal clinical features are cutaneous (due to the skin‐damaging effects of excess deposited porphyrins) or neurovisceral attacks of pain, sometimes with weakness, delirium, seizures, and the like (probably due mainly to neurotoxic effects of ALA). The treatment of choice for the acute hepatic porphyrias is intravenous heme therapy, which repletes a critical regulatory heme pool in hepatocytes and leads to downregulation of hepatic ALA synthase, which is a biochemical hallmark of all forms of acute porphyria in relapse. © 2013 American Physiological Society. Compr Physiol 3:365‐401, 2013.

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Figure 1. Figure 1.

The heme biosynthetic pathway showing major intermediates and enzymatic steps. Adapted from reference (), used by permission of the author and publisher.

Figure 2. Figure 2.

The heme biosynthetic pathway and aspects of its regulation in hepatocytes. Key roles are played by δ‐aminolevulinic acid synthase‐1 (ALAS1), heme oxygenase 1 (HMOX1), nuclear receptors (NRs), and hydroxymethylbilane synthase (HMBS) [also known as porphobilinogen (PBG) deaminase]. Heme itself downregulates several steps in the synthetic pathway, especially ALA synthase‐1, by down regulating transcription, upregulating mRNA breakdown, blocking uptake into mitochondria, and increasing Lon peptidase 1 breakdown of the mature mitochondrial enzyme. Heme upregulates HMOX1, mainly by increasing its transcription through binding to Bach1, a tonic repressor. HMBS is present in low amounts and becomes rate controlling when ALA synthase‐1 is induced. Fifty percent deficiency of HMBS, the defect in acute intermittent porphyria (AIP), can lead to critical deficiency of heme and uncontrolled induction of ALAS1. Heme administered IV is taken up well by hepatocytes, and can replete heme pools rapidly and correct the defects caused by HMBS and other synthetic enzyme deficiencies.

Figure 3. Figure 3.

The structure and nomenclature of the porphyrin macrocycle according to the Fischer and IUPAC nomenclatures. From reference (), used by permission of the author and publisher

Figure 4. Figure 4.

Chemical structures of different types of heme. (A) Heme b; (B) Heme c; (C) Heme d; (D) Heme a; and (E) Heme o. The differences between non‐b types of heme and heme b are shown inside the dashed lines.

Figure 5. Figure 5.

Three‐dimensional structures of single‐ and multiheme proteins. (A) Yeast iso‐1‐cytochrome c [PDB: 1YCC ()]; (B) cytochrome c from rhodothermus marinus [3CP5 ()], the covalent bonds between heme and the cysteine residues of the protein are shown in circles; (C) cytochrome c nitrite reductase of Wolinella succinogenes [PDB: 1FS7 ()] with five heme b molecules; (D) thioalkalivibrio nitratireducens cytochrome c nitrite reductase (PDB: 3F29) with eight heme c molecules. For better visualization, the heme molecules in multiheme proteins (C and D) are shown using spacefill while the single heme in A and B is rendered with sticks (red: oxygen; blue: nitrogen; purple: carbon). The images were generated using Pymol (http://www.pymol.org).

Figure 6. Figure 6.

The pathway of physiologic breakdown of heme.

Figure 7. Figure 7.

Role of heme and BACH1 in regulation of expression of the heme oxygenase‐1 gene.

Figure 8. Figure 8.

Summary diagnostic algorithm for the acute porphyrias.

Figure 9. Figure 9.

Effect of intravenous heme on plasma levels of aminolevulinic acid (ALA) and porphobilinogen (PBG) in the first patient so treated. Adapted from reference (), with permission of the author and publisher.

Figure 10. Figure 10.

Typical cutaneous manifestations of porphyria cutanea tarda (PCT). Cutaneous lesions with bullae, vesicles, and erosions on the dorsum of the hand. From reference (), used by permission of the authors and publisher.

Figure 11. Figure 11.

Hepatic histopathology in porphyria cutanea tarda (PCT). Fresh unfixed liver fluoresces a bright pink (A) due to excess porphyrins. Typically, there is some degree of iron loading (B) and fatty change and inflammation (C). The latter is often due to alcohol or chronic hepatitis C. Sometimes, cirrhosis and/or hepatocellular carcinoma develop (D). Photomicrographs kindly provided by J.R. Bloomer.

Figure 12. Figure 12.

Pathogenesis of porphyria cutanea tarda. The figure shows a summary of the normal pathway of heme biosynthesis, with emphasis on uroporphyrinogen decarboxylase (UROD) and its inhibition by an oxidation product thought to be derived from uroporphyrinogen. Formation of the inhibitor is thought also to require the action of CYP1A2. Several sites of action of iron are shown, including synergistic induction of ALA synthase 1, increases in oxidative stress [reactive oxygen species (ROS)], induction of heme oxygenase. Alcohol and estrogens also increase ROS and induce δ‐aminolevulinic acid synthase‐1 (ALAS1). Hepatitis C virus (HCV) infection increases ROS and decreases hepcidin production. The latter decrease is due to upregulation of histone deacetylase (HDAC) and ccat enhancer binding protein (CEBP) homology protein (CHOP), which result in decreased binding of CEBP to the hepcidin gene promoter region and thus decreased hepcidin production. Mutations in the HFE, HJV, and/or TfR2 genes also lead to decreased hepcidin production. The decrease in hepcidin leads to increased absorption of iron from the small intestine, leading to further hepatic iron overload and to amplification of the metabolic disarray.

