nucleotide

(nū'klē-ə-tīd', nyū'-)

[Alteration of NUCLEOSIDE.]

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A cellular constituent that is one of the building blocks of ribonucleic acids (RNA) and deoxyribonucleic acid (DNA). In biological systems, nucleotides are linked by enzymes in order to make long, chainlike polynucleotides of defined sequence. The order or sequence of the nucleotide units along a polynucleotide chain plays an important role in the storage and transfer of genetic information. Many nucleotides also perform other important functions in biological systems. See also Coenzyme; Cyclic nucleotides; Nucleic acid.

Nucleotides are generally classified as either ribonucleotides or deoxyribonucleotides. Both classes consist of a phosphorylated pentose sugar that is linked via an N-glycosidic bond to a purine or pyrimidine base. The combination of the pentose sugar and the purine or pyrimidine base without the phosphate moiety is called a nucleoside. See also Purine; Pyrimidine.

Compounds of purine or pyrimidine base with a sugar phosphate. Natural constituents of human milk, often used to supplement infant formulae.

Nucleotides are the building blocks of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Individual nucleotide monomers (single units) are linked together to form polymers, or long chains. DNA chains store genetic information, while RNA chains perform a variety of roles integral to protein synthesis. Individual nucleotides also play important roles in cell metabolism.

Structure

The nucleotide molecule contains three functional groups: a base, a sugar, and a phosphate (see diagram). It may seem puzzling that a nucleic acid should contain a base. While the base portion does have weakly basic properties, the nucleotide as a whole acts as an acid, due to the phosphate group.

The names DNA and RNA are generated from the deoxyribose and ribose sugars found in these two polymers. Both are five-carbon sugars, whose carbons are numbered around the ring from 1′ to 5′ ("one prime" to "five prime"). The prime distinguishes the carbons on the sugar from the carbons on the base. The sugar in RNA nucleotides is ribose. The sugar in DNA is 2′-deoxyribose, which lacks an-OH group at the 2′ position. This small difference has some important consequences: The extra oxygen in RNA interferes with double helix formation between RNA chains (though it does not completely prevent it), and makes RNA more susceptible than DNA to base-catalyzed cleavage (breakdown into individual monomers).

A base attaches to the sugar at the sugar's 1′ position. Because of their nitrogen content, the bases are called nitrogenous bases, and are further classified as either purines or pyrimidines. Purine structures have two rings, while pyrimidines have one. The two purine bases found in both DNA and in RNA are guanine (G) and adenine (A). The two pyrimidine bases found in DNA are cytosine (C) and thymine (T), and the two pyrimidine bases found in RNA are cytosine and uracil (U). The only difference between thymine and uracil is the presence of a methyl group in thymine that is lacking in uracil. A base plus a sugar is called a nucleoside.

The phosphate groups are linked to the sugars at the 5′ position. The addition of one to three phosphate groups generates a nucleotide, also known as a nucleoside monophosphate, nucleoside diphosphate, or nucleoside triphosphate. For instance, guanosine triphosphate (GTP) is an RNA nucleotide with three phosphates attached. Deoxycytosine monophosphate (dCMP) is a DNA nucleotide with one phosphate attached.

Adenosine triphosphate, ATP, is the universal energy currency of cells. The breakdown of energy-rich nutrients is coupled to ATP synthesis, allowing temporary energy storage and transfer. When the ATP is later broken back down to ADP or AMP (adenosine diphosphate or monophosphate), it provides energy to power cell reactions such as protein synthesis or cell movement.

Polymer Formation

DNA and RNA polymers are constructed by forming phosphodiester bonds between nucleotides. In this arrangement, a phosphate group acts as a bridge between the 5′ position of one sugar and the 3′ position of the next. This arrangement is called the "sugar-phosphate backbone" of DNA or RNA; the bases hang off to the side.

In the cell, DNA or RNA polymers are synthesized using nucleoside triphosphate monomers as precursors. During polymer synthesis, two of the phosphate groups of the incoming nucleoside triphosphate are cleaved off, and this provides the energy needed to power the reaction. The remaining phosphate takes its place in the sugar-phosphate backbone of the growing nucleic acid chain. A pyrophosphate molecule (two linked phosphates) is released.

Just as an arrow has a tip and a tail, DNA or RNA chains have directionality, due to the structure of the sugar. At one end of a chain, a 5′ carbon will be left free. This is known as the 5′ end of the chain. At the other end, the 3′ carbon will be free; this is the 3′ end of the chain. Segments of DNA that are not free at their ends can also be discussed in terms of their 5′ and 3′ ends. This directionality has important consequences. When DNA replication occurs, it always moves from the 5′ end to the 3′ end, and the incoming triphosphate joins the 3′ end of the chain. Transcription (RNA synthesis from a DNA gene) also moves in this 5′-to-3′ direction. The 5′ end is considered the "upstream" end of the gene, and is the end on which the gene promoter (the transcription initiator) is located.

The Double Helix of Dna

In the double helix of DNA, guanine nucleotides are base-paired opposite cytosine nucleotides. Adenine nucleotides are base-paired opposite thymine nucleotides. This pairing is due to the complementary natures of the structures involved. Note that G is a two-ringed purine, while its partner C is a one-ringed pyrimidine. Similarly, A is a purine and T is a pyrimidine. These pairings give the interior of the helix a fixed diameter, without bulges or gaps. Just as importantly, the arrangement of atoms in the rings allows the partners to form sets of weak attractions, called hydrogen bonds, across the interior of the helix. The hydrogen bonds contribute greatly to the stability of the double helix, and the specificity of the G-C, A-T pairing is the structural basis of faithful replication of DNA.

