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Nucleic acid metabolism is a collective term that refers to the variety of chemical reactions by which
nucleic acids Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main cl ...
( DNA and/or RNA) are either synthesized or degraded. Nucleic acids are polymers (so-called "biopolymers") made up of a variety of monomers called
nucleotides 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 with ...
. Nucleotide synthesis is an
anabolic Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breakin ...
mechanism generally involving the chemical reaction of
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 phosph ...
, pentose
sugar Sugar is the generic name for sweet-tasting, soluble carbohydrates, many of which are used in food. Simple sugars, also called monosaccharides, include glucose, fructose, and galactose. Compound sugars, also called disaccharides or do ...
, and a nitrogenous base. Degradation of nucleic acids is a
catabolic Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lip ...
reaction and the resulting parts of 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 biomolecu ...
s or
nucleobase Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides, which, in turn, are components of nucleotides, with all of these monomers constituting the basi ...
s can be salvaged to recreate new nucleotides. Both synthesis and degradation reactions require multiple
enzymes 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. ...
to facilitate the event. Defects or deficiencies in these enzymes can lead to a variety of diseases.


Synthesis of nucleotides

Nucleotides are the monomers which polymerize into nucleic acids. All nucleotides contain a sugar, a phosphate, and a nitrogenous base. The bases found in nucleic acids are either
purine Purine is a 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 include substituted purines ...
s or
pyrimidine Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The othe ...
s. In the more complex multicellular animals, they are both primarily produced in the liver but the two different groups are synthesized in different ways. However, all nucleotide synthesis requires the use of phosphoribosyl pyrophosphate (PRPP) which donates the ribose and phosphate necessary to create a nucleotide.


Purine synthesis

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 deriv ...
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 ...
are the two nucleotides classified as purines. In purine synthesis, PRPP is turned into inosine monophosphate, or IMP. Production of IMP from PRPP requires
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 ...
,
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 proteinog ...
,
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 ...
, and 6 ATP, among other things. IMP is then converted to AMP (
adenosine monophosphate Adenosine monophosphate (AMP), also known as 5'-adenylic acid, is a nucleotide. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine; it is an ester of phosphoric acid and the nucleoside adenosine. As a substit ...
) using GTP and aspartate, which is converted into
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 ...
. While IMP can be directly converted to AMP, synthesis of GMP (
guanosine monophosphate Guanosine monophosphate (GMP), also known as 5′-guanidylic acid or guanylic acid (conjugate base guanylate), is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid with the nucleoside guanosine. GMP consists of the ...
) requires an intermediate step, in which NAD+ is used to form the intermediate xanthosine monophosphate, or XMP. XMP is then converted into GMP by using the hydrolysis of 1 ATP and the conversion of glutamine to
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 synt ...
. AMP and GMP can then be converted into ATP and GTP, respectively, by
kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
s that add additional phosphates. ATP stimulates production of GTP, while GTP stimulates production of ATP. This cross regulation keeps the relative amounts of ATP and GTP the same. Excess of either nucleotide could increase the likelihood of DNA mutations, where the wrong purine nucleotide is inserted. Lesch–Nyhan syndrome is caused by a deficiency in
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 ...
or HGPRT, the enzyme that catalyzes the reversible reaction of producing guanine from GMP. This is a sex-linked congenital defect that causes overproduction of uric acid along with mental retardation, spasticity, and an urge to self-mutilate.


