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Nucleotides are
organic molecules , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, catenate (form chains with other carbon ...
consisting of a
nucleoside Nucleosides are s that can be thought of as s without a . A nucleoside consists simply of a (also termed a nitrogenous base) and a five-carbon sugar ( or 2'-deoxyribose) whereas a nucleotide is composed of a nucleobase, a five-carbon sugar, and ...

nucleoside
and a
phosphate In chemistry, a phosphate is an anion, salt (chemistry), salt, functional group or ester derived from a phosphoric acids and phosphates, phosphoric acid. It most commonly means orthophosphate, a derivative of phosphoric acid, orthophosphoric a ...

phosphate
. They serve as
monomer In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and the changes they undergo during a ...

monomer
ic units of the
nucleic acid Nucleic acids are biopolymer Biopolymers are natural polymer A polymer (; Greek ''wikt:poly-, poly-'', "many" + ''wikt:-mer, -mer'', "part") is a Chemical substance, substance or material consisting of very large molecules, or macromolecule ...

nucleic acid
polymers A polymer (; Greek ''poly- Poly, from the Greek :wikt:πολύς, πολύς meaning "many" or "much", may refer to: Businesses * China Poly Group Corporation, a Chinese business group, and its subsidiaries: ** Poly Property, a Hong Kong inco ...

polymers
deoxyribonucleic acid File:DNA animation.gif, The structure of part of a DNA double helix Deoxyribonucleic acid (; DNA) is a molecule composed of two polynucleotide chains that coil around each other to form a Nucleic acid double helix, double helix carrying genet ...
(DNA) and
ribonucleic acid Ribonucleic acid (RNA) is a polymer A polymer (; Greek '' poly-'', "many" + '' -mer'', "part") is a substance or material consisting of very large molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of ...
(RNA), both of which are essential
biomolecules , showing alpha helices The alpha helix (α-helix) is a common motif in the secondary structure Biomolecular structure is the intricate folded, three-dimensional shape that is formed by a molecule File:Pentacene on Ni(111) STM.jpg, A scan ...
within all life-forms on Earth. Nucleotides are obtained in the diet and are also synthesized from common nutrients by the liver. Nucleotides are composed of three subunit molecules: a
nucleobase 230px, Pyrimidine nucleobases are simple ring molecules. Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides Nucleosides are glycosylamines that can be ...
, a (
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 compoun ...

ribose
or
deoxyribose Deoxyribose, or more precisely 2-deoxyribose, is a monosaccharide Monosaccharides (from Greek#REDIRECT Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially the Hellenic Rep ...

deoxyribose
), and a phosphate group consisting of one to three
phosphate In chemistry, a phosphate is an anion, salt (chemistry), salt, functional group or ester derived from a phosphoric acids and phosphates, phosphoric acid. It most commonly means orthophosphate, a derivative of phosphoric acid, orthophosphoric a ...

phosphate
s. The four nucleobases in DNA are
guanine Guanine () (symbol A symbol is a mark, sign, or word In linguistics, a word of a spoken language can be defined as the smallest sequence of phonemes that can be uttered in isolation with semantic, objective or pragmatics, practical me ...

guanine
,
adenine Adenine (A, Ade) is a nucleobase 230px, Pyrimidine nucleobases are simple ring molecules. Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides Nucleos ...

adenine
,
cytosine Cytosine () (symbol A symbol is a mark, sign, or that indicates, signifies, or is understood as representing an , , or . Symbols allow people to go beyond what is n or seen by creating linkages between otherwise very different s and s. Al ...

cytosine
and
thymine Thymine () (symbol A symbol is a mark, sign, or word In linguistics, a word of a spoken language can be defined as the smallest sequence of phonemes that can be uttered in isolation with semantic, objective or pragmatics, practical m ...

thymine
; in RNA,
uracil Uracil () ( U or Ura) is one of the four s in the that are represented by the letters A, G, C and U. The others are (A), (C), and (G). In RNA, uracil binds to via two . In , the uracil nucleobase is replaced by . Uracil is a form of . Ura ...

uracil
is used in place of thymine. Nucleotides also play a central role in
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life Life is a characteristic that distinguishes physical entities A bubble of exhaled gas in water In common usage and classical mechanics, a phys ...

