Purine metabolism refers to the
metabolic pathway
In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...
s to synthesize and break down
purine
Purine is a heterocyclic compound, heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which includ ...
s that are present in many organisms.
Biosynthesis
Purines are biologically synthesized as
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
s and in particular as ribotides, i.e. bases attached to
ribose 5-phosphate
Ribose 5-phosphate (R5P) is both a product and an intermediate of the pentose phosphate pathway. The last step of the oxidative reactions in the pentose phosphate pathway is the production of ribulose 5-phosphate. Depending on the body's state, r ...
. Both
adenine
Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its derivati ...
and
guanine
Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is called ...
are derived from the nucleotide
inosine monophosphate
Inosinic acid or inosine monophosphate (IMP) is a nucleotide (that is, a nucleoside monophosphate). Widely used as a flavor enhancer, it is typically obtained from chicken byproducts or other meat industry waste. Inosinic acid is important in met ...
(IMP), which is the first compound in the pathway to have a completely formed purine ring system.
IMP
Inosine monophosphate is synthesized on a pre-existing ribose-phosphate through a complex pathway (as shown in the figure on the right). The source of the
carbon
Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent
In chemistry, the valence (US spelling) or valency (British spelling) of an element is the measure of its combining capacity with o ...
and
nitrogen
Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...
atoms of the purine ring, 5 and 4 respectively, come from multiple sources. The amino acid
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
contributes all its carbon (2) and nitrogen (1) atoms, with additional nitrogen atoms from glutamine (2) and
aspartic acid
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
(1), and additional carbon atoms from
formyl group
In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl group ...
s (2), which are transferred from the
coenzyme
A cofactor is a non-protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can be considered "helper molecules" that ass ...
tetrahydrofolate
Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative.
Metabolism
Human synthesis
Tetrahydrofolic acid is produced from dihydrofolic acid by dihydrofolate reductase. This reaction is inhibited by methotrexate.
It is co ...
as
10-formyltetrahydrofolate, and a carbon atom from
bicarbonate
In inorganic chemistry, bicarbonate (IUPAC-recommended nomenclature: hydrogencarbonate) is an intermediate form in the deprotonation of carbonic acid. It is a polyatomic anion with the chemical formula .
Bicarbonate serves a crucial biochemic ...
(1). Formyl groups build carbon-2 and carbon-8 in the purine ring system, which are the ones acting as bridges between two nitrogen atoms.
A key regulatory step is the production of 5-phospho-α-
D-ribosyl 1-pyrophosphate (
PRPP
Phosphoribosyl pyrophosphate (PRPP) is a pentose phosphate. It is a biochemical intermediate in the formation of purine nucleotides via inosine-5-monophosphate, as well as in pyrimidine nucleotide formation. Hence it is a building block for DNA ...
) by ribose phosphate pyrophosphokinase, which is activated by
inorganic phosphate
In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid .
The phosphate or orthophosphate ion is derived from phosphor ...
and inactivated by purine ribonucleotides. It is not the committed step to purine synthesis because PRPP is also used in pyrimidine synthesis and salvage pathways.
The first committed step is the reaction of PRPP,
glutamine
Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral, ...
and water to
5'-phosphoribosylamine (PRA),
glutamate
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
, and
pyrophosphate
In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P–O–P linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate (Na2H2P2O7) and tetrasodium pyrophosphate (Na4P2O7), among other ...
- catalyzed by
amidophosphoribosyltransferase
Amidophosphoribosyltransferase (ATase), also known as glutamine phosphoribosylpyrophosphate amidotransferase (GPAT), is an enzyme responsible for catalyzing the conversion of 5-phosphoribosyl-1-pyrophosphate (PRPP) into 5-phosphoribosyl-1-amine ...
, which is activated by PRPP and inhibited by
AMP #REDIRECT Amp
{{Redirect category shell, {{R from other capitalisation{{R from ambiguous page ...
