Hemoprotein

Hemeproteins have diverse biological functions including oxygen transport, which is completed via hemeproteins including hemoglobin, hemocyanin,{{Cite web |title=hemoproteins - Humpath.com - Human pathology |url=https://www.humpath.com/spip.php?article14129 |access-date=2023-04-27 |website=www.humpath.com |archive-date=2023-04-27 |archive-url=https://web.archive.org/web/20230427032941/https://www.humpath.com/spip.php?article14129 |url-status=dead }} myoglobin, neuroglobin, cytoglobin, and leghemoglobin.{{cite book | vauthors = Lippard J, Berg JM | title = Principles of Bioinorganic Chemistry | publisher = University Science Books | location = Mill Valley, CA | date = 1994 | isbn = 0-935702-73-3}}

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.{{Cite journal |last1=Mahinthichaichan |first1=Paween |last2=Gennis |first2=Robert B. |last3=Tajkhorshid |first3=Emad |date=2018-04-10 |title=Cytochrome aa 3 Oxygen Reductase Utilizes the Tunnel Observed in the Crystal Structures To Deliver O 2 for Catalysis |journal=Biochemistry |language=en |volume=57 |issue=14 |pages=2150–2161 |doi=10.1021/acs.biochem.7b01194 |pmid=29546752 |pmc=5936630 |issn=0006-2960}} 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 are examples of hemeproteins that respectively transport and store of oxygen in mammals and in some fish.{{Cite journal |last1=Gerber |first1=Lucie |last2=Clow |first2=Kathy A. |last3=Driedzic |first3=William R. |last4=Gamperl |first4=Anthony K. |date=July 2021 |title=The Relationship between Myoglobin, Aerobic Capacity, Nitric Oxide Synthase Activity and Mitochondrial Function in Fish Hearts |journal=Antioxidants |language=en |volume=10 |issue=7 |pages=1072 |doi=10.3390/antiox10071072 |pmid=34356305 |pmc=8301165 |issn=2076-3921 |doi-access=free }} 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 is found in vertebrate muscle cells and is a water-soluble globular protein.{{Cite web |title=Hemoglobin and Myoglobin {{!}} Integrative Medical Biochemistry Examination and Board Review {{!}} AccessPharmacy {{!}} McGraw Hill Medical |url=https://accesspharmacy.mhmedical.com/content.aspx?bookid=1696§ionid=111398218#:~:text=Hemoglobin%20is%20a%20heterotetrameric%20oxygen,intracellular%20storage%20site%20for%20oxygen. |access-date=2023-04-27 |website=accesspharmacy.mhmedical.com}} 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.

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. 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.

Found in neurons, neuroglobin is responsible for driving nitric oxide to promote neuron cell survival{{Cite journal |last1=DellaValle |first1=Brian |last2=Hempel |first2=Casper |last3=Kurtzhals |first3=Jørgen A. L. |last4=Penkowa |first4=Milena |date=2010-08-01 |title=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 |url=https://onlinelibrary.wiley.com/doi/10.1002/glia.21002 |journal=Glia |language=en |volume=58 |issue=10 |pages=1220–1227 |doi=10.1002/glia.21002|pmid=20544857 |s2cid=8563830 |url-access=subscription }} Neuroglobin is believed to increase the oxygen supply for neurons, sustaining ATP production, but they also function as storage proteins.{{Cite journal |last1=Burmester |first1=Thorsten |last2=Hankeln |first2=Thomas |date=June 2004 |title=Neuroglobin: A Respiratory Protein of the Nervous System |url=https://www.physiology.org/doi/10.1152/nips.01513.2003 |journal=Physiology |language=en |volume=19 |issue=3 |pages=110–113 |doi=10.1152/nips.01513.2003 |pmid=15143204 |issn=1548-9213|url-access=subscription }}

Almost all human peroxidases are hemoproteins, except glutathione peroxidase. They use hydrogen peroxide as a substrate. Metalloenzymes catalyze reactions using peroxide as an oxidant.{{Citation |last=Winterbourn |first=Christine C. |chapter=Chapter One - The Biological Chemistry of Hydrogen Peroxide |date=2013-01-01 |url=https://www.sciencedirect.com/science/article/pii/B978012405881100001X |series=Methods in Enzymology |volume=528 |pages=3–25 |editor-last=Cadenas |editor-first=Enrique |access-date=2023-04-27 |title=Hydrogen Peroxide and Cell Signaling, Part C |publisher=Academic Press |doi=10.1016/B978-0-12-405881-1.00001-X |pmid=23849856 |isbn=978-0-12-405881-1 |language=en |editor2-last=Packer |editor2-first=Lester|url-access=subscription }}

Catalases are hemoproteins responsible for the catalysis of converting hydrogen peroxide into water and oxygen.{{Cite journal |last1=Brzozowska |first1=Ewa |last2=Bazan |first2=Justyna |last3=Gamian |first3=Andrzej |date=2011-03-25 |title=Funkcje białek bakteriofagowych |journal=Postępy Higieny i Medycyny Doświadczalnej |volume=65 |pages=167–176 |doi=10.5604/17322693.936090 |pmid=21502693 |issn=1732-2693|doi-access=free }} They are made up of 4 subunits, each subunit having a Fe3+ heme group. They have an average molecular weight of ~240,000 g/mol.

