Heme

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Binding of oxygen to a heme prosthetic group

Heme (

biosynthesized in both the bone marrow and the liver.[2]

Heme plays a critical role in multiple different

oxidative metabolism (cytochrome c oxidase, succinate dehydrogenase), xenobiotic detoxification via cytochrome P450 pathways (including metabolism of some drugs), gas sensing (guanyl cyclases, nitric oxide synthase), and microRNA processing (DGCR8).[3][4]

Heme is a

The word haem is derived from

Greek
αἷμα haima meaning 'blood'.

Space-filling model of the Fe-protoporphyrin IX subunit of heme B. Axial ligands omitted. Color scheme: grey=iron, blue=nitrogen, black=carbon, white=hydrogen, red=oxygen

Function

electron transfer chain. The large semi-transparent sphere indicates the location of the iron ion. From PDB: 1YQ3
​.

diatomic gases, chemical catalysis, diatomic gas detection, and electron transfer. The heme iron serves as a source or sink of electrons during electron transfer or redox chemistry. In peroxidase reactions, the porphyrin molecule also serves as an electron source, being able to delocalize radical electrons in the conjugated ring. In the transportation or detection of diatomic gases, the gas binds to the heme iron. During the detection of diatomic gases, the binding of the gas ligand to the heme iron induces conformational changes in the surrounding protein.[10]
In general, diatomic gases only bind to the reduced heme, as ferrous Fe(II) while most peroxidases cycle between Fe(III) and Fe(IV) and hemeproteins involved in mitochondrial redox, oxidation-reduction, cycle between Fe(II) and Fe(III).

It has been speculated that the original evolutionary function of

organisms before the appearance of molecular oxygen.[11]

Hemoproteins achieve their remarkable functional diversity by modifying the environment of the heme macrocycle within the protein matrix.

steric organization of the globin chain; a histidine residue, located adjacent to the heme group, becomes positively charged under acidic conditions (which are caused by dissolved CO2 in working muscles, etc.), releasing oxygen from the heme group.[15]

Types

Major hemes

There are several biologically important kinds of heme:

Heme A Heme B Heme C Heme O
PubChem number 7888115 444098 444125 6323367
Chemical formula C49H56O6N4Fe C34H32O4N4Fe C34H36O4N4S2Fe C49H58O5N4Fe
Functional group at C3 –CH(OH)CH2Far –CH=CH2 –CH(cystein-S-yl)CH3 –CH(OH)CH2Far
Functional group at C8 –CH=CH2 –CH=CH2 –CH(cystein-S-yl)CH3 –CH=CH2
Functional group at C18
–CH=O
–CH3
–CH3 –CH3
Structure of Fe-porphyrin subunit of heme B.
Structure of Fe-porphyrin subunit of heme A.[16] Heme A is synthesized from heme B. In two sequential reactions a 17-hydroxyethylfarnesyl moiety is added at the 2-position and an aldehyde is added at the 8-position.[17]

The most common type is heme B; other important types include heme A and heme C. Isolated hemes are commonly designated by capital letters while hemes bound to proteins are designated by lower case letters. Cytochrome a refers to the heme A in specific combination with membrane protein forming a portion of cytochrome c oxidase.[18]