,
GMP
GMP may refer to:
Finance and economics
* Gross metropolitan product
* Guaranteed maximum price
* Guaranteed Minimum Pension
Science and technology
* GNU Multiple Precision Arithmetic Library, a software library
* Granulocyte-macrophage progenit ...
and
IMP
IMP or imp may refer to:
* Imp, a fantasy creature
Arts and entertainment Fictional characters
* Imp (She-Ra), a character in ''She-Ra: Princess of Power''
* Imp a character in '' Artemis Fowl: The Lost Colony''
* Imp, a character in the '' Clan ...
.
:PRPP + L-Glutamine + H
2O → PRA + L-Glutamate + PPi
In the second step react
PRA,
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
and ATP to create
GAR
Gars are members of the family Lepisosteidae, which are the only surviving members of the Ginglymodi, an ancient holosteian group of ray-finned fish, which first appeared during the Triassic, over 240 million years ago. Gars comprise seven livin ...
, ADP, and pyrophosphate - catalyzed by
phosphoribosylamine—glycine ligase
''Phosphoribosylamine—glycine ligase'', also known as glycinamide ribonucleotide synthetase (GARS), () is an enzyme that catalyzes the chemical reaction
:ATP + 5-phospho-D-ribosylamine + glycine \rightleftharpoons ADP + phosphate +
which i ...
(GAR synthetase). Due to the chemical lability of PRA, which has a half-life of 38 seconds at PH 7.5 and 37 °C, researchers have suggested that the compound is channeled from amidophosphoribosyltransferase to GAR synthetase ''in vivo.''
:PRA + Glycine + ATP → GAR + ADP + Pi
The third is catalyzed by
phosphoribosylglycinamide formyltransferase
Phosphoribosylglycinamide formyltransferase (, ''2-amino-N-ribosylacetamide 5'-phosphate transformylase'', ''GAR formyltransferase'', ''GAR transformylase'', ''glycinamide ribonucleotide transformylase'', ''GAR TFase'', ''5,10-methenyltetrahydrofol ...
.
:GAR +
fTHF →
fGAR +
THF
Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water- miscible organic liquid with low viscosity. It is ...
The fourth is catalyzed by
phosphoribosylformylglycinamidine synthase
In enzymology, a phosphoribosylformylglycinamidine synthase () is an enzyme that catalyzes the chemical reaction
:ATP + ''N''2-formyl-''N''1-(5-phospho-D-ribosyl)glycinamide + L-glutamine + H2O \rightleftharpoons ADP + phosphate + 2-(formamido)- ...
.
:fGAR + L-Glutamine + ATP →
fGAM + L-Glutamate + ADP + Pi
The fifth is catalyzed by
AIR synthetase (FGAM cyclase)
Phosphoribosylformylglycinamidine cyclo-ligase (AIR synthetase) is the fifth enzyme () in the ''de novo'' synthesis of purine nucleotides. It catalyzes the reaction to form 5-aminoimidazole ribotide (AIR) from formylglycinamidine-ribonucleotide F ...
.
:fGAM + ATP →
AIR
The atmosphere of Earth is the layer of gases, known collectively as air, retained by Earth's gravity that surrounds the planet and forms its planetary atmosphere. The atmosphere of Earth protects life on Earth by creating pressure allowing for ...
+ ADP + Pi + H
2O
The sixth is catalyzed by
phosphoribosylaminoimidazole carboxylase
The enzyme Phosphoribosylaminoimidazole carboxylase, or AIR carboxylase () is involved in nucleotide biosynthesis and in particular in purine biosynthesis. It catalyzes the conversion of 5'-phosphoribosyl-5-aminoimidazole ("AIR") into 5'-phos ...
.
:AIR + CO
2 →
CAIR +
2H+
The seventh is catalyzed by
phosphoribosylaminoimidazolesuccinocarboxamide synthase
In molecular biology, the protein domain SAICAR synthase is an enzyme which catalyses a reaction to create SAICAR. In enzymology, this enzyme is also known as phosphoribosylaminoimidazolesuccinocarboxamide synthase (). It is an enzyme that c ...
.
:CAIR +
L-Aspartate
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
+ ATP →
SAICAR + ADP + Pi
The eight is catalyzed by
adenylosuccinate lyase
Adenylosuccinate lyase (or adenylosuccinase) is an enzyme that in humans is encoded by the ADSL gene.
