Adenosine deaminase
Encyclopedia
Adenosine deaminase is an enzyme
involved in purine metabolism
. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acid
s in tissues.
adenosine, converting it to the related nucleoside
inosine
by the substitution of the amino group for a hydroxyl group.
Inosine can then be deribosylated (removed from ribose
) by another enzyme called purine nucleoside phosphorylase
(PNP), converting it to hypoxanthine
.
s in the gene for adenosine deaminase cause it to be not expressed. The resulting deficiency is one cause of (SCID).
Conversely, mutations causing this enzyme to be overexpressed are one cause of .
There is some evidence that a different allele
(ADA2) may lead to autism
.
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
, 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[4]. It is the absence of ADA1 that causes SCID.
ADA can also be used in the workup of lymphocytic pleural effusions, in that such specimens with low ADA levels essentially excludes tuberculosis from consideration. .
Tuberculosis pleural effusions can now be diagnosed accurately by increased levels of pleural fluid adenosine deaminase, above 40 U per liter.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
involved in purine metabolism
Purine metabolism
-Biosynthesis:Purines are biologically synthesized as nucleotides and in particular as ribotides, i.e. bases attached to ribose 5-phosphate. A key regulatory step is the production of 5-phospho-α-D-ribosyl 1-pyrophosphate by PRPP synthetase, which is activated by inorganic phosphate and...
. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acid
Nucleic acid
Nucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...
s in tissues.
Reactions
ADA irreversibly deaminatesDeamination
Deamination is the removal of an amine group from a molecule. Enzymes which catalyse this reaction are called deaminases.In the human body, deamination takes place primarily in the liver, however glutamate is also deaminated in the kidneys. Deamination is the process by which amino acids are...
adenosine, converting it to the related nucleoside
Nucleoside
Nucleosides are glycosylamines consisting of a nucleobase bound to a ribose or deoxyribose sugar via a beta-glycosidic linkage...
inosine
Inosine
Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring via a β-N9-glycosidic bond....
by the substitution of the amino group for a hydroxyl group.
 |
|
| Adenosine | Inosine Inosine Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring via a β-N9-glycosidic bond.... |
Inosine can then be deribosylated (removed from ribose
Ribose
Ribose is an organic compound with the formula C5H10O5; specifically, a monosaccharide with linear form H––4–H, which has all the hydroxyl groups on the same side in the Fischer projection....
) by another enzyme called purine nucleoside phosphorylase
Purine nucleoside phosphorylase
Purine nucleoside phosphorylase also known as PNPase and inosine phosphorylase is an enzyme that in humans is encoded by the NP gene.- Function :Purine nucleoside phosphorylase is an enzyme involved in purine metabolism...
(PNP), converting it to hypoxanthine
Hypoxanthine
Hypoxanthine is a naturally occurring purine derivative. It is occasionally found as a constituent of nucleic acids where it is present in the anticodon of tRNA in the form of its nucleoside inosine. It has a tautomer known as 6-Hydroxypurine. Hypoxanthine is a necessary additive in certain cell,...
.
Pathology
Some mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in the gene for adenosine deaminase cause it to be not expressed. The resulting deficiency is one cause of (SCID).
Conversely, mutations causing this enzyme to be overexpressed are one cause of .
There is some evidence that a different allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
(ADA2) may lead to autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
.
Isoforms
There are 2 isoforms of ADA: ADA1 and ADA2.- ADA1 is found in most body cells, particularly lymphocyteLymphocyteA lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s and macrophageMacrophageMacrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s, 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-4Dipeptidyl peptidase-4Dipeptidyl peptidase-4 , also known as adenosine deaminase complexing protein 2 or CD26 is a protein that, in humans, is encoded by the DPP4 gene.-Function:...
(aka, CD26).
- 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.
- ADARADARDouble-stranded RNA-specific adenosine deaminase is an enzyme that in humans is encoded by the ADAR gene.-Further reading:...
is an RNA-specific ADA.
- ADAT is a tRNA-specific ADA, changing the tRNA to allow for a wobble base pairWobble base pairIn molecular biology, a wobble base pair is a non-Watson-Crick base pairing between two nucleotides in RNA molecules. The four main wobble base pairs are guanine-uracil, inosine-uracil, inosine-adenine, and inosine-cytosine . The thermodynamic stability of a wobble base pair is comparable to that...
ing.
Clinical significance
ADA2 is the predominant form present in human blood plasmaBlood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
and is increased in many diseases, particularly those associated with the immune system: for example rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
, psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
and sarcoidosis
Sarcoidosis
Sarcoidosis , also called sarcoid, Besnier-Boeck disease or Besnier-Boeck-Schaumann disease, is a disease in which abnormal collections of chronic inflammatory cells form as nodules in multiple organs. The cause of sarcoidosis is unknown...
. 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
High performance liquid chromatography
High-performance liquid chromatography , HPLC, is a chromatographic technique that can separate a mixture of compounds and is used in biochemistry and analytical chemistry to identify, quantify and purify the individual components of the mixture.HPLC typically utilizes different types of stationary...
, enzymatic or colorimetric techniques. Perhaps the simplest system is the measurement of the ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
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
EHNA is a phosphodiesterase inhibitor that selectively inhibits phosphodiesterase type 2 ....
(EHNA) is added prior to incubation so as to inhibit the enzymatic activity of ADA1[4]. It is the absence of ADA1 that causes SCID.
ADA can also be used in the workup of lymphocytic pleural effusions, in that such specimens with low ADA levels essentially excludes tuberculosis from consideration. .
Tuberculosis pleural effusions can now be diagnosed accurately by increased levels of pleural fluid adenosine deaminase, above 40 U per liter.