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Purine metabolism refers to the metabolic pathways to synthesize and break down purines that are present in many organisms.


Biosynthesis

Purines are biologically synthesized as nucleotides 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, ...
. 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 derivativ ...
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 and nitrogen 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 proteinogen ...
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
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 con ...
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) 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 and water to 5'-phosphoribosylamine (PRA), glutamate, and pyrophosphate - 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, GMP and IMP. :PRPP + L-Glutamine + H2O → 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 proteinogen ...
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 livi ...
, 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 is ...
(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. :GAR + fTHFfGAR +
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 ma ...
The fourth is catalyzed by phosphoribosylformylglycinamidine synthase. :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 ...
. :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 + H2O The sixth is catalyzed by phosphoribosylaminoimidazole carboxylase. :AIR + CO2CAIR + 2H+ The seventh is catalyzed by phosphoribosylaminoimidazolesuccinocarboxamide synthase. :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 th ...
. :SAICAR → AICAR + Fumarate 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. :AICAR + fTHF → FAICAR + THF The last step is catalyzed by Inosine monophosphate synthase. :FAICAR → IMP + H2O In eukaryotes 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 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 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 ...
*
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 th ...
converts adenylosuccinate into AMP *
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 enzymes:


Guanine

* A nuclease frees the nucleotide * A nucleotidase creates guanosine *
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 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 Guanine deaminase also known as cypin, guanase, guanine aminase, GAH, and guanine aminohydrolase is an aminohydrolase enzyme which converts guanine to xanthine. Cypin is a major cytosolic protein that interacts with PSD-95. It promotes localized m ...
converts guanine 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 ...
(a form of xanthine oxidoreductase) catalyzes the oxidation 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 o ...


Adenine

* A nuclease frees the nucleotide ** A nucleotidase 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 b ...
, then adenosine deaminase 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 ...
** 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, then a nucleotidase 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 ...
*
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 *
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 o ...


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 (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 derivativ ...
. * The enzyme hypoxanthine-guanine phosphoribosyltransferase (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. (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. LN ...
.)


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 intensi ...
, 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. 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, a ...
, an immunosuppressant used in organ transplantation,
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 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. Mycophenolate mofetil 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 (it is an inhibitor of the dihydrofolate reductase).
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 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, eukaryotes, bacteria and archaea, 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 macromolecule ...
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 (DMARD)


References


External links


The Medical Biochemistry Page



PUMPA: Purine Metabolic Patients’ Association
{{Purinergics * Metabolic pathways Biochemistry