Adenylosuccinate lyase converts adenylosuccinate to AMP and fumarate as part of the purine nucleotide cycle. ASL catalyzes two reactions in the ...
.
:SAICAR →
AICAR +
Fumarate
Fumaric acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297.
The salts and esters are known as f ...
The products AICAR and fumarate move on to two different pathways. AICAR serves as the reactant for the ninth step, while fumarate is transported to the citric acid cycle which can then skip the carbon dioxide evolution steps to produce malate. The conversion of fumarate to malate is catalyzed by fumarase. In this way, fumarate connects purine synthesis to the citric acid cycle.
The ninth is catalyzed by
phosphoribosylaminoimidazolecarboxamide formyltransferase
In enzymology, a phosphoribosylaminoimidazolecarboxamide formyltransferase (), also known by the shorter name AICAR transformylase, is an enzyme that catalyzes the chemical reaction
:10-formyltetrahydrofolate + AICAR \rightleftharpoons tetrahydr ...
.
:AICAR + fTHF →
FAICAR + THF
The last step is catalyzed by
Inosine monophosphate synthase
Bifunctional purine biosynthesis protein PURH is a protein that in humans is encoded by the ''ATIC'' gene.
ATIC encodes an enzyme which generates inosine monophosphate
Inosinic acid or inosine monophosphate (IMP) is a nucleotide (that is, a ...
.
:FAICAR → IMP + H
2O
In
eukaryote
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
s the second, third, and fifth step are catalyzed by
trifunctional purine biosynthetic protein adenosine-3
Trifunctional purine biosynthetic protein adenosine-3 is an enzyme that in humans is encoded by the ''GART'' gene.
This protein is a trifunctional polypeptide. It has Phosphoribosylamine—glycine ligase (EC 6.3.4.13), Phosphoribosylglycinamide ...
, which is encoded by the GART gene.
Both ninth and tenth step are accomplished by a single protein named Bifunctional purine biosynthesis protein PURH, encoded by the ATIC gene.
GMP
*
IMP dehydrogenase
IMP or imp may refer to:
* Imp, a fantasy creature
Arts and entertainment Fictional characters
* Imp (She-Ra), a character in ''She-Ra: Princess of Power''
* Imp a character in '' Artemis Fowl: The Lost Colony''
* Imp, a character in the '' Clan ...
(IMPDH) converts
IMP
IMP or imp may refer to:
* Imp, a fantasy creature
Arts and entertainment Fictional characters
* Imp (She-Ra), a character in ''She-Ra: Princess of Power''
* Imp a character in '' Artemis Fowl: The Lost Colony''
* Imp, a character in the '' Clan ...
into
XMP
*
GMP synthase
Guanosine monophosphate synthetase, () also known as GMPS is an enzyme that converts xanthosine monophosphate to guanosine monophosphate.
In the de novo synthesis of purine nucleotides, IMP is the branch point metabolite at which point the pathw ...
converts XMP into
GMP
GMP may refer to:
Finance and economics
* Gross metropolitan product
* Guaranteed maximum price
* Guaranteed Minimum Pension
Science and technology
* GNU Multiple Precision Arithmetic Library, a software library
* Granulocyte-macrophage progenit ...
*
GMP reductase converts GMP back into IMP
AMP
*
adenylosuccinate synthase
In molecular biology, adenylosuccinate synthase (or adenylosuccinate synthetase) () is an enzyme that plays an important role in purine biosynthesis, by catalysing the guanosine triphosphate (GTP)-dependent conversion of inosine monophosphate (I ...
converts IMP to
adenylosuccinate
Adenylosuccinate is an intermediate in the interconversion of purine nucleotides inosine monophosphate (IMP) and adenosine monophosphate (AMP). The enzyme adenylosuccinate synthase carries out the reaction by the addition of aspartate to IMP and r ...
*
adenylosuccinate lyase
Adenylosuccinate lyase (or adenylosuccinase) is an enzyme that in humans is encoded by the ADSL gene.
