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Review
. 2009 Oct;109(10):4596-616.
doi: 10.1021/cr9001116.

Trafficking of heme and porphyrins in metazoa

Scott Severance  1 , Iqbal Hamza
Affiliations
Review

Trafficking of heme and porphyrins in metazoa

Scott Severance et al. Chem Rev. 2009 Oct.
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1. The porphyrin molecule
(A) Structures for heme b with the pyrrole rings lettered using the Hans Fischer system. Hemes a and c are synthesized from heme b via side chain modifications (red). (B) Six most frequent nonplanar distortions of the porphyrin macrocycle (Reprinted with permission from Reference . Copyright 1998 Elsevier)
Figure 2
Figure 2. Schematic model of intracellular heme trafficking
Presumptive heme pathways (black arrows) that are currently unknown are marked with a (?). In eukaryotic cells, the final step of heme synthesis occurs in mitochondrial matrix. The nascent heme moiety is somehow transported through mitochondrial membranes and incorporated into a multitude of hemoproteins found in different cellular compartments (green). This process is presumably mediated by hemochaperones and transporters. Heme transport proteins that have been already identified are highlighted in blue.
Figure 3
Figure 3. Heme biosynthesis in metazoans
(A) Heme biosynthesis is an eight-step enzymatic pathway that begins with the synthesis of ALA in the mitochondria from the amino acid glycine and succinyl-CoA, derived from the Krebs Cycle. The processes for import of glycine and the export of ALA for heme synthesis are unknown. ALA is then transported from the mitochondria into the cytosol where, in mammals. the subsequent four steps occur. The intermediate CPgenIII is transported back into the mitochondria for the final three steps. Researchers have demonstrated that ABCB6 or OGC may import CPgenIII into the mitochondria. The final step is the insertion of ferrous iron, transported by Mitoferrin (Mfrn), into the protoporphyrin IX (PPIX) ring, and this reaction is catalyzed by ferrochelatase (FECH). Mitochondrial enzymes are highlighted in red and cytosolic enzymes in green. (B) Structures of 2-oxoglutarate and the fluorescent porphyrin derivatives palladium meso-tetra(4-carboxyphenyl)porphyrin and palladium meso-tetra(4-aminophenyl)porphyrin. Compare Fig. 3B with the structure of heme b in Fig. 1A.
Figure 3
Figure 3. Heme biosynthesis in metazoans
(A) Heme biosynthesis is an eight-step enzymatic pathway that begins with the synthesis of ALA in the mitochondria from the amino acid glycine and succinyl-CoA, derived from the Krebs Cycle. The processes for import of glycine and the export of ALA for heme synthesis are unknown. ALA is then transported from the mitochondria into the cytosol where, in mammals. the subsequent four steps occur. The intermediate CPgenIII is transported back into the mitochondria for the final three steps. Researchers have demonstrated that ABCB6 or OGC may import CPgenIII into the mitochondria. The final step is the insertion of ferrous iron, transported by Mitoferrin (Mfrn), into the protoporphyrin IX (PPIX) ring, and this reaction is catalyzed by ferrochelatase (FECH). Mitochondrial enzymes are highlighted in red and cytosolic enzymes in green. (B) Structures of 2-oxoglutarate and the fluorescent porphyrin derivatives palladium meso-tetra(4-carboxyphenyl)porphyrin and palladium meso-tetra(4-aminophenyl)porphyrin. Compare Fig. 3B with the structure of heme b in Fig. 1A.
Figure 4
Figure 4. Model for heme transfer from the mitochondria to intracellular organelles
(A) Based upon models for transfer of other metabolites, it is possible that heme can be directly transported by either membrane-bound transporters and chaperones via the cytoplasm (top) or by physical contact between the mitochondria and organelle (e.g., endoplasmic reticulum) using membrane tethering proteins (right). Interorganellar heme transfer could also be mediated by either single or double membrane mitochondria derived vesicles (MDVs) to deliver mitochondrial cargo (bottom) by membrane fusion. (B) Transport of heme synthesis intermediates in the mitochondria. Conversion of CPgenIII to heme is catalyzed by three membrane-associated enzymes: CPOX located on the OM facing the IMS, PPOX on the IM facing the IMS, and FECH located on the matrix side of the IM facing the IMS. A possible mechanism for transfer of heme intermediates between the three enzymes would be to bring them in close proximity using tethering proteins. For instance, the dynamin-like protein (DLP) OPA1 resides on the IM to form tight cristae and intracristae regions which contain proteases and cytochrome c. A similar process might also take place to tether the OM and IM to form junctions for metabolite transfer during heme synthesis. Heme synthesized in the IM could be transported out of the mitochondria to organelles by either membrane-associated chaperones, transmembrane transporters, or direct transfer via the OM by interorganellar membrane tethering.