metabolism
at a fundamental, cellular level. They provide chemical energy—in the form of the
nucleoside triphosphate Nucleosides are glycosylamine 120px, Cyclic hemiaminal ether bond derived from an aldehyde Glycosylamines are a class of biochemical compounds consisting of a Glycosyl, glycosyl group attached to an amine, amino group, -NR2. They are also known ...
s,
adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properti ...

adenosine triphosphate
(ATP),
guanosine triphosphate Guanosine-5'-triphosphate (GTP) is a purine Purine is a heterocyclic 125px, Pyridine, a heterocyclic compound A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different chemical element, elemen ...
(GTP),
cytidine triphosphate Cytidine triphosphate is a pyrimidine Pyrimidine is an aromatic heterocyclic compound, heterocyclic organic compound similar to pyridine. One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has the ni ...
(CTP) and
uridine triphosphate Uridine-5′-triphosphate (UTP) is a pyrimidine nucleoside triphosphate, consisting of the organic base uracil linked to the 1′ carbon of the ribose Ribose is a simple sugar and carbohydrate with molecular formula C5H10O5 and the linear-form ...
(UTP)—throughout the cell for the many cellular functions that demand energy, including:
amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acid
,
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
and
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane A biological membrane, biomembrane or cell membrane is a selectively permeable membra ...

cell membrane
synthesis, moving the cell and cell parts (both internally and intercellularly), cell division, etc.Alberts B, Johnson A, Lewis J, Raff M, Roberts K & Walter P (2002). ''Molecular Biology of the Cell'' (4th ed.). Garland Science. . pp. 120–121. In addition, nucleotides participate in
cell signaling In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanisms ...
(
cyclic guanosine monophosphate Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases i ...
or cGMP and
cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate Adenosine is an organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds tha ...
or cAMP), and are incorporated into important cofactors of enzymatic reactions (e.g.
coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the Fatty acid metabolism#Synthesis, synthesis and Fatty acid metabolism#.CE.B2-Oxidation, oxidation of fatty acids, and the oxidation of pyruvic acid, pyruvate in the citric aci ...
,
FAD A fad is any form of collective behavior that develops within a culture, a generation or social group in which a group of people enthusiastically follow an impulse (psychology), impulse for a short period. Fads are objects or behaviors that ach ...

FAD
, ,
NAD #REDIRECT NAD NAD or Nad may refer to: Geography * Nad, County Cork, a village in Ireland * North American Datum The North American Datum (NAD) is the horizontal datum now used to define the geodetic network in North America. A datum is a fo ...
, and ). In experimental
biochemistry Biochemistry or biological chemistry, is the study of chemical process In a scientific Science () is a systematic enterprise that Scientific method, builds and organizes knowledge in the form of Testability, testable explanations and pr ...

biochemistry
, nucleotides can be radiolabeled using
radionuclide A radionuclide (radioactive nuclide, radioisotope or radioactive isotope) is a nuclide A nuclide (or nucleide, from atomic nucleus, nucleus, also known as nuclear species) is a class of atoms characterized by their number of protons, ''Z'', their ...
s to yield radionucleotides.


Structure

A nucleotide is composed of three distinctive chemical sub-units: a five-carbon sugar molecule, a
nucleobase 230px, Pyrimidine nucleobases are simple ring molecules. Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides Nucleosides are glycosylamines that can be ...
—the two of which together are called a —and one
phosphate group In chemistry Chemistry is the science, scientific study of the properties and behavior of matter. It is a natural science that covers the Chemical element, elements that make up matter to the chemical compound, compounds composed of atoms ...

phosphate group
. With all three joined, a nucleotide is also termed a "nucleoside ''mono''phosphate", "nucleoside ''di''phosphate" or "nucleoside ''tri''phosphate", depending on how many phosphates make up the phosphate group. In
nucleic acid Nucleic acids are biopolymer Biopolymers are natural polymer A polymer (; Greek ''wikt:poly-, poly-'', "many" + ''wikt:-mer, -mer'', "part") is a Chemical substance, substance or material consisting of very large molecules, or macromolecule ...

nucleic acid
s, nucleotides contain either a
purine Purine is a heterocyclic 125px, Pyridine, a heterocyclic compound A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different chemical element, elements as members of its ring(s). Heterocyclic chemi ...