Adenylosuccinate lyase converts adenylosuccinate to AMP and fumarate as part of the purine nucleotide cycle. ASL catalyzes two reactions in the ...
converts adenylosuccinate into
AMP #REDIRECT Amp
{{Redirect category shell, {{R from other capitalisation{{R from ambiguous page ...
*
AMP deaminase
AMP deaminase 1 is an enzyme that in humans is encoded by the ''AMPD1'' gene.
Adenosine monophosphate deaminase is an enzyme that converts adenosine monophosphate (AMP) to inosine monophosphate (IMP), freeing an ammonia molecule in the process.
...
converts AMP back into IMP
Degradation
Purines are metabolised by several
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s:
Guanine
* A
nuclease
A nuclease (also archaically known as nucleodepolymerase or polynucleotidase) is an enzyme capable of cleaving the phosphodiester bonds between nucleotides of nucleic acids. Nucleases variously effect single and double stranded breaks in their ta ...
frees the
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
* A
nucleotidase
A nucleotidase is a hydrolytic enzyme that catalyzes the hydrolysis of a nucleotide into a nucleoside and a phosphate.
: A nucleotide + H2O = a nucleoside + phosphate
For example, it converts adenosine monophosphate to adenosine, and guanosine mon ...
creates
guanosine
Guanosine (symbol G or Guo) is a purine nucleoside comprising guanine attached to a ribose (ribofuranose) ring via a β-N9-glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate (GMP), cyclic guanosine monophosphate (c ...
*
Purine nucleoside phosphorylase
Purine nucleoside phosphorylase, PNP, PNPase or inosine phosphorylase () is an enzyme that in humans is encoded by the ''NP'' gene. It catalyzes the chemical reaction
:purine nucleoside + phosphate \rightleftharpoons purine + alpha-D-ribose 1- ...
converts
guanosine
Guanosine (symbol G or Guo) is a purine nucleoside comprising guanine attached to a ribose (ribofuranose) ring via a β-N9-glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate (GMP), cyclic guanosine monophosphate (c ...
to
guanine
Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is called ...
*
Guanase converts guanine to
xanthine
Xanthine ( or ; archaically xanthic acid; systematic name 3,7-dihydropurine-2,6-dione) is a purine base (genetics), base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, incl ...
*
Xanthine oxidase
Xanthine oxidase (XO, sometimes XAO) is a form of xanthine oxidoreductase, a type of enzyme that generates reactive oxygen species. These enzymes catalyze the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthin ...
(a form of xanthine oxidoreductase) catalyzes the
oxidation
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
of xanthine to
uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown of ...
Adenine
* A
nuclease
A nuclease (also archaically known as nucleodepolymerase or polynucleotidase) is an enzyme capable of cleaving the phosphodiester bonds between nucleotides of nucleic acids. Nucleases variously effect single and double stranded breaks in their ta ...
frees the
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
** A
nucleotidase
A nucleotidase is a hydrolytic enzyme that catalyzes the hydrolysis of a nucleotide into a nucleoside and a phosphate.
: A nucleotide + H2O = a nucleoside + phosphate
For example, it converts adenosine monophosphate to adenosine, and guanosine mon ...
creates
adenosine
Adenosine ( symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building ...
, then
adenosine deaminase
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 ...
creates
inosine
Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring (also known as a ribofuranose) via a β-N9-glycosidic bond. It was discovered in 1965 in analysis of RNA transferase.
Inosine is commonly found in tRNAs and is e ...
** Alternatively,
AMP deaminase
AMP deaminase 1 is an enzyme that in humans is encoded by the ''AMPD1'' gene.
Adenosine monophosphate deaminase is an enzyme that converts adenosine monophosphate (AMP) to inosine monophosphate (IMP), freeing an ammonia molecule in the process.
...
creates
inosinic acid
Inosinic acid or inosine monophosphate (IMP) is a nucleotide (that is, a nucleoside monophosphate). Widely used as a flavor enhancer, it is typically obtained from chicken byproducts or other meat industry waste. Inosinic acid is important in met ...
, then a
nucleotidase
A nucleotidase is a hydrolytic enzyme that catalyzes the hydrolysis of a nucleotide into a nucleoside and a phosphate.
