Heme
Heme (
Heme plays a critical role in multiple different
Heme is a
The word haem is derived from
Function
It has been speculated that the original evolutionary function of
Hemoproteins achieve their remarkable functional diversity by modifying the environment of the heme macrocycle within the protein matrix.
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 |
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
The enzymatic process that produces heme is properly called
The pathway is initiated by the synthesis of
The organs mainly involved in heme synthesis are the
Synthesis for food
Degradation
Degradation begins inside macrophages of the
In the first step, heme is converted to
In addition, heme degradation appears to be an evolutionarily-conserved response to
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
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
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:
- ALAD: aminolevulinic acid, δ-, dehydratase (deficiency causes ala-dehydratase deficiency porphyria)[53]
- ALAS1: aminolevulinate, δ-, synthase 1
- ALAS2: aminolevulinate, δ-, synthase 2 (deficiency causes sideroblastic/hypochromic anemia)
- CPOX: coproporphyrinogen oxidase (deficiency causes hereditary coproporphyria)[54]
- FECH: ferrochelatase (deficiency causes erythropoietic protoporphyria)
- decarboxylase (deficiency causes porphyria cutanea tarda)[57]
- UROS: uroporphyrinogen III synthase(deficiency causes congenital erythropoietic porphyria)
Notes and references
- ISBN 978-0-12-420169-9. Retrieved 2024-02-21.
- S2CID 25224821.
- PMID 35508203.
- PMID 30726014, retrieved 2024-02-22
- ISBN 978-0-9678550-9-7. Archivedfrom the original on 22 August 2017. Retrieved 28 April 2018.
- ISBN 1-57259-153-6.)
- PMID 24400737.
- (PDF) from the original on 2018-07-24.
- PMID 11463332.
- PMID 15598494.
- S2CID 123532036.
- PMID 24400737.
- PMID 23388674.
- ^ 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) - S2CID 6696041.
- PMID 170266.
- PMID 15236569.
- PMID 22236806.
- S2CID 25780396.
- PMID 6341231.
- PMID 12921773.
- S2CID 19631565.
- (PDF) from the original on 2018-07-24.
- S2CID 36465802.
- ^ Fischer H, Orth H (1934). Die Chemie des Pyrrols. Liepzig: Ischemia Verlagsgesellschaft.
- PMID 2068092.
- PMID 13877421.
- PMID 170266.
- PMID 11152419.
- from the original on 8 August 2016. Retrieved 28 April 2018.
- ^ PMID 15917143.
- S2CID 208791867.
- PMID 29642729.
- ^ "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.
- ISSN 0013-0613. Retrieved 2019-04-08.
- S2CID 22652094.
- ISBN 978-0-7167-7108-1.
- PMID 23092321.
- S2CID 12792155.
- PMID 18276984.
- PMID 11465080.
- PMID 38172624.
- ^ Helmenstine AM. "The Chemicals Responsible for the Color of Urine and Feces". ThoughtCo. Retrieved 2020-01-24.
- PMID 5230192.
- PMID 1846966.
- PMID 9034247.
- PMID 15917143.
- S2CID 20675040.
- S2CID 423446.
- PMID 21209396.
- ^ "Diet, nutrition, physical activity and colorectal cancer". wcrf.org. Retrieved 12 February 2022.
- PMID 31170936.)
{{cite journal}}
: CS1 maint: multiple names: authors list (link - PMID 2063868.
- PMID 19267996.
- PMID 23815679.
- PMID 12699245.
- PMID 19419417.