Other hemes

The following carbon numbering system of porphyrins is an older numbering used by biochemists and not the 1–24 numbering system recommended by
IUPAC
, which is shown in the table above.
  • Heme l is the derivative of heme B which is covalently attached to the protein of
    aspartyl-225 of lactoperoxidase forms ester bonds between these amino acid residues and the heme 1- and 5-methyl groups, respectively.[19] Similar ester bonds with these two methyl groups are thought to form in eosinophil and thyroid peroxidases. Heme l is one important characteristic of animal peroxidases; plant peroxidases incorporate heme B. Lactoperoxidase and eosinophil peroxidase are protective enzymes responsible for the destruction of invading bacteria and virus. Thyroid peroxidase is the enzyme catalyzing the biosynthesis of the important thyroid hormones. Because lactoperoxidase destroys invading organisms in the lungs and excrement, it is thought to be an important protective enzyme.[20]
  • Heme m is the derivative of heme B covalently bound at the active site of
    sulfonamide ion linkage between the sulfur of a methionyl amino-acid residue and the heme 2-vinyl group is formed, giving this enzyme the unique capability of easily oxidizing chloride and bromide ions to hypochlorite and hypobromite. Myeloperoxidase is present in mammalian neutrophils and is responsible for the destruction of invading bacteria and viral agents. It perhaps synthesizes hypobromite by "mistake". Both hypochlorite and hypobromite are very reactive species responsible for the production of halogenated nucleosides, which are mutagenic compounds.[21][22]
  • Heme D is another derivative of heme B, but in which the propionic acid side chain at the carbon of position 6, which is also hydroxylated, forms a γ-spirolactone. Ring III is also hydroxylated at position 5, in a conformation trans to the new lactone group.[23] Heme D is the site for oxygen reduction to water of many types of bacteria at low oxygen tension.[24]
  • Heme S is related to heme B by having a formyl group at position 2 in place of the 2-vinyl group. Heme S is found in the hemoglobin of a few species of marine worms. The correct structures of heme B and heme S were first elucidated by German chemist Hans Fischer.[25]

The names of cytochromes typically (but not always) reflect the kinds of hemes they contain: cytochrome a contains heme A, cytochrome c contains heme C, etc. This convention may have been first introduced with the publication of the structure of heme A.

Use of capital letters to designate the type of heme

The practice of designating hemes with upper case letters was formalized in a footnote in a paper by Puustinen and Wikstrom,[26] which explains under which conditions a capital letter should be used: "we prefer the use of capital letters to describe the heme structure as isolated. Lowercase letters may then be freely used for cytochromes and enzymes, as well as to describe individual protein-bound heme groups (for example, cytochrome bc, and aa3 complexes, cytochrome b5, heme c1 of the bc1 complex, heme a3 of the aa3 complex, etc)." In other words, the chemical compound would be designated with a capital letter, but specific instances in structures with lowercase. Thus cytochrome oxidase, which has two A hemes (heme a and heme a3) in its structure, contains two moles of heme A per mole protein. Cytochrome bc1, with hemes bH, bL, and c1, contains heme B and heme C in a 2:1 ratio. The practice seems to have originated in a paper by Caughey and York in which the product of a new isolation procedure for the heme of cytochrome aa3 was designated heme A to differentiate it from previous preparations: "Our product is not identical in all respects with the heme a obtained in solution by other workers by the reduction of the hemin a as isolated previously (2). For this reason, we shall designate our product heme A until the apparent differences can be rationalized.".[27] In a later paper,[28] Caughey's group uses capital letters for isolated heme B and C as well as A.

Synthesis

Heme synthesis in the cytoplasm and mitochondrion

The enzymatic process that produces heme is properly called

cobalamin (vitamin B12).[29]

The pathway is initiated by the synthesis of

inborn error of metabolism of this process, by reducing transcription of ALA synthase.[30]

The organs mainly involved in heme synthesis are the

]

Synthesis for food

yeast, adding the resulting heme to items such as meatless (vegan) Impossible burger patties. The DNA for leghemoglobin production was extracted from the soybean root nodules and expressed in yeast cells to overproduce heme for use in the meatless burgers.[33] This process claims to create a meaty flavor in the resulting products.[34][35]

Degradation

Heme breakdown

Degradation begins inside macrophages of the

erythrocytes
from the circulation.

In the first step, heme is converted to

NADPH is used as the reducing agent, molecular oxygen enters the reaction, carbon monoxide (CO) is produced and the iron is released from the molecule as the ferrous ion (Fe2+).[37] CO acts as a cellular messenger and functions in vasodilation.[38]

In addition, heme degradation appears to be an evolutionarily-conserved response to

heme oxygenase-1 (HMOX1) isoenzyme that catabolizes heme (see below).[39] The reason why cells must increase exponentially their capability to degrade heme in response to oxidative stress remains unclear but this appears to be part of a cytoprotective response that avoids the deleterious effects of free heme. When large amounts of free heme accumulates, the heme detoxification/degradation systems get overwhelmed, enabling heme to exert its damaging effects.[31]

heme
heme oxygenase-1
biliverdin + Fe2+
 
H+ +
NADPH
+ O2
NADP+ + CO
 
 