: A nucleotide + H2O = a nucleoside + phosphate
For example, it converts adenosine monophosphate to adenosine, and guanosine mon ...
creates
inosine
Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring (also known as a ribofuranose) via a β-N9-glycosidic bond. It was discovered in 1965 in analysis of RNA transferase.
Inosine is commonly found in tRNAs and is e ...
*
Purine nucleoside phosphorylase
Purine nucleoside phosphorylase, PNP, PNPase or inosine phosphorylase () is an enzyme that in humans is encoded by the ''NP'' gene. It catalyzes the chemical reaction
:purine nucleoside + phosphate \rightleftharpoons purine + alpha-D-ribose 1- ...
acts upon inosine to create
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. Hyp ...
*
Xanthine oxidase
Xanthine oxidase (XO, sometimes XAO) is a form of xanthine oxidoreductase, a type of enzyme that generates reactive oxygen species. These enzymes catalyze the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthin ...
catalyzes the biotransformation of hypoxanthine to xanthine
*
Xanthine oxidase
Xanthine oxidase (XO, sometimes XAO) is a form of xanthine oxidoreductase, a type of enzyme that generates reactive oxygen species. These enzymes catalyze the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthin ...
acts upon xanthine to create
uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown of ...
Regulations of purine nucleotide biosynthesis
The formation of 5'-phosphoribosylamine from glutamine and PRPP catalysed by PRPP amino transferase is the regulation point for purine synthesis. The enzyme is an allosteric enzyme, so it can be converted from IMP, GMP and AMP in high concentration binds the enzyme to exerts inhibition while PRPP is in large amount binds to the enzyme which causes activation. So IMP, GMP and AMP are inhibitors while PRPP is an activator. Between the formation of 5'-phosphoribosyl, aminoimidazole and IMP, there is no known regulation step.
Salvage
Purines from turnover of cellular nucleic acids (or from food) can also be salvaged and reused in new nucleotides.
* The enzyme
adenine phosphoribosyltransferase
Adenine phosphoribosyltransferase (APRTase) is an enzyme encoded by the ''APRT'' gene, found in humans on chromosome 16. It is part of the Type I PRTase family and is involved in the nucleotide salvage pathway, which provides an alternative to nuc ...
(APRT) salvages
adenine
Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its derivati ...
.
* The enzyme
hypoxanthine-guanine phosphoribosyltransferase
Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is an enzyme encoded in humans by the ''HPRT1'' gene.
HGPRT is a transferase that catalyzes conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate. This r ...
(HGPRT) salvages
guanine
Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is called ...
and
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. Hyp ...
.
(Genetic deficiency of HGPRT causes
Lesch–Nyhan syndrome
Lesch–Nyhan syndrome (LNS) is a rare inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This deficiency occurs due to mutations in the ''HPRT1'' gene located on the X chromosome. LNS ...
.)
Disorders
When a defective gene causes gaps to appear in the metabolic recycling process for purines and pyrimidines, these chemicals are not metabolised properly, and adults or children can suffer from any one of twenty-eight hereditary disorders, possibly some more as yet unknown. Symptoms can include
gout
Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by deposition of monosodium urate monohydrate crystals. Pain typically comes on rapidly, reaching maximal intensit ...
, anaemia, epilepsy, delayed development, deafness, compulsive self-biting, kidney failure or stones, or loss of immunity.
Purine metabolism can have imbalances that can arise from harmful nucleotide triphosphates incorporating into DNA and RNA which further lead to genetic disturbances and mutations, and as a result, give rise to several types of diseases. Some of the diseases are:
#Severe immunodeficiency by loss of adenosine deaminase.
#Hyperuricemia and Lesch–Nyhan syndrome by the loss of hypoxanthine-guanine phosphoribosyltransferase.
#Different types of cancer by an increase in the activities of enzymes like IMP dehydrogenase.
Pharmacotherapy
Modulation of purine metabolism has pharmacotherapeutic value.