Pyrimidine synthesis

Pyrimidine nucleosides include
cytidine Cytidine (symbol C or Cyd) is a nucleoside molecule that is formed when cytosine is attached to a ribose ring (also known as a ribofuranose) via a β-N1- glycosidic bond. Cytidine is a component of RNA. It is a white water-soluble solid. which ...
, uridine, and
thymidine Thymidine (symbol dT or dThd), also known as deoxythymidine, deoxyribosylthymine, or thymine deoxyriboside, is a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine (A) in double-stranded DNA. ...
. The synthesis of any pyrimidine nucleotide begins with the formation of uridine. This reaction requires
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 ...
,
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 ...
,
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 biochemi ...
, and 2 ATP molecules (to provide energy), as well as
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 ...
which provides the ribose-monophosphate. Unlike in purine synthesis, the sugar/phosphate group from PRPP is not added to the nitrogenous base until towards the end of the process. After uridine-monophosphate is synthesized, it can react with 2 ATP to form uridine-triphosphate or UTP. UTP can be converted to CTP (cytidine-triphosphate) in a reaction catalyzed by
CTP synthetase CTP synthase is an enzyme () involved in pyrimidine biosynthesis that interconverts UTP and CTP. Reaction mechanism CTP (cytidine triphosphate) synthetase catalyzes the last committed step in pyrimidine nucleotide biosynthesis: ATP + UTP + ...
. Thymidine synthesis first requires reduction of the uridine to deoxyuridine ( see next section), before the base can be methylated to produce thymidine. ATP, a purine nucleotide, is an activator of pyrimidine synthesis, while CTP, a pyrimidine nucleotide, is an inhibitor of pyrimidine synthesis. This regulation helps to keep the purine/pyrimidine amounts similar, which is beneficial because equal amounts of purines and pyrimidines are required for DNA synthesis. Deficiencies of enzymes involved in pyrimidine synthesis can lead to the genetic disease
Orotic aciduria Orotic aciduria (AKA hereditary orotic aciduria) is a disease caused by an enzyme deficiency resulting in a decreased ability to synthesize pyrimidines. It was the first described enzyme deficiency of the ''de novo'' pyrimidine synthesis pathway. ...
which causes excessive excretion of orotic acid in the urine.


Converting nucleotides to deoxynucleotides

Nucleotides are initially made with
ribose Ribose is a simple sugar and carbohydrate with molecular formula C5H10O5 and the linear-form composition H−(C=O)−(CHOH)4−H. The naturally-occurring form, , is a component of the ribonucleotides from which RNA is built, and so this com ...
as the sugar component, which is a feature of RNA. DNA, however, requires ''deoxy''ribose, which is missing the 2'-hydroxyl (-OH group) on the ribose. The reaction to remove this -OH is catalyzed by
ribonucleotide reductase Ribonucleotide reductase (RNR), also known as ribonucleoside diphosphate reductase (rNDP), is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. It catalyzes this formation by removing the 2'-hydroxyl group of t ...
. This enzyme converts NDPs (nucleoside-diphosphate) to dNDPs (deoxynucleoside-diphosphate). The nucleotides must be in the diphosphate form for the reaction to occur. In order to synthesize
thymidine Thymidine (symbol dT or dThd), also known as deoxythymidine, deoxyribosylthymine, or thymine deoxyriboside, is a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine (A) in double-stranded DNA. ...
, a component of DNA which only exists in the deoxy form, uridine is converted to
deoxyuridine Deoxyuridine (dU) is a compound and a nucleoside.It belongs to a class of compounds known as Pyrimidine 2'-deoxyribonucleosides and closely resembles the chemical composition of uridine but without the presence of the 2' hydroxyl group. Idoxuridin ...
(by
ribonucleotide reductase Ribonucleotide reductase (RNR), also known as ribonucleoside diphosphate reductase (rNDP), is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. It catalyzes this formation by removing the 2'-hydroxyl group of t ...
), and then is methylated by
thymidylate synthase Thymidylate synthase (TS) () is an enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thymidine is one of the nucleotides in DNA. With inhibition of TS, an imbalance of deoxynucle ...
to create thymidine.


Degradation of nucleic acids

The breakdown of DNA and RNA is occurring continuously in the cell. Purine and pyrimidine nucleosides can either be degraded to waste products and excreted or can be salvaged as nucleotide components.


Pyrimidine catabolism

Cytosine and uracil are converted into beta-alanine and later to
malonyl-CoA Malonyl-CoA is a coenzyme A derivative of malonic acid. Functions It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis. Fatty acid biosynthesis Malonyl-CoA provides 2-carbon units to fatty acids and com ...
which is needed for
fatty acid synthesis In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes called fatty acid synthases. This process takes place in the cytoplasm of the cell. Most of the acetyl-CoA which is co ...
, among other things. Thymine, on the other hand, is converted into β-aminoisobutyric acid which is then used to form methylmalonyl-CoA. The leftover carbon skeletons such as
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...
and
Succinyl-CoA Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid and coenzyme A. Sources It is an important intermediate in the citric acid cycle, where it is synthesized from α-ketoglutarate by α-ketoglutarate d ...
can then be oxidized by the
citric acid cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and prot ...
. Pyrimidine degradation ultimately ends in the formation of
ammonium The ammonium cation is a positively-charged polyatomic ion with the chemical formula or . It is formed by the protonation of ammonia (). Ammonium is also a general name for positively charged or protonated substituted amines and quaterna ...
, water, and
carbon dioxide Carbon dioxide ( chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is t ...
. The ammonium can then enter the
urea cycle The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic. The urea cycle converts h ...
which occurs in the cytosol and the mitochondria of cells. Pyrimidine bases can also be salvaged. For example, the
uracil Uracil () (symbol U or Ura) is one of the four nucleobases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced b ...
base can be combined with ribose-1-phosphate to create
uridine monophosphate Uridine monophosphate (UMP), also known as 5′-uridylic acid (conjugate base uridylate), is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid with the nucleoside uridine. UMP consists of the phosphate group, th ...
or UMP. A similar reaction can also be done with
thymine Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidin ...
and deoxyribose-1-phosphate. Deficiencies in enzymes involved in pyrimidine catabolism can lead to diseases such as Dihydropyrimidine dehydrogenase deficiency which has negative neurological effects.