Haloperoxidases involved in the innate immune system also contain a heme prosthetic group.

Cytochromes, cytochrome c oxidase, and coenzyme Q – cytochrome c reductase are heme-containing proteins or protein subunits embedded in the inner membrane of mitochondria which play an essential role in cellular respiration.

Sulfite oxidase, a molybdenum-dependent cytochrome, oxidizes sulfite to sulfate.

{{Main|Nitric oxide synthase}}

File:Pincer-1_beta_heme_peptide.png. ]]

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:

• Helichrome{{Cite journal | vauthors = Sasaki T, Kaiser ET |date=1989-01-01 |title=Helichrome: synthesis and enzymic activity of a designed hemeprotein |journal=Journal of the American Chemical Society |language=en |volume=111 |issue=1 |pages=380–381 |doi=10.1021/ja00183a065 |issn=0002-7863}}{{cite journal | vauthors = Sasaki T, Kaiser ET | title = Synthesis and structural stability of helichrome as an artificial hemeproteins | journal = Biopolymers | volume = 29 | issue = 1 | pages = 79–88 | date = January 1990 | pmid = 2328295 | doi = 10.1002/bip.360290112 | s2cid = 35536899 }}
• Globin-1{{cite journal | vauthors = Isogai Y, Ota M, Fujisawa T, Izuno H, Mukai M, Nakamura H, Iizuka T, Nishikawa K | display-authors = 6 | title = Design and synthesis of a globin fold | journal = Biochemistry | volume = 38 | issue = 23 | pages = 7431–7443 | date = June 1999 | pmid = 10360940 | doi = 10.1021/bi983006y }}
• Cy-AA-EK{{cite journal | vauthors = Rosenblatt MM, Wang J, Suslick KS | title = De novo designed cyclic-peptide heme complexes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 23 | pages = 13140–13145 | date = November 2003 | pmid = 14595023 | pmc = 263730 | doi = 10.1073/pnas.2231273100 | bibcode = 2003PNAS..10013140R | doi-access = free }}
• Peptides IIa/IId{{cite journal | vauthors = Robertson DE, Farid RS, Moser CC, Urbauer JL, Mulholland SE, Pidikiti R, Lear JD, Wand AJ, DeGrado WF, Dutton PL | display-authors = 6 | title = Design and synthesis of multi-haem proteins | journal = Nature | volume = 368 | issue = 6470 | pages = 425–432 | date = March 1994 | pmid = 8133888 | doi = 10.1038/368425a0 | bibcode = 1994Natur.368..425R | s2cid = 4360174 }}
• α2{{Cite journal | vauthors = Choma CT, Lear JD, Nelson MJ, Dutton PL, Robertson DE, DeGrado WF |date=1994-02-01 |title=Design of a heme-binding four-helix bundle |journal=Journal of the American Chemical Society |language=en |volume=116 |issue=3 |pages=856–865 |doi=10.1021/ja00082a005 |issn=0002-7863}}
• Transmembrane helical designs{{cite journal | vauthors = Discher BM, Noy D, Strzalka J, Ye S, Moser CC, Lear JD, Blasie JK, Dutton PL | display-authors = 6 | title = Design of amphiphilic protein maquettes: controlling assembly, membrane insertion, and cofactor interactions | journal = Biochemistry | volume = 44 | issue = 37 | pages = 12329–12343 | date = September 2005 | pmid = 16156646 | pmc = 2574520 | doi = 10.1021/bi050695m }}{{cite journal | vauthors = Mahajan M, Bhattacharjya S | title = Designed di-heme binding helical transmembrane protein | journal = ChemBioChem | volume = 15 | issue = 9 | pages = 1257–1262 | date = June 2014 | pmid = 24829076 | doi = 10.1002/cbic.201402142 | s2cid = 20982919 }}{{cite journal | vauthors = Korendovych IV, Senes A, Kim YH, Lear JD, Fry HC, Therien MJ, Blasie JK, Walker FA, Degrado WF | display-authors = 6 | title = De novo design and molecular assembly of a transmembrane diporphyrin-binding protein complex | journal = Journal of the American Chemical Society | volume = 132 | issue = 44 | pages = 15516–15518 | date = November 2010 | pmid = 20945900 | pmc = 3016712 | doi = 10.1021/ja107487b }}