purine
or a
pyrimidine Pyrimidine is an aromatic In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts ...

pyrimidine
base—i.e., the nucleobase molecule, also known as a nitrogenous base—and are termed ''ribo''nucleotides if the sugar is ribose, or ''deoxyribo''nucleotides if the sugar is deoxyribose. Individual phosphate molecules repetitively connect the molecules in two adjacent nucleotide monomers, thereby connecting the nucleotide monomers of a nucleic acid end-to-end into a long chain. These chain-joins of sugar and phosphate molecules create a 'backbone' strand for a single- or
double helix In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, molecular synthesis, modification, mech ...
. In any one strand, the chemical orientation ( directionality) of the chain-joins runs from the 5'-end to the 3'-end (''read'': 5 prime-end to 3 prime-end)—referring to the five carbon sites on sugar molecules in adjacent nucleotides. In a double helix, the two strands are oriented in opposite directions, which permits
base pairing A base pair (bp) is a fundamental unit of double-stranded nucleic acids Nucleic acids are biopolymer Biopolymers are natural polymers produced by the cells of Organism, living organisms. Biopolymers consist of monomeric units that are Covalent_ ...
and complementarity between the base-pairs, all which is essential for or transcribing the encoded information found in DNA. Nucleic acids then are
polymeric A polymer (; Greek '' poly-'', "many" + '' -mer'', "part") is a substance Substance may refer to: * Substance (Jainism), a term in Jain ontology to denote the base or owner of attributes * Chemical substance, a material with a definite chemical ...
macromolecule macromolecule A macromolecule is a very large molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically neu ...
s assembled from nucleotides, the . The purine bases
adenine Adenine (A, Ade) is a nucleobase 230px, Pyrimidine nucleobases are simple ring molecules. Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides Nucleos ...

adenine
and
guanine Guanine () (symbol A symbol is a mark, sign, or word In linguistics, a word of a spoken language can be defined as the smallest sequence of phonemes that can be uttered in isolation with semantic, objective or pragmatics, practical me ...

guanine
and pyrimidine base
cytosine Cytosine () (symbol A symbol is a mark, sign, or that indicates, signifies, or is understood as representing an , , or . Symbols allow people to go beyond what is n or seen by creating linkages between otherwise very different s and s. Al ...

cytosine
occur in both DNA and RNA, while the pyrimidine bases
thymine Thymine () (symbol A symbol is a mark, sign, or word In linguistics, a word of a spoken language can be defined as the smallest sequence of phonemes that can be uttered in isolation with semantic, objective or pragmatics, practical m ...

thymine
(in DNA) and
uracil Uracil () ( U or Ura) is one of the four s in the that are represented by the letters A, G, C and U. The others are (A), (C), and (G). In RNA, uracil binds to via two . In , the uracil nucleobase is replaced by . Uracil is a form of . Ura ...

uracil
(in RNA) occur in just one. Adenine forms a
base pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids Nucleic acids are biopolymer Biopolymers are natural polymers produced by the cells of Organism, living organisms. Biopolymers consist of monomeric units that are Covalent_ ...
with thymine with two hydrogen bonds, while guanine pairs with cytosine with three hydrogen bonds. In addition to being building blocks for the construction of nucleic acid polymers, singular nucleotides play roles in cellular energy storage and provision, cellular signaling, as a source of phosphate groups used to modulate the activity of proteins and other signaling molecules, and as enzymatic cofactors, often carrying out
redox Redox (reduction–oxidation, pronunciation: or ) is a type of chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substance A chemical substance is a form of matter ...

redox
reactions. Signaling cyclic nucleotides are formed by binding the phosphate group twice to the same sugar
molecule A molecule is an electrically Electricity is the set of physical phenomena associated with the presence and motion Image:Leaving Yongsan Station.jpg, 300px, Motion involves a change in position In physics, motion is the phenomenon ...
, bridging the 5'- and 3'-
hydroxyl group A hydroxy or hydroxyl group is a functional group with the chemical formula -OH and composed of one oxygen Oxygen is the chemical element Image:Simple Periodic Table Chart-blocks.svg, 400px, Periodic table, The periodic table of the ...