Figure 13. Figure 13.

Clinical presentation of congenital erythropoietic porphyria (CEP). From reference (), used by permission of the authors and publisher.



Figure 1.

The heme biosynthetic pathway showing major intermediates and enzymatic steps. Adapted from reference (), used by permission of the author and publisher.



Figure 2.

The heme biosynthetic pathway and aspects of its regulation in hepatocytes. Key roles are played by δ‐aminolevulinic acid synthase‐1 (ALAS1), heme oxygenase 1 (HMOX1), nuclear receptors (NRs), and hydroxymethylbilane synthase (HMBS) [also known as porphobilinogen (PBG) deaminase]. Heme itself downregulates several steps in the synthetic pathway, especially ALA synthase‐1, by down regulating transcription, upregulating mRNA breakdown, blocking uptake into mitochondria, and increasing Lon peptidase 1 breakdown of the mature mitochondrial enzyme. Heme upregulates HMOX1, mainly by increasing its transcription through binding to Bach1, a tonic repressor. HMBS is present in low amounts and becomes rate controlling when ALA synthase‐1 is induced. Fifty percent deficiency of HMBS, the defect in acute intermittent porphyria (AIP), can lead to critical deficiency of heme and uncontrolled induction of ALAS1. Heme administered IV is taken up well by hepatocytes, and can replete heme pools rapidly and correct the defects caused by HMBS and other synthetic enzyme deficiencies.



Figure 3.

The structure and nomenclature of the porphyrin macrocycle according to the Fischer and IUPAC nomenclatures. From reference (), used by permission of the author and publisher



Figure 4.

Chemical structures of different types of heme. (A) Heme b; (B) Heme c; (C) Heme d; (D) Heme a; and (E) Heme o. The differences between non‐b types of heme and heme b are shown inside the dashed lines.



Figure 5.

Three‐dimensional structures of single‐ and multiheme proteins. (A) Yeast iso‐1‐cytochrome c [PDB: 1YCC ()]; (B) cytochrome c from rhodothermus marinus [3CP5 ()], the covalent bonds between heme and the cysteine residues of the protein are shown in circles; (C) cytochrome c nitrite reductase of Wolinella succinogenes [PDB: 1FS7 ()] with five heme b molecules; (D) thioalkalivibrio nitratireducens cytochrome c nitrite reductase (PDB: 3F29) with eight heme c molecules. For better visualization, the heme molecules in multiheme proteins (C and D) are shown using spacefill while the single heme in A and B is rendered with sticks (red: oxygen; blue: nitrogen; purple: carbon). The images were generated using Pymol (http://www.pymol.org).



Figure 6.

The pathway of physiologic breakdown of heme.



Figure 7.

Role of heme and BACH1 in regulation of expression of the heme oxygenase‐1 gene.



Figure 8.

Summary diagnostic algorithm for the acute porphyrias.



Figure 9.

Effect of intravenous heme on plasma levels of aminolevulinic acid (ALA) and porphobilinogen (PBG) in the first patient so treated. Adapted from reference (), with permission of the author and publisher.



Figure 10.

Typical cutaneous manifestations of porphyria cutanea tarda (PCT). Cutaneous lesions with bullae, vesicles, and erosions on the dorsum of the hand. From reference (), used by permission of the authors and publisher.



Figure 11.

Hepatic histopathology in porphyria cutanea tarda (PCT). Fresh unfixed liver fluoresces a bright pink (A) due to excess porphyrins. Typically, there is some degree of iron loading (B) and fatty change and inflammation (C). The latter is often due to alcohol or chronic hepatitis C. Sometimes, cirrhosis and/or hepatocellular carcinoma develop (D). Photomicrographs kindly provided by J.R. Bloomer.



Figure 12.

Pathogenesis of porphyria cutanea tarda. The figure shows a summary of the normal pathway of heme biosynthesis, with emphasis on uroporphyrinogen decarboxylase (UROD) and its inhibition by an oxidation product thought to be derived from uroporphyrinogen. Formation of the inhibitor is thought also to require the action of CYP1A2. Several sites of action of iron are shown, including synergistic induction of ALA synthase 1, increases in oxidative stress [reactive oxygen species (ROS)], induction of heme oxygenase. Alcohol and estrogens also increase ROS and induce δ‐aminolevulinic acid synthase‐1 (ALAS1). Hepatitis C virus (HCV) infection increases ROS and decreases hepcidin production. The latter decrease is due to upregulation of histone deacetylase (HDAC) and ccat enhancer binding protein (CEBP) homology protein (CHOP), which result in decreased binding of CEBP to the hepcidin gene promoter region and thus decreased hepcidin production. Mutations in the HFE, HJV, and/or TfR2 genes also lead to decreased hepcidin production. The decrease in hepcidin leads to increased absorption of iron from the small intestine, leading to further hepatic iron overload and to amplification of the metabolic disarray.



Figure 13.

Clinical presentation of congenital erythropoietic porphyria (CEP). From reference (), used by permission of the authors and publisher.

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Herbert L. Bonkovsky, Jun‐Tao Guo, Weihong Hou, Ting Li, Tarun Narang, Manish Thapar. Porphyrin and Heme Metabolism and the Porphyrias. Compr Physiol 2013, 3: 365-401. doi: 10.1002/cphy.c120006