Biology:Hemoprotein

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Short description: Protein containing a heme prosthetic group
Binding of oxygen to a heme prosthetic group, which would be part of a hemoprotein.

A hemeprotein (or haemprotein; also hemoprotein or haemoprotein), or heme protein, is a protein that contains a heme prosthetic group.[1] They are a very large class of metalloproteins. The heme group confers functionality, which can include oxygen carrying, oxygen reduction, electron transfer, and other processes. Heme is bound to the protein either covalently or noncovalently or both.[2]

The heme consists of iron cation bound at the center of the conjugate base of the porphyrin, as well as other ligands attached to the "axial sites" of the iron. The porphyrin ring is a planar dianionic, tetradentate ligand. The iron is typically Fe2+ or Fe3+. One or two ligands are attached at the axial sites. The porphyrin ring has 4 nitrogen atoms that bind to the iron, leaving two other coordination positions of the iron available for bonding to the histidine of the protein and a divalent atom.[2]

Hemeproteins probably evolved to incorporate the iron atom contained within the protoporphyrin IX ring of heme into proteins. As it makes hemeproteins responsive to molecules that can bind divalent iron, this strategy has been maintained throughout evolution as it plays crucial physiological functions. The serum iron pool maintains iron in soluble form, making it more accessible for cells.[3] Oxygen (O2), nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) bind to the iron atom in heme proteins. Once bound to the prosthetic heme groups, these molecules can modulate the activity/function of those hemeproteins, affording signal transduction. Therefore, when produced in biologic systems (cells), these gaseous molecules are referred to as gasotransmitters.

A model of the Fe-protoporphyrin IX subunit of the Heme B cofactor.

Because of their diverse biological functions and widespread abundance, hemeproteins are among the most studied biomolecules.[4] Data on heme protein structure and function has been aggregated into The Heme Protein Database (HPD), a secondary database to the Protein Data Bank.[5]

Roles

Hemeproteins have diverse biological functions including oxygen transport, which is completed via hemeproteins including hemoglobin, hemocyanin,[6] myoglobin, neuroglobin, cytoglobin, and leghemoglobin.[7]

Some hemeproteins - cytochrome P450s, cytochrome c oxidase, ligninases, catalase and peroxidases - are enzymes. They often activate O2 for oxidation or hydroxylation.

Hemeproteins also enable electron transfer as they form part of the electron transport chain. Cytochrome a, cytochrome b, and cytochrome c have such electron transfer functions. It is now known that cytochrome a and cytochrome a3 make up one protein and was deemed the name cytochrome aa3.[8] The sensory system also relies on some hemeproteins including FixL, an oxygen sensor, CooA, a carbon monoxide sensor, and soluble guanylyl cyclase.

Hemoglobin and myoglobin

Hemoglobin and myoglobin are examples of hemeproteins that respectively transport and store of oxygen in mammals and in some fish.[9] Hemoglobin is a quaternary protein that occurs in the red blood cell, whereas, myoglobin is a tertiary protein found in the muscle cells of mammals. Although they might differ in location and size, their function are similar. Being hemeproteins, they both contain a heme prosthetic group.

His-F8 of the myoglobin, also known as the proximal histidine, is covalently bonded to the 5th coordination position of the iron. Oxygen interacts with the distal His by way of a hydrogen bond, not a covalent one. It binds to the 6th coordination position of the iron, His-E7 of the myoglobin binds to the oxygen that is now covalently bonded to the iron. The same is true for hemoglobin; however, being a protein with four subunits, hemoglobin contains four heme units in total, allowing four oxygen molecules in total to bind to the protein.

Myoglobin and hemoglobin are globular proteins that serve to bind and deliver oxygen using a prosthetic group. These globins dramatically improve the concentration of molecular oxygen that can be carried in the biological fluids of vertebrates and some invertebrates.

Differences occur in ligand binding and allosteric regulation.

Myoglobin

Myoglobin is found in vertebrate muscle cells and is a water-soluble globular protein.[10] Muscle cells, when put into action, can quickly require a large amount of oxygen for respiration due to their energy requirements. Therefore, muscle cells use myoglobin to accelerate oxygen diffusion and act as localized oxygen reserves for times of intense respiration. Myoglobin also stores the required amount of oxygen and makes it available for the muscle cell mitochondria.