hydroxyl group
s of the sugar. Some signaling nucleotides differ from the standard single-phosphate group configuration, in having multiple phosphate groups attached to different positions on the sugar. Nucleotide cofactors include a wider range of chemical groups attached to the sugar via the
glycosidic bond A glycosidic bond or glycosidic linkage is a type of covalent bond that joins a carbohydrate (sugar) molecule to another group, which may or may not be another carbohydrate. A glycosidic bond is formed between the hemiacetal or hemiketal group ...
, including
nicotinamide Niacinamide or Nicotinamide (NAM) is a form of vitamin B3, vitamin B3 found in food and used as a dietary supplement and medication. As a supplement, it is used by mouth to prevent and treat pellagra (niacin deficiency). While nicotinic acid (nia ...

nicotinamide
and , and in the latter case, the ribose sugar is linear rather than forming the ring seen in other nucleotides.


Synthesis

Nucleotides can be
synthesized Synthesis or synthesize may also refer to: Science Chemistry and biochemistry *Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors **Organic synthesis, the chemical synthesis of or ...
by a variety of means both
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies Study or studies may refer to: General * Education **Higher education * Clinical trial * Experiment * Observational study * Research * Study skills, abilities and approaches applie ...

in vitro
and
in vivo Studies Study or studies may refer to: General * Education **Higher education * Clinical trial * Experiment * Observational study * Research * Study skills, abilities and approaches applied to learning Other * Study (art), a drawing or series ...
. In vitro,
protecting group A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep synthesis, multistep organic ...
s may be used during laboratory production of nucleotides. A purified
nucleoside Nucleosides are s that can be thought of as s without a . A nucleoside consists simply of a (also termed a nitrogenous base) and a five-carbon sugar ( or 2'-deoxyribose) whereas a nucleotide is composed of a nucleobase, a five-carbon sugar, and ...

nucleoside
is protected to create a
phosphoramidite A phosphoramidite (RO)2PNR2 is a monoamide of a phosphite diester. The key feature of phosphoramidites is their markedly high reactivity towards nucleophile In chemistry, a nucleophile is a chemical species that forms bonds with Electrophile, electr ...

phosphoramidite
, which can then be used to obtain analogues not found in nature and/or to synthesize an oligonucleotide. In vivo, nucleotides can be synthesized
de novo In general usage, ''de novo'' (literally 'of new') is Latin expression used in English to mean 'from the beginning', 'anew'. De novo may also refer to: Biology * ''De novo'', mutation, an alteration in a gene that is present for the first time in ...
or recycled through salvage pathways. The components used in de novo nucleotide synthesis are derived from biosynthetic precursors of carbohydrate and
amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acid
metabolism, and from ammonia and carbon dioxide. The liver is the major organ of de novo synthesis of all four nucleotides. De novo synthesis of pyrimidines and purines follows two different pathways. Pyrimidines are synthesized first from aspartate and carbamoyl-phosphate in the cytoplasm to the common precursor ring structure orotic acid, onto which a phosphorylated ribosyl unit is covalently linked. Purines, however, are first synthesized from the sugar template onto which the ring synthesis occurs. For reference, the syntheses of the
purine Purine is a heterocyclic 125px, Pyridine, a heterocyclic compound A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different chemical element, elements as members of its ring(s). Heterocyclic chemi ...

purine
and
pyrimidine Pyrimidine is an aromatic In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts ...

pyrimidine
nucleotides are carried out by several enzymes in the
cytoplasm In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes ...
of the cell, not within a specific
organelle In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, ...
. Nucleotides undergo breakdown such that useful parts can be reused in synthesis reactions to create new nucleotides.


Pyrimidine ribonucleotide synthesis

The synthesis of the pyrimidines CTP and UTP occurs in the cytoplasm and starts with the formation of carbamoyl phosphate from
glutamine Glutamine (symbol Gln or Q) is an α-amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bo ...

glutamine
and CO2. Next,
aspartate carbamoyltransferase Aspartate carbamoyltransferase (also known as aspartate transcarbamoylase or ATCase) catalyzes the first step in the pyrimidine biosynthetic pathway (). In '' E. coli'', the enzyme is a multi- subunit protein Proteins are large biomolecules ...
catalyzes a condensation reaction between aspartate and
carbamoyl phosphate Carbamoyl phosphate is an anion An ion () is a particle, atom or molecule with a net electric charge, electrical charge. The charge of the electron is considered negative by convention. The negative charge of an ion is equal and opposite to ...
to form
carbamoyl aspartic acid Carbamoyl aspartic acid (or ureidosuccinic acid) is a carbamate derivative, serving as an intermediate in pyrimidine biosynthesis. References