''Purine synthesis inhibitors'' inhibit the proliferation of cells, especially
leukocytes
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
. These inhibitors include
azathioprine
Azathioprine (AZA), sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used in rheumatoid arthritis, granulomatosis with polyangiitis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus, ...
, an immunosuppressant used in
organ transplant
Organ transplantation is a medical procedure in which an organ is removed from one body and placed in the body of a recipient, to replace a damaged or missing organ. The donor and recipient may be at the same location, or organs may be transpo ...
ation,
autoimmune disease
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
such as
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
or inflammatory bowel disease such as
Crohn's disease
Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension ...
and
ulcerative colitis
Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and a ...
.
Mycophenolate mofetil
Mycophenolic acid (MPA) is an immunosuppressant medication used to prevent rejection following organ transplantation and to treat autoimmune conditions such as Crohn's disease and lupus. Specifically it is used following kidney, heart, and live ...
is an immunosuppressant drug used to prevent rejection in organ transplantation; it inhibits purine synthesis by blocking inosine monophosphate dehydrogenase (IMPDH).
Methotrexate
Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...
also indirectly inhibits purine synthesis by blocking the metabolism of
folic acid
Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...
(it is an inhibitor of the
dihydrofolate reductase
Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry. In ...
).
Allopurinol
Allopurinol is a medication used to decrease high blood uric acid levels. It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy. It is taken by mouth ...
is a drug that inhibits the enzyme xanthine oxidoreductase and, thus, lowers the level of uric acid in the body. This may be useful in the treatment of gout, which is a disease caused by excess uric acid, forming crystals in joints.
Prebiotic synthesis of purine ribonucleosides
In order to understand how
life
Life is a quality that distinguishes matter that has biological processes, such as signaling and self-sustaining processes, from that which does not, and is defined by the capacity for growth, reaction to stimuli, metabolism, energ ...
arose, knowledge is required of the chemical pathways that permit formation of the key building blocks of life under plausible
prebiotic conditions. Nam et al. demonstrated the direct condensation of purine and pyrimidine nucleobases with ribose to give ribonucleosides in aqueous microdroplets, a key step leading to RNA formation. Also, a plausible prebiotic process for synthesizing purine ribonucleosides was presented by Becker et al.
Purine biosynthesis in the three domains of life
Organisms in all three domains of life,
eukaryote
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
s,
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
and
archaea
Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebac ...
, are able to carry out ''de novo''
biosynthesis
Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. ...
of purines. This ability reflects the essentiality of purines for life. The biochemical pathway of synthesis is very similar in eukaryotes and bacterial species, but is more variable among archaeal species.
[Brown AM, Hoopes SL, White RH, Sarisky CA. Purine biosynthesis in archaea: variations on a theme. Biol Direct. 2011 Dec 14;6:63. doi: 10.1186/1745-6150-6-63. PMID 22168471; PMCID: PMC3261824] A nearly complete, or complete, set of genes required for purine biosynthesis was determined to be present in 58 of the 65 archaeal species studied.
[ However, also identified were seven archaeal species with entirely, or nearly entirely, absent purine encoding genes. Apparently the archaeal species unable to synthesize purines are able to acquire exogenous purines for growth.,][ and are thus similar to purine mutants of eukaryotes, e.g. purine mutants of the Ascomycete fungus ''Neurospora crassa'',][Bernstein, H. Imidazole compounds accumulated by purine mutants of Neurospora crassa J. Gen. Microbiol. 5:41-46 (1961)] that also require exogenous purines for growth.
See also
* Purinergic signaling
Purinergic signalling (or signaling: see American and British English differences) is a form of extracellular signalling mediated by purine nucleotides and nucleosides such as adenosine and ATP. It involves the activation of purinergic receptor ...
* Disease-modifying antirheumatic drug
Disease-modifying antirheumatic drugs (DMARDs) comprise a category of otherwise unrelated disease-modifying drugs defined by their use in rheumatoid arthritis to slow down disease progression. The term is often used in contrast to nonsteroidal ...
(DMARD)
References
External links
The Medical Biochemistry Page
PUMPA: Purine Metabolic Patients’ Association
{{Purinergics
*
Metabolic pathways
Biochemistry