Hemoglobin

In vertebrates, hemoglobin is found in the cytosol of red blood cells. Hemoglobin is sometimes referred to as the oxygen transport protein, in order to contrast it with myoglobin, which is stationary.

In vertebrates, oxygen is taken into the body by the tissues of the lungs, and passed to the red blood cells in the bloodstream where it's used in aerobic metabolic pathways.[10] Oxygen is then distributed to all of the tissues in the body and offloaded from the red blood cells to respiring cells. The hemoglobin then picks up carbon dioxide to be returned to the lungs. Thus, hemoglobin binds and off-loads both oxygen and carbon dioxide at the appropriate tissues, serving to deliver the oxygen needed for cellular metabolism and removing the resulting waste product, CO2.

Nueroglobin

Found in neurons, nueroglobin is responsible for driving nitric oxide to promote neuron cell survival[11] Neuroglobin is believed to increase the oxygen supply for neurons, sustaining ATP production, but they also function as storage proteins.[12]

Peroxidases

Almost all, except glutathione peroxidase, peroxides are hemoproteins. They use hydrogen peroxide as a substrate. Metalloenzymes catalyze reactions using peroxide as an oxidant.[13]

Catalases

With an average molecular weight of ~240,000 g/mol, these hemoproteins are known to be responsible for the catalyzing hydrogen peroxide into water and oxygen.[14] They are made up of 4 subunits, each subunit having a Fe3+ heme group.

Cytochrome c oxidase

Cytochrome c oxidase is an enzyme embedded in the inner membrane of mitochondria. Its main function is to oxidise the cytochrome c protein. Cytochrome c oxidase contains several metal active sites.

Designed heme proteins

Pincer-1:[15] A designed heme-binding peptide adopting an all-beta secondary structure. ABOVE: Topological representation of Pincer-1 showing the secondary structure and designed interacting residues. BELOW: All-atom 3-dimensional model of Pincer-1. This model was partially confirmed using NMR.

Due to the diverse functions of the heme molecule: as an electron transporter, an oxygen carrier, and as an enzyme cofactor, heme binding proteins have consistently attracted the attention of protein designers. Initial design attempts focused on α-helical heme binding proteins, in part, due to the relative simplicity of designing self-assembling helical bundles. Heme binding sites were designed inside the inter-helical hydrophobic grooves. Examples of such designs include:

Later design attempts focused on creating functional heme binding helical bundles, such as:

Design techniques have matured to such an extent that it is now possible to generate entire libraries of heme binding helical proteins.[31]

Recent design attempts have focused on creating all-beta heme binding proteins, whose novel topology is very rare in nature. Such designs include:

  • Pincer-1[15]
  • β-hairpin peptides[32]
  • β-sheet miniproteins[33]
  • Multi-stranded β-sheet peptides[34]

Some methodologies attempt to incorporate cofactors into the hemoproteins who typically endure harsh conditions. In order to incorporate a synthetic cofactor, what must first occur is the denaturing of the holoprotein to remove the heme. The apoprotein is then rebuilt with the cofactor.[35]