Ureas Dicarboxylic acids {{organic-compound-stub ...
, which is cyclized into 4,5-dihydroorotic acid by
dihydroorotase Dihydroorotase (, ''carbamoylaspartic dehydrase'', ''dihydroorotate hydrolase'') is an enzyme which converts carbamoyl aspartic acid into 4,5-dihydroorotic acid in the biosynthesis of pyrimidines. It forms a multifunctional enzyme with carbamoyl p ...
. The latter is converted to
orotate Orotic acid is a pyrimidinedione and a carboxylic acid A carboxylic acid is an organic acid that contains a carboxyl group (C(=O)OH) attached to an R-group. The general formula of a carboxylic acid is R−COOH or R−CO2H, with R referring ...
by dihydroorotate oxidase. The net reaction is: :(''S'')-Dihydroorotate + O2 → Orotate + H2O2 Orotate is covalently linked with a phosphorylated ribosyl unit. The covalent linkage between the ribose and pyrimidine occurs at position C1 of the
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 compoun ...

ribose
unit, which contains a
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 others ...
, and N1 of the pyrimidine ring.
Orotate phosphoribosyltransferase Orotate phosphoribosyltransferase (OPRTase) or orotic acid phosphoribosyltransferase is an enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzyme ...
(PRPP transferase) catalyzes the net reaction yielding orotidine monophosphate (OMP): :Orotate + → Orotidine 5'-phosphate + Pyrophosphate Orotidine 5'-monophosphate is decarboxylated by orotidine-5'-phosphate decarboxylase to form uridine monophosphate (UMP). PRPP transferase catalyzes both the ribosylation and decarboxylation reactions, forming UMP from orotic acid in the presence of PRPP. It is from UMP that other pyrimidine nucleotides are derived. UMP is phosphorylated by two kinases to uridine triphosphate (UTP) via two sequential reactions with ATP. First, the diphosphate from UDP is produced, which in turn is phosphorylated to UTP. Both steps are fueled by ATP hydrolysis: :ATP + UMP → ADP + UDP :UDP + ATP → UTP + ADP CTP is subsequently formed by the amination of UTP by the catalytic activity of CTP synthetase. Glutamine is the NH3 donor and the reaction is fueled by ATP hydrolysis, too: :UTP + Glutamine + ATP + H2O → CTP + ADP + Pi Cytidine monophosphate (CMP) is derived from cytidine triphosphate (CTP) with subsequent loss of two phosphates.


Purine ribonucleotide synthesis

The atoms that are used to build the purine nucleotides come from a variety of sources: The
de novo synthesis ''De novo'' synthesis refers to the synthesis of complex molecules from simple molecules such as sugar Sugar is the generic name for Sweetness, sweet-tasting, soluble carbohydrates, many of which are used in food. Table sugar, granulated sugar, ...
of purine nucleotides by which these precursors are incorporated into the purine ring proceeds by a 10-step pathway to the branch-point intermediate
IMP An imp is a European European, or Europeans, may refer to: In general * ''European'', an adjective referring to something of, from, or related to Europe ** Ethnic groups in Europe ** Demographics of Europe ** European cuisine, the cuisines of E ...

IMP
, the nucleotide of the base
hypoxanthine Hypoxanthine is a naturally occurring purine Purine is a heterocyclic compound, heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole). It is water-soluble. Purine also gives its name to the wider class of mo ...

hypoxanthine
. AMP and GMP are subsequently synthesized from this intermediate via separate, two-step pathways. Thus, purine moieties are initially formed as part of the
ribonucleotides In biochemistry, a ribonucleotide is a nucleotide Nucleotides are organic molecules , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bon ...
rather than as free bases. Six enzymes take part in IMP synthesis. Three of them are multifunctional: * GART (reactions 2, 3, and 5) * PAICS (reactions 6, and 7) * ATIC (reactions 9, and 10) The pathway starts with the formation of PRPP. PRPS1 is the
enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates in ...

enzyme
that activates
R5P Ribose 5-phosphate (R5P) is both a product and an intermediate of the pentose phosphate pathway The pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt) is a metabolic pathway In biochemistry ...
, which is formed primarily by the
pentose phosphate pathway In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts A fact is an occurrence in the ...

pentose phosphate pathway
, to PRPP by reacting it with
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals * American Technical Publishers * ', a Danish pension * Armenia Tree Project * Association for Transpersonal Psychology * ATP architects engineers office * ATP ...

