CoFactor: Heme

General information

2D representation

Key facts

Tags

• porphyrin-like cofactors
• fat-slouble cofactors

Molecular function

Hemes are a group of molecules rather than just one. ChEBI defines: "A heme is any tetrapyrrolic chelate of iron".

Heme is essential for all aerobic organisms [4].

Heme cofactor functions comprise:

• Source of electrons
• Heme mediates the oxidative metabolism of xenobiotics and drugs in cytochrome P450s[3]
• Heme catalyses the monooxigenation of substrates: R-H -> R-OH [3]

• Transfer and storage of gases
• Regulation: induces heme oxygenase 1, which produces biliverdin an later bilirubin (antioxidants). Heme therefore functions as an oxidative stress sensor; heme also suppresses ALAS1 (1st Step of heme synthesis)[4]
• Heme regulates the formation of the cell signalling molecule NO [3]

Siroheme acts as a cofactor in the reduction of sulphate and nitrate [5].

Chemical properties

A schema of all the different heme groups in enzymes was recently published in a review [1]. The figure can be viewed here, and is displayed with permission from the authors.

Hemoproteins have various functions: Oxygen binding (haemoglobins), electron transport in the respiratory chain and photosynthesis (cytochromes), detoxification of xenobiotics (cytochromes P450) and more (peroxidase, catalase) [2].

Heme is lipid soluble [2] and in the majority of hemoproteins, heme is not covalently attached to the apoprotein [2].

For cytochrome c, there are 3 systems for the covalent linkage of the vinyl-groups to Cys residues in the apoprotein. They include 12, 4 and 1 enzymes in different groups of species [2].

In heme oxygenase (1 and 2), heme has a His as 5th ligand and a water molecule as distal ligand [3].

Pathways

Heme is also involved in regulating hemoproteins [4]. It induces Heme oxygenase 1 (but not 2) and therefore induces its own degradation [4].

Heme also regulates ion channels (K+) [4].

Comment

CP is a heme-binding motif in proteins [4].

AIP (Acute intermittent porphyria) is an autosomal dominant mutation of hydroxymethylbilane synthase (HMBS). Precipitating factors are drugs, hormones, alcohol, starvation, stresses and they induce ALAS-1 expression in the liver, which leads to accumulation of ALA (5-aminolevulinic acid) and PBG (prophobilinogen), which in turn leads to symptoms like abdominal pain, vomiting, nausea. Therefore, ALAS-1 is considered a drug target. A mutation in ALAS-1 can be treated by supplying heme to repress ALAS-1. The mutation of ALAS-2 is X-linked and causes XLSA (X-linked sideroblastic anemia), which is treated by supplying pyridoxal because ALAS-2 requires PLP. [4]

References

[1]	pubmed:20544970
[2]	pubmed:17898892
[3]	pubmed:18237198
[4]	pubmed:17785948
[5]	pubmed:20037471
[6]	pubmed:11293549