References

  1. ↑ "Heme Prosthetic Group Definition". https://earth.callutheran.edu/Academic_Programs/Departments/BioDev/omm/catalase/frames/hemetx.htm#:~:text=Heme%20group:%20A%20prosthetic%20group,propionate%20side%20chains%20are%20attached.. 
  2. ↑ 2.0 2.1 Lehninger, Principles of Biochemistry (3rd ed.). New Yorkm: Worth Publishing. 2000. ISBN 1-57259-153-6. 
  3. ↑ Frazer, David M.; Anderson, Gregory J. (March 2014). "The regulation of iron transport: The Regulation of Iron Transport" (in en). BioFactors 40 (2): 206–214. doi:10.1002/biof.1148. PMID 24132807. https://onlinelibrary.wiley.com/doi/10.1002/biof.1148. 
  4. ↑ "Development of a heme protein structure-electrochemical function database". Nucleic Acids Research 36 (Database issue): D307–D313. January 2008. doi:10.1093/nar/gkm814. PMID 17933771. 
  5. ↑ "Heme Protein Database". Brooklyn, NY: Brooklyn College. https://hemeprotein.info/heme.php. 
  6. ↑ "hemoproteins - Humpath.com - Human pathology". https://www.humpath.com/spip.php?article14129. 
  7. ↑ Principles of Bioinorganic Chemistry. Mill Valley, CA: University Science Books. 1994. ISBN 0-935702-73-3. 
  8. ↑ Mahinthichaichan, Paween; Gennis, Robert B.; Tajkhorshid, Emad (2018-04-10). "Cytochrome aa 3 Oxygen Reductase Utilizes the Tunnel Observed in the Crystal Structures To Deliver O 2 for Catalysis" (in en). Biochemistry 57 (14): 2150–2161. doi:10.1021/acs.biochem.7b01194. ISSN 0006-2960. PMID 29546752. 
  9. ↑ Gerber, Lucie; Clow, Kathy A.; Driedzic, William R.; Gamperl, Anthony K. (July 2021). "The Relationship between Myoglobin, Aerobic Capacity, Nitric Oxide Synthase Activity and Mitochondrial Function in Fish Hearts" (in en). Antioxidants 10 (7): 1072. doi:10.3390/antiox10071072. ISSN 2076-3921. PMID 34356305. 
  10. ↑ 10.0 10.1 "Hemoglobin and Myoglobin | Integrative Medical Biochemistry Examination and Board Review | AccessPharmacy | McGraw Hill Medical". https://accesspharmacy.mhmedical.com/content.aspx?bookid=1696&sectionid=111398218#:~:text=Hemoglobin%20is%20a%20heterotetrameric%20oxygen,intracellular%20storage%20site%20for%20oxygen.. 
  11. ↑ DellaValle, Brian; Hempel, Casper; Kurtzhals, Jørgen A. L.; Penkowa, Milena (2010-08-01). "In vivo expression of neuroglobin in reactive astrocytes during neuropathology in murine models of traumatic brain injury, cerebral malaria, and autoimmune encephalitis: Neuroglobin in Reactive Astrogliosis" (in en). Glia 58 (10): 1220–1227. doi:10.1002/glia.21002. PMID 20544857. https://onlinelibrary.wiley.com/doi/10.1002/glia.21002. 
  12. ↑ Burmester, Thorsten; Hankeln, Thomas (June 2004). "Neuroglobin: A Respiratory Protein of the Nervous System" (in en). Physiology 19 (3): 110–113. doi:10.1152/nips.01513.2003. ISSN 1548-9213. PMID 15143204. https://www.physiology.org/doi/10.1152/nips.01513.2003. 
  13. ↑ Winterbourn, Christine C. (2013-01-01), "Chapter One - The Biological Chemistry of Hydrogen Peroxide", in Cadenas, Enrique; Packer, Lester (in en), Hydrogen Peroxide and Cell Signaling, Part C, Methods in Enzymology, 528, Academic Press, pp. 3–25, doi:10.1016/B978-0-12-405881-1.00001-X, PMID 23849856, https://www.sciencedirect.com/science/article/pii/B978012405881100001X, retrieved 2023-04-27 
  14. ↑ Brzozowska, Ewa; Bazan, Justyna; Gamian, Andrzej (2011-03-25). "Funkcje białek bakteriofagowych". Postępy Higieny i Medycyny Doświadczalnej 65: 167–176. doi:10.5604/17322693.936090. ISSN 1732-2693. PMID 21502693. 
  15. ↑ 15.0 15.1 "Design of a heme-binding peptide motif adopting a β-hairpin conformation" (in English). The Journal of Biological Chemistry 293 (24): 9412–9422. June 2018. doi:10.1074/jbc.RA118.001768. PMID 29695501. 
  16. ↑ "Helichrome: synthesis and enzymic activity of a designed hemeprotein" (in en). Journal of the American Chemical Society 111 (1): 380–381. 1989-01-01. doi:10.1021/ja00183a065. ISSN 0002-7863. 