ATP
. The reaction is unusual in that a pyrophosphoryl group is directly transferred from ATP to C1 of R5P and that the product has the α configuration about C1. This reaction is also shared with the pathways for the synthesis of , , and the pyrimidine nucleotides. Being on a major metabolic crossroad and requiring much energy, this reaction is highly regulated. In the first reaction unique to purine nucleotide biosynthesis, PPAT catalyzes the displacement of PRPP's
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 others ...
group (PPi) by an amide nitrogen donated from either
glutamine Glutamine (symbol Gln or Q) is an α-amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bo ...

glutamine
(N),
glycine Glycine (symbol Gly or G; ) is an amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond ...

glycine
(N&C), aspartate (N),
folic acid Folate, also known as vitamin B9 and folacin, is one of the B vitamins B vitamins are a class of water-soluble vitamin A vitamin is an organic molecule , CH4; is among the simplest organic compounds. In chemistry, organic compounds ar ...

folic acid
(C1), or CO2. This is the committed step in purine synthesis. The reaction occurs with the inversion of configuration about ribose C1, thereby forming β- 5-phosphorybosylamine (5-PRA) and establishing the anomeric form of the future nucleotide. Next, a glycine is incorporated fueled by ATP hydrolysis, and the carboxyl group forms an amine bond to the NH2 previously introduced. A one-carbon unit from folic acid coenzyme N10-formyl-THF is then added to the amino group of the substituted glycine followed by the closure of the imidazole ring. Next, a second NH2 group is transferred from glutamine to the first carbon of the glycine unit. A carboxylation of the second carbon of the glycin unit is concomitantly added. This new carbon is modified by the addition of a third NH2 unit, this time transferred from an aspartate residue. Finally, a second one-carbon unit from formyl-THF is added to the nitrogen group and the ring is covalently closed to form the common purine precursor inosine monophosphate (IMP). Inosine monophosphate is converted to adenosine monophosphate in two steps. First, GTP hydrolysis fuels the addition of aspartate to IMP by adenylosuccinate synthase, substituting the carbonyl oxygen for a nitrogen and forming the intermediate adenylosuccinate. Fumarate is then cleaved off forming adenosine monophosphate. This step is catalyzed by adenylosuccinate lyase. Inosine monophosphate is converted to guanosine monophosphate by the oxidation of IMP forming xanthylate, followed by the insertion of an amino group at C2. NAD+ is the electron acceptor in the oxidation reaction. The amide group transfer from glutamine is fueled by ATP hydrolysis.


Pyrimidine and purine degradation

In humans, pyrimidine rings (C, T, U) can be degraded completely to CO2 and NH3 (urea excretion). That having been said, purine rings (G, A) cannot. Instead, they are degraded to the metabolically inert
uric acid Uric acid is a heterocyclic compound A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different chemical element, elements as members of its ring(s). Heterocyclic chemistry is the branch of orga ...

uric acid
which is then excreted from the body. Uric acid is formed when GMP is split into the base guanine and ribose. Guanine is deaminated to xanthine which in turn is oxidized to uric acid. This last reaction is irreversible. Similarly, uric acid can be formed when AMP is deaminated to IMP from which the ribose unit is removed to form hypoxanthine. Hypoxanthine is oxidized to xanthine and finally to uric acid. Instead of uric acid secretion, guanine and IMP can be used for recycling purposes and nucleic acid synthesis in the presence of PRPP and aspartate (NH3 donor).


