Adenosine deaminase (also known as adenosine aminohydrolase, or ADA) is an enzyme () involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues.

Its primary function in humans is the development and maintenance of the immune system. However, the full physiological role of ADA is not yet completely understood.

Structure

ADA exists in both small form (as a monomer) and large form (as a dimer-complex). folded into eight strands of parallel α/β barrels, which surround a central deep pocket that is the active site. By either mechanism, Zn<sup>2+</sup> as a strong electrophile activates a water molecule, which is deprotonated by the basic Asp295 to form the attacking hydroxide.

Function

ADA is considered one of the key enzymes of purine metabolism. It has also been proposed that ADA, in addition to adenosine breakdown, stimulates release of excitatory amino acids and is necessary to the coupling of A1 adenosine receptors and heterotrimeric G proteins. suggesting that chronic exposure to high levels of adenosine can exacerbate inflammation responses rather than suppressing them. It has also been recognized that AMP deaminase protein and activity is upregulated in mouse hearts that overexpress HIF-1α, which in part explains the attenuated levels of adenosine in HIF-1α expressing hearts during ischemic stress.

Pathology

Some mutations in the gene for adenosine deaminase cause it not to be expressed. The resulting deficiency is one cause of severe combined immunodeficiency (SCID), particularly of autosomal recessive inheritance. Deficient levels of ADA have also been associated with pulmonary inflammation, thymic cell death, and defective T-cell receptor signaling.

Conversely, mutations causing this enzyme to be overexpressed are one cause of hemolytic anemia.

There is some evidence that a different allele (ADA2) may lead to autism.

Elevated levels of ADA has also been associated with AIDS.

Isoforms

There are two isoforms of ADA: ADA1 and ADA2.

  • ADA1 is found in most body cells, particularly lymphocytes and macrophages, where it is present not only in the cytosol and nucleus but also as the ecto- form on the cell membrane attached to dipeptidyl peptidase-4 (aka, CD26). ADA1 is involved mostly in intracellular activity, and exists both in small form (monomer) and large form (dimer).
  • ADA2 was first identified in human spleen. It was subsequently found in other tissues including the macrophage where it co-exists with ADA1. The two isoforms regulate the ratio of adenosine to deoxyadenosine potentiating the killing of parasites. ADA2 is found predominantly in the human plasma and serum, and exists solely as a homodimer.

Clinical significance

ADA2 is the predominant form present in human blood plasma and is increased in many diseases, particularly those associated with the immune system: for example rheumatoid arthritis, psoriasis, and sarcoidosis. The plasma ADA2 isoform is also increased in most cancers. ADA2 is not ubiquitous but co-exists with ADA1 only in monocytes-macrophages.

Total plasma ADA can be measured using high performance liquid chromatography or enzymatic or colorimetric techniques. Perhaps the simplest system is the measurement of the ammonia released from adenosine when broken down to inosine. After incubation of plasma with a buffered solution of adenosine the ammonia is reacted with a Berthelot reagent to form a blue colour which is proportionate to the amount of enzyme activity. To measure ADA2, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) is added prior to incubation so as to inhibit the enzymatic activity of ADA1.

Tuberculosis pleural effusions can now be diagnosed accurately by increased levels of pleural fluid adenosine deaminase, above 40 U per liter.

Cladribine and Pentostatin are anti-neoplastic agents used in the treatment of hairy cell leukemia; their mechanism of action is inhibition of adenosine deaminase.

See also

  • Adenosine deaminase deficiency

References

Further reading

  • PDBe-KB provides an overview of all the structure information available in the PDB for Human Adenosine deaminase
  • PDBe-KB provides an overview of all the structure information available in the PDB for Mouse Adenosine deaminase