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

• Oxidoreductases{{cite journal | vauthors = Farid TA, Kodali G, Solomon LA, Lichtenstein BR, Sheehan MM, Fry BA, Bialas C, Ennist NM, Siedlecki JA, Zhao Z, Stetz MA, Valentine KG, Anderson JL, Wand AJ, Discher BM, Moser CC, Dutton PL | display-authors = 6 | title = Elementary tetrahelical protein design for diverse oxidoreductase functions | journal = Nature Chemical Biology | volume = 9 | issue = 12 | pages = 826–833 | date = December 2013 | pmid = 24121554 | doi = 10.1038/nchembio.1362 | pmc = 4034760 }}{{cite journal | vauthors = Huang SS, Koder RL, Lewis M, Wand AJ, Dutton PL | title = The HP-1 maquette: from an apoprotein structure to a structured hemoprotein designed to promote redox-coupled proton exchange | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 15 | pages = 5536–5541 | date = April 2004 | pmid = 15056758 | doi = 10.1073/pnas.0306676101 | pmc = 397418 | doi-access = free }}
• Peroxidases{{cite journal | vauthors = Faiella M, Maglio O, Nastri F, Lombardi A, Lista L, Hagen WR, Pavone V | title = De novo design, synthesis and characterisation of MP3, a new catalytic four-helix bundle hemeprotein | journal = Chemistry: A European Journal | volume = 18 | issue = 50 | pages = 15960–15971 | date = December 2012 | pmid = 23150230 | doi = 10.1002/chem.201201404 }}{{cite journal | vauthors = Cherry JR, Lamsa MH, Schneider P, Vind J, Svendsen A, Jones A, Pedersen AH | title = Directed evolution of a fungal peroxidase | journal = Nature Biotechnology | volume = 17 | issue = 4 | pages = 379–384 | date = April 1999 | pmid = 10207888 | doi = 10.1038/7939 | s2cid = 41233353 }}
• Electron transport proteins{{cite journal | vauthors = Anderson JL, Armstrong CT, Kodali G, Lichtenstein BR, Watkins DW, Mancini JA, Boyle AL, Farid TA, Crump MP, Moser CC, Dutton PL | display-authors = 6 | title = Constructing a man-made c-type cytochrome maquette in vivo: electron transfer, oxygen transport and conversion to a photoactive light harvesting maquette | journal = Chemical Science | volume = 5 | issue = 2 | pages = 507–514 | date = February 2014 | pmid = 24634717 | doi = 10.1039/C3SC52019F | pmc = 3952003 }}
• Oxygen transport proteins{{cite journal | vauthors = Koder RL, Anderson JL, Solomon LA, Reddy KS, Moser CC, Dutton PL | title = Design and engineering of an O(2) transport protein | journal = Nature | volume = 458 | issue = 7236 | pages = 305–309 | date = March 2009 | pmid = 19295603 | doi = 10.1038/nature07841 | pmc = 3539743 | bibcode = 2009Natur.458..305K }}
• Photosensitive proteins

Design techniques have matured to such an extent that it is now possible to generate entire libraries of heme binding helical proteins.{{cite journal | vauthors = Moffet DA, Foley J, Hecht MH | title = Midpoint reduction potentials and heme binding stoichiometries of de novo proteins from designed combinatorial libraries | journal = Biophysical Chemistry | volume = 105 | issue = 2–3 | pages = 231–239 | date = September 2003 | pmid = 14499895 | doi = 10.1016/S0301-4622(03)00072-3 | series = Walter Kauzmann's 85th Birthday | doi-access = free }}

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
• β-hairpin peptides{{cite journal | vauthors = Mahajan M, Bhattacharjya S | title = β-Hairpin peptides: heme binding, catalysis, and structure in detergent micelles | journal = Angewandte Chemie | volume = 52 | issue = 25 | pages = 6430–6434 | date = June 2013 | pmid = 23640811 | doi = 10.1002/anie.201300241 }}
• β-sheet miniproteins{{cite journal | vauthors = D'Souza A, Wu X, Yeow EK, Bhattacharjya S | title = Designed Heme-Cage β-Sheet Miniproteins | journal = Angewandte Chemie | volume = 56 | issue = 21 | pages = 5904–5908 | date = May 2017 | pmid = 28440962 | doi = 10.1002/anie.201702472 }}
• Multi-stranded β-sheet peptides{{cite journal | vauthors = D'Souza A, Mahajan M, Bhattacharjya S | title = Designed multi-stranded heme binding β-sheet peptides in membrane | journal = Chemical Science | volume = 7 | issue = 4 | pages = 2563–2571 | date = April 2016 | pmid = 28660027 | pmc = 5477022 | doi = 10.1039/C5SC04108B }}

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.{{Cite journal |last1=Lemon |first1=Christopher M. |last2=Marletta |first2=Michael A. |date=2021-12-21 |title=Designer Heme Proteins: Achieving Novel Function with Abiological Heme Analogues |journal=Accounts of Chemical Research |language=en |volume=54 |issue=24 |pages=4565–4575 |doi=10.1021/acs.accounts.1c00588 |issn=0001-4842 |pmc=8754152 |pmid=34890183}}

{{Reflist}}

• [http://hemeprotein.info/heme.php Heme Protein Database]
• {{MeshName|Hemeproteins}}

{{Globins}}

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