Prebiotic synthesis of nucleotides

Theories about how
life Life is a characteristic that distinguishes physical entities A bubble of exhaled gas in water In common usage and classical mechanics, a physical object or physical body (or simply an object or body) is a collection of matter within a ...

life
arose require knowledge of chemical pathways that permit formation of life’s key building blocks under plausible prebiotic conditions. The
RNA world The RNA world is a hypothetical stage in the evolutionary history of life The history of life on Earth Earth is the third planet from the Sun and the only astronomical object known to harbour and support life. 29.2% of Earth's surfa ...
hypothesis holds that in the
primordial soupPrimordial soup, or prebiotic soup (also sometimes referred as prebiotic broth), is the hypothetical set of conditions present on the Earth around 4.0 to 3.7 billion years ago. It is a fundamental aspect to the heterotrophic theory of the origin of ...
there existed free-floating
ribonucleotide In biochemistry, a ribonucleotide is a nucleotide containing ribose as its pentose component. It is considered a molecular precursor of nucleic acids. Nucleotides are the basic building blocks of DNA and RNA. Ribonucleotides themselves are basic mon ...
s, the fundamental molecules that combine in series to form
RNA Ribonucleic acid (RNA) is a polymer A polymer (; Greek ''wikt:poly-, poly-'', "many" + ''wikt:-mer, -mer'', "part") is a Chemical substance, substance or material consisting of very large molecules, or macromolecules, composed of many Re ...

RNA
. Complex molecules like RNA must have arisen form small molecules whose reactivity was governed by physico-chemical processes. RNA is composed of
purine Purine is a heterocyclic 125px, Pyridine, a heterocyclic compound A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different chemical element, elements as members of its ring(s). Heterocyclic chemi ...

purine
and
pyrimidine Pyrimidine is an aromatic In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts ...

pyrimidine
nucleotides, both of which are necessary for reliable information transfer, and thus Darwinian
evolution Evolution is change in the heritable Heredity, also called inheritance or biological inheritance, is the passing on of Phenotypic trait, traits from parents to their offspring; either through asexual reproduction or sexual reproduction, ...

evolution
. Becker et al. showed how pyrimidine
nucleoside Nucleosides are s that can be thought of as s without a . A nucleoside consists simply of a (also termed a nitrogenous base) and a five-carbon sugar ( or 2'-deoxyribose) whereas a nucleotide is composed of a nucleobase, a five-carbon sugar, and ...

nucleoside
s can be synthesized from small molecules and
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 compoun ...

ribose
, driven solely by wet-dry cycles.Becker S, Feldmann J, Wiedemann S, Okamura H, Schneider C, Iwan K, Crisp A, Rossa M, Amatov T, Carell T. Unified prebiotically plausible synthesis of pyrimidine and purine RNA ribonucleotides. Science. 2019 Oct 4;366(6461):76-82. doi: 10.1126/science.aax2747. PMID: 31604305 Purine nucleosides can be synthesized by a similar pathway. 5’-mono- and di-phosphates also form selectively from phosphate-containing minerals, allowing concurrent formation of polyribonucleotides with both the purine and pyrimidine bases. Thus a reaction network towards the purine and pyrimidine RNA building blocks can be established starting from simple atmospheric or volcanic molecules.


Unnatural base pair (UBP)

An unnatural base pair (UBP) is a designed subunit (or
nucleobase 230px, Pyrimidine nucleobases are simple ring molecules. Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides Nucleosides are glycosylamines that can be ...
) of
DNA Deoxyribonucleic acid (; DNA) is a molecule A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically Electricity is the set of physical ...

DNA
which is created in a laboratory and does not occur in nature. Examples include
d5SICS d5SICS is an artificial nucleoside containing 6-methylisoquinoline-1-thione-2-yl group instead of a base. It Base pair#Unnatural base pair (UBP), pairs up with dNaM in a hydrophobic interaction. It was not able to be removed by the error-correctin ...

d5SICS
and
dNaM dNaM is an artificial nucleobase Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides Nucleosides are glycosylamines that can be thought of as nucleo ...

dNaM
. These artificial nucleotides bearing hydrophobic
nucleobase 230px, Pyrimidine nucleobases are simple ring molecules. Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides Nucleosides are glycosylamines that can be ...
s, feature two fused
aromatic rings forms of benzene (top) combine to produce an average structure (bottom) In chemistry, aromaticity is a property of cyclic compound, cyclic (ring (chemistry), ring-shaped), plane (geometry), planar (flat) structures with pi bonds in Resonance (che ...
that form a (d5SICS–dNaM) complex or base pair in DNA. ''E. coli'' have been induced to replicate a plasmid containing UBPs through multiple generations. This is the first known example of a living organism passing along an expanded genetic code to subsequent generations.