  17. ↑ "Synthesis and structural stability of helichrome as an artificial hemeproteins". Biopolymers 29 (1): 79–88. January 1990. doi:10.1002/bip.360290112. PMID 2328295. 
  18. ↑ "Design and synthesis of a globin fold". Biochemistry 38 (23): 7431–7443. June 1999. doi:10.1021/bi983006y. PMID 10360940. 
  19. ↑ "De novo designed cyclic-peptide heme complexes". Proceedings of the National Academy of Sciences of the United States of America 100 (23): 13140–13145. November 2003. doi:10.1073/pnas.2231273100. PMID 14595023. Bibcode: 2003PNAS..10013140R. 
  20. ↑ "Design and synthesis of multi-haem proteins". Nature 368 (6470): 425–432. March 1994. doi:10.1038/368425a0. PMID 8133888. Bibcode: 1994Natur.368..425R. 
  21. ↑ "Design of a heme-binding four-helix bundle" (in en). Journal of the American Chemical Society 116 (3): 856–865. 1994-02-01. doi:10.1021/ja00082a005. ISSN 0002-7863. 
  22. ↑ "Design of amphiphilic protein maquettes: controlling assembly, membrane insertion, and cofactor interactions". Biochemistry 44 (37): 12329–12343. September 2005. doi:10.1021/bi050695m. PMID 16156646. 
  23. ↑ "Designed di-heme binding helical transmembrane protein". ChemBioChem 15 (9): 1257–1262. June 2014. doi:10.1002/cbic.201402142. PMID 24829076. 
  24. ↑ "De novo design and molecular assembly of a transmembrane diporphyrin-binding protein complex". Journal of the American Chemical Society 132 (44): 15516–15518. November 2010. doi:10.1021/ja107487b. PMID 20945900. 
  25. ↑ 25.0 25.1 "Elementary tetrahelical protein design for diverse oxidoreductase functions". Nature Chemical Biology 9 (12): 826–833. December 2013. doi:10.1038/nchembio.1362. PMID 24121554. 
  26. ↑ "The HP-1 maquette: from an apoprotein structure to a structured hemoprotein designed to promote redox-coupled proton exchange". Proceedings of the National Academy of Sciences of the United States of America 101 (15): 5536–5541. April 2004. doi:10.1073/pnas.0306676101. PMID 15056758. 
  27. ↑ "De novo design, synthesis and characterisation of MP3, a new catalytic four-helix bundle hemeprotein". Chemistry: A European Journal 18 (50): 15960–15971. December 2012. doi:10.1002/chem.201201404. PMID 23150230. 
  28. ↑ "Directed evolution of a fungal peroxidase". Nature Biotechnology 17 (4): 379–384. April 1999. doi:10.1038/7939. PMID 10207888. 
  29. ↑ "Constructing a man-made c-type cytochrome maquette in vivo: electron transfer, oxygen transport and conversion to a photoactive light harvesting maquette". Chemical Science 5 (2): 507–514. February 2014. doi:10.1039/C3SC52019F. PMID 24634717. 
  30. ↑ "Design and engineering of an O(2) transport protein". Nature 458 (7236): 305–309. March 2009. doi:10.1038/nature07841. PMID 19295603. Bibcode: 2009Natur.458..305K. 
  31. ↑ "Midpoint reduction potentials and heme binding stoichiometries of de novo proteins from designed combinatorial libraries". Biophysical Chemistry. Walter Kauzmann's 85th Birthday 105 (2–3): 231–239. September 2003. doi:10.1016/S0301-4622(03)00072-3. PMID 14499895. 
  32. ↑ "β-Hairpin peptides: heme binding, catalysis, and structure in detergent micelles". Angewandte Chemie 52 (25): 6430–6434. June 2013. doi:10.1002/anie.201300241. PMID 23640811. 
  33. ↑ "Designed Heme-Cage β-Sheet Miniproteins". Angewandte Chemie 56 (21): 5904–5908. May 2017. doi:10.1002/anie.201702472. PMID 28440962. 
  34. ↑ "Designed multi-stranded heme binding β-sheet peptides in membrane". Chemical Science 7 (4): 2563–2571. April 2016. doi:10.1039/C5SC04108B. PMID 28660027. 
  35. ↑ Lemon, Christopher M.; Marletta, Michael A. (2021-12-21). "Designer Heme Proteins: Achieving Novel Function with Abiological Heme Analogues" (in en). Accounts of Chemical Research 54 (24): 4565–4575. doi:10.1021/acs.accounts.1c00588. ISSN 0001-4842. PMID 34890183. 

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