Purine catabolism

Purine degradation takes place mainly in the liver of humans and requires an assortment of enzymes to degrade purines to uric acid. First, the nucleotide will lose its phosphate through
5'-nucleotidase 5′-Nucleotidase (EC 3.1.3.5) is an enzyme which catalyzes the phosphorylytic cleavage of 5′-nucleotides. Although originally found in snake venom, the activity of 5'nucleotidase has been described for bacteria and plant cells, and is widely di ...
. The nucleoside, adenosine, is then deaminated and hydrolyzed to form
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 ...
via
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 ...
and nucleosidase respectively. Hypoxanthine is then oxidized to form
xanthine Xanthine ( or ; archaically xanthic acid; systematic name 3,7-dihydropurine-2,6-dione) is a purine base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, including caffein ...
and then uric acid through the action of xanthine oxidase. The other purine nucleoside, guanosine, is cleaved to form guanine. Guanine is then deaminated via guanine deaminase to form xanthine which is then converted to uric acid. Oxygen is the final electron acceptor in the degradation of both purines. Uric acid is then excreted from the body in different forms depending on the animal. Free purine and pyrimidine bases that are released into the cell are typically transported intercellularly across membranes and salvaged to create more nucleotides via nucleotide salvage. For example, adenine +
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 ...
--> AMP + PPi. This reaction requires 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 ...
. Free guanine is salvaged in the same way except it requires
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 ...
. Defects in purine catabolism can result in a variety of diseases including
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 intens ...
, which stems from an accumulation of uric acid crystals in various joints, and
adenosine deaminase deficiency Adenosine deaminase deficiency (ADA deficiency) is a metabolic disorder that causes immunodeficiency. It is caused by mutations in the ADA gene. It accounts for about 10–15% of all cases of autosomal recessive forms of severe combined immuno ...
, which causes
immunodeficiency Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
.


Interconversion of nucleotides

Once the nucleotides are synthesized they can exchange phosphates among one another in order to create mono-, di-, and tri-phosphate molecules. The conversion of a nucleoside-diphosphate (NDP) to a nucleoside-triphosphate (NTP) is catalyzed by nucleoside diphosphate kinase, which uses ATP as the phosphate donor. Similarly, nucleoside-monophosphate kinase carries out the phosphorylation of nucleoside-monophosphates.
Adenylate kinase Adenylate kinase ( ECbr>2.7.4.3 (also known as ADK or myokinase) is a phosphotransferase enzyme that catalyzes the interconversion of the various adenosine phosphates (ATP, ADP, and AMP). By constantly monitoring phosphate nucleotide levels inside ...
is a specific nucleoside-monophosphate kinase that functions only on adenosine-monophosphate.


See also

*
Carbohydrate metabolism Carbohydrate metabolism is the whole of the biochemistry, biochemical processes responsible for the metabolic anabolism, formation, catabolism, breakdown, and interconversion of carbohydrates in life, living organisms. Carbohydrates are central t ...
* DNA *
Nucleic acid Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main ...
*
Protein metabolism Protein metabolism denotes the various biochemical processes responsible for the synthesis of proteins and amino acids (anabolism), and the breakdown of proteins by catabolism. The steps of protein synthesis include transcription, translation, and ...
* RNA


References


External links


Nucleic Acids Book (free online book on the chemistry and biology of nucleic acids)


{{Protein metabolism Nucleic acids Purines Pyrimidines Metabolic pathways Metabolism