Figure 4
Figure 4. Model for heme transfer from the mitochondria to intracellular organelles
(A) Based upon models for transfer of other metabolites, it is possible that heme can be directly transported by either membrane-bound transporters and chaperones via the cytoplasm (top) or by physical contact between the mitochondria and organelle (e.g., endoplasmic reticulum) using membrane tethering proteins (right). Interorganellar heme transfer could also be mediated by either single or double membrane mitochondria derived vesicles (MDVs) to deliver mitochondrial cargo (bottom) by membrane fusion. (B) Transport of heme synthesis intermediates in the mitochondria. Conversion of CPgenIII to heme is catalyzed by three membrane-associated enzymes: CPOX located on the OM facing the IMS, PPOX on the IM facing the IMS, and FECH located on the matrix side of the IM facing the IMS. A possible mechanism for transfer of heme intermediates between the three enzymes would be to bring them in close proximity using tethering proteins. For instance, the dynamin-like protein (DLP) OPA1 resides on the IM to form tight cristae and intracristae regions which contain proteases and cytochrome c. A similar process might also take place to tether the OM and IM to form junctions for metabolite transfer during heme synthesis. Heme synthesized in the IM could be transported out of the mitochondria to organelles by either membrane-associated chaperones, transmembrane transporters, or direct transfer via the OM by interorganellar membrane tethering.
Figure 5
Figure 5. Heme acquisition by gram-negative bacteria
(A) Hemolysin secreted by bacteria degrades red blood cells (RBC), releasing hemoglobin and heme. Once released, heme may be transported into the bacterial cell by different mechanisms (i) direct binding of hemoglobin or heme to a specific TonB-dependent outer membrane receptor results in transport of heme into the periplasm. (ii) Capture of hemoproteins such as hemoglobin or hemopexin by hemophores, which deliver these hemoproteins to a specific TonB-dependent outer membrane receptor. (iii) Degradation of hemoproteins by either membrane bound or secreted bacterial proteases to release heme. (B) Heme derived from hemoproteins binds to specific outer membrane (OM) receptors. The energy for heme transport is provided by the energy transducing complex TonB in association with helper proteins ExbB and ExbD. Internalized heme in the periplasm is bound to periplasmic heme transport protein which ferries heme to the cytoplasmic membrane (CM) ABC transporter complex, a system composed of a membrane-associated permease and an ATPase. Heme translocated to the cytoplasm is either degraded by heme oxygenases or sequestered by heme storage proteins or chaperones.
Figure 5
Figure 5. Heme acquisition by gram-negative bacteria
(A) Hemolysin secreted by bacteria degrades red blood cells (RBC), releasing hemoglobin and heme. Once released, heme may be transported into the bacterial cell by different mechanisms (i) direct binding of hemoglobin or heme to a specific TonB-dependent outer membrane receptor results in transport of heme into the periplasm. (ii) Capture of hemoproteins such as hemoglobin or hemopexin by hemophores, which deliver these hemoproteins to a specific TonB-dependent outer membrane receptor. (iii) Degradation of hemoproteins by either membrane bound or secreted bacterial proteases to release heme. (B) Heme derived from hemoproteins binds to specific outer membrane (OM) receptors. The energy for heme transport is provided by the energy transducing complex TonB in association with helper proteins ExbB and ExbD. Internalized heme in the periplasm is bound to periplasmic heme transport protein which ferries heme to the cytoplasmic membrane (CM) ABC transporter complex, a system composed of a membrane-associated permease and an ATPase. Heme translocated to the cytoplasm is either degraded by heme oxygenases or sequestered by heme storage proteins or chaperones.
Figure 6
Figure 6. Heme transport pathways in C. elegans
C. elegans lacks the entire heme biosynthetic pathway and acquires heme in toto for incorporation into hemoproteins. Worms absorb heme as a nutrient in the gut via the apical intestinal surface. The heme is either transported directly via membrane-bound transporters (HRG-1) and hemochaperones or may be transported via intracellular vesicles. Worms must also have an intercellular heme transport system to mobilize heme from the twenty intestinal cells to other cell types including neurons, muscles, and developing embryos.
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