In the second reaction, biliverdin is converted to bilirubin by biliverdin reductase (BVR):[40]

biliverdin biliverdin reductase bilirubin
 
H+ +
NADPH
NADP+
 
 

Bilirubin is transported into the liver by facilitated diffusion bound to a protein (serum albumin), where it is conjugated with glucuronic acid to become more water-soluble. The reaction is catalyzed by the enzyme UDP-glucuronosyltransferase.[41]

bilirubin UDP-glucuronosyltransferase bilirubin diglucuronide
 
2 UDP-glucuronide 2 UMP + 2 Pi
 
 

This form of bilirubin is excreted from the liver in

intestinal bacteria deconjugate bilirubin diglucuronide releasing free bilirubin, which can either be reabsorbed or reduced to urobilinogen by the bacterial enzyme bilirubin reductase.[42]

bilirubin bilirubin reductase urobilinogen
 
4
NAD(P)H
+ 4 H+
4 NAD(P)+
 
 


Some urobilinogen is absorbed by intestinal cells and transported into the
kidneys and excreted with urine (urobilin, which is the product of oxidation of urobilinogen, and is responsible for the yellow colour of urine). The remainder travels down the digestive tract and is converted to stercobilinogen. This is oxidized to stercobilin, which is excreted and is responsible for the brown color of feces.[43]

In health and disease

Under

Fenton's reagent to catalyze in an unfettered manner the production of free radicals.[46] It catalyzes the oxidation and aggregation of protein, the formation of cytotoxic lipid peroxide via lipid peroxidation and damages DNA through oxidative stress. Due to its lipophilic properties, it impairs lipid bilayers in organelles such as mitochondria and nuclei.[47] These properties of free heme can sensitize a variety of cell types to undergo programmed cell death in response to pro-inflammatory agonists, a deleterious effect that plays an important role in the pathogenesis of certain inflammatory diseases such as malaria[48] and sepsis.[49]

Cancer

There is an association between high intake of heme iron sourced from meat and increased risk of colorectal cancer.[50]

The American Institute for Cancer Research (AICR) and World Cancer Research Fund International (WCRF) concluded in a 2018 report that there is limited but suggestive evidence that foods containing heme iron increase risk of colorectal cancer.[51] A 2019 review found that heme iron intake is associated with increased breast cancer risk.[52]

Genes

The following genes are part of the chemical pathway for making heme:

Notes and references

  1. . Retrieved 2024-02-21.
  2. .
  3. .
  4. , retrieved 2024-02-22
  5. from the original on 22 August 2017. Retrieved 28 April 2018.
  6. .)
  7. .
  8. (PDF) from the original on 2018-07-24.
  9. .
  10. .
  11. .
  12. .
  13. .
  14. ^ Bohr, Hasselbalch, Krogh. "Concerning a Biologically Important Relationship - The Influence of the Carbon Dioxide Content of Blood on its Oxygen Binding". Archived from the original on 2017-04-18. {{cite journal}}: Cite journal requires |journal= (help)
  15. S2CID 6696041
    .
  16. .
  17. .
  18. .
  19. .
  20. .
  21. .
  22. .
  23. (PDF) from the original on 2018-07-24.
  24. .
  25. ^ Fischer H, Orth H (1934). Die Chemie des Pyrrols. Liepzig: Ischemia Verlagsgesellschaft.
  26. PMID 2068092
    .
  27. .
  28. .
  29. .
  30. from the original on 8 August 2016. Retrieved 28 April 2018.
  31. ^ .
  32. .
  33. .
  34. ^ "Inside the Strange Science of the Fake Meat That 'Bleeds'". Wired. 2017-09-20. Archived from the original on 24 March 2018. Retrieved 28 April 2018.
  35. ISSN 0013-0613
    . Retrieved 2019-04-08.
  36. .
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  38. .
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  40. .
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  42. .
  43. ^ Helmenstine AM. "The Chemicals Responsible for the Color of Urine and Feces". ThoughtCo. Retrieved 2020-01-24.
  44. PMID 5230192
    .
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  46. .
  47. .
  48. .
  49. .
  50. .
  51. ^ "Diet, nutrition, physical activity and colorectal cancer". wcrf.org. Retrieved 12 February 2022.
  52. PMID 31170936.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  53. .
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