Medical applications of synthetic nucleotides

Several nucleotide derivatives have been used as antivirals against
hepatitis Hepatitis is inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogen In biology Biology is the natural science that studies life and living or ...

hepatitis
and
HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus ''Lentivirus'' is a genus Genus (plural genera) is a taxonomic rank Taxonomy (general) is the practice and science of classification of things or concepts, inc ...

HIV
.
Tenofovir disoproxil Tenofovir disoproxil, sold under the trade name Viread among others, is a medication used to treat chronic hepatitis B Hepatitis B is an infectious disease caused by the hepatitis B virus (HBV) that affects the liver; it is a type of viral h ...
,
Tenofovir alafenamide Tenofovir alafenamide, sold under the brand name Vemlidy, is a hepatitis B virus (HBV) nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers deoxyr ...

Tenofovir alafenamide
and
Sofosbuvir Sofosbuvir, sold under the brand name Sovaldi among others, is a medication used to treat hepatitis C Hepatitis C is an infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-ca ...

Sofosbuvir
are examples of NRTI used against hepatitis. Whereas certain drugs like ,
Lamivudine Lamivudine, commonly called 3TC, is an antiretroviral medication used to prevent and treat HIV/AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection ...

Lamivudine
,
Entecavir Entecavir (ETV), sold under the brand name Baraclude, is an antiviral medication used in the treatment of hepatitis B virus (HBV) infection. In those with both HIV/AIDS and HBV antiretroviral medication should also be used. Entecavir is taken by m ...

Entecavir
and for example are nucleosides, but they are metabolized into their bioactive nucleotide forms through phosphorylation.


Length unit

Nucleotide (abbreviated "nt") is a common unit of length for single-stranded nucleic acids, similar to how
base pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids Nucleic acids are biopolymer Biopolymers are natural polymers produced by the cells of Organism, living organisms. Biopolymers consist of monomeric units that are Covalent_ ...
is a unit of length for double-stranded nucleic acids.


Abbreviation codes for degenerate bases

The
IUPAC The International Union of Pure and Applied Chemistry (IUPAC ) is an international federation of National Adhering OrganizationsNational Adhering Organizations in chemistry are the organizations that work as the authoritative power over chemist ...
has designated the symbols for nucleotides. Apart from the five (A, G, C, T/U) bases, often degenerate bases are used especially for designing PCR primers. These nucleotide codes are listed here. Some primer sequences may also include the character "I", which codes for the non-standard nucleotide
inosine Inosine is a nucleoside Nucleosides are s that can be thought of as s without a . A nucleoside consists simply of a (also termed a nitrogenous base) and a five-carbon sugar ( or 2'-deoxyribose) whereas a nucleotide is composed of a nucleobase, ...

inosine
. Inosine occurs in tRNAs and will pair with adenine, cytosine, or thymine. This character does not appear in the following table, however, because it does not represent a degeneracy. While inosine can serve a similar function as the degeneracy "D", it is an actual nucleotide, rather than a representation of a mix of nucleotides that covers each possible pairing needed.


See also

*
Biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanisms, Development ...

Biology
*
Chromosome A chromosome is a long DNA molecule with part or all of the genome, genetic material of an organism. Most eukaryotic chromosomes include packaging proteins called histones which, aided by Chaperone (protein), chaperone proteins, bind to and ...

Chromosome
* Gene * Genetics * * *


References


Further reading

* *Freisinger, E., & Sigel, R. K. (2007)
From nucleotides to ribozymes—a comparison of their metal ion binding properties
''Coordination Chemistry Reviews'', ''251''(13-14), 1834-1851.


External links


Abbreviations and Symbols for Nucleic Acids, Polynucleotides and their Constituents
(
IUPAC The International Union of Pure and Applied Chemistry (IUPAC ) is an international federation of National Adhering OrganizationsNational Adhering Organizations in chemistry are the organizations that work as the authoritative power over chemist ...
)
Provisional Recommendations 2004
(IUPAC)

{{Authority control Nucleotides, * DNA Molecular biology