Bibliography

Watson, James. The Double Helix: A Personal Account of the Discovery of the Structure of DNA. New York: Atheneum, 1968.

Stryer, Lubert. Biochemistry, 4th ed. New York: W. H. Freeman, 1995.

—Fred Perrino

The molecules that form the basic modular structure of the double helix of the DNA molecule. A nucleotide consists of three molecules — a sugar, a phosphate group, and a molecule called a base. If the double helix is a twisted ladder, the sugar and phosphates form the sides of the ladder and pairs of bases form the rungs. There are four different bases, usually abbreviated A, C, G, and T for adenine, cytosine, guanine, and thymine). The order of bases in DNA determines the genetic code.

1. The 'brain' of the cell. Where the genetic code of the cell resides. This genetic code lies in the configuration of the DNA molecule that further makes up the chromosomal structure of the genes. A specific gene structure or piece, which carries the code for a function structure or trait, is called a genome.
   
2. The center of an atom containing protons, neutrons, and many subatomic particles.
   

1. or mononucleotide or nucleoside [mono]phosphate any compound that consists of a nucleoside (def. 1) esterified with [ortho]phosphate at either the 3′- or the 5′-hydroxyl group of its glycose moiety (ribonucleosides giving ribonucleotides, and deoxyribonucleosides giving deoxyribonucleotides). Nucleotides are the constitutional units into which nucleic acids are broken down by partial hydrolysis and from which they are considered to be built up.
2. any compound consisting of a nucleoside (def. 2) that is esterified with [ortho]phosphate or an oligophosphate at any hydroxyl group on its glycose moiety. In this sense the term includes nucleoside cyclic phosphate, nucleoside diphosphate, nucleoside diphosphosugar, nucleoside triphosphate, and pyridine nucleotide.
3. any compound containing a moiety of a nucleotide (def. 1, 2). Included are: any carrying an additional phosphoric group at another position on the glycose moiety; any formed (actually or conceptually) from two or more such nucleotides, whether the same or not, joined together in phosphoric-ester linkage (to form an oligonucleotide or a polynucleotide); and, in certain instances, any formed from such a nucleotide joined through a phosphoric anhydride link either to a second nucleotide or to some other phosphate ester. Exceptionally, the term includes also certain analogous compounds (especially flavin mononucleotide, and hence also flavin-adenine dinucleotide) that, being derivatives of ribitol, are not true nucleoside phosphates or else are not formed exclusively from them.

Any of a group of compounds obtained by hydrolysis of nucleic acids, consisting of a purine or pyrimidine base linked to a sugar (ribose or deoxyribose), which in turn is esterified with phosphoric acid. See also nucleoside, deoxyribonucleic acid.

• cyclic n's — those in which the phosphate group bonds to two atoms of the sugar forming a ring, as in cyclic AMP and cyclic GMP, which act as intracellular second messengers.
• n. sequences — see dna sequencing.
• single n. polymorphisms (SNPs) — single base pair changes that distinguish one individual from another of the same species.

• Genetics, Heredity, and Evolution - nucleotide: structural segment of nucleic acid chain, composed of phosphate group, five-carbon sugar, and purine or pyrimidine base

Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling (cGMP and cAMP), and are incorporated into important cofactors of enzymatic reactions (coenzyme A, FAD, FMN, and NADP⁺).

Nucleotide derivatives such as the nucleoside triphosphates play central roles in metabolism, in which capacity they serve as sources of chemical energy (ATP and GTP).^[1]

Structural elements of the most common nucleotides

Contents 1 Nucleotide structure 2 Synthesis 2.1 Pyrimidine ribonucleotide synthesis 2.2 Purine ribonucleotide synthesis 2.3 Pyrimidine and purine degradation 3 Length unit 4 Abbreviation codes for degenerate bases 5 See also 6 References 7 External links

Nucleotide structure

Ribose structure indicating numbering of carbon atoms

A nucleotide is composed of a nucleobase (nitrogenous base), a five-carbon sugar (either ribose or 2'-deoxyribose), and one phosphate group.^[2] Together, the nucleobase and sugar compose a nucleoside. The phosphate groups form bonds with either the 2, 3, or 5-carbon of the sugar, with the 5-carbon site most common. Cyclic nucleotides form when the phosphate group is bound to two of the sugar's hydroxyl groups.^[1] Ribonucleotides are nucleotides where the sugar is ribose, and deoxyribonucleotides contain the sugar deoxyribose. Nucleotides can contain either a purine or a pyrimidine base.

Nucleic acids are polymeric macromolecules made from nucleotide monomers. In DNA, the purine bases are adenine and guanine, while the pyrimidines are thymine and cytosine. RNA uses uracil in place of thymine. Adenine always pairs with thymine by 2 hydrogen bonds, while guanine pairs with cytosine through 3 hydrogen bonds, each due to their unique structures.

Synthesis

Nucleotides can be synthesized by a variety of means both in vitro and in vivo.

In vivo, nucleotides can be synthesized de novo or recycled through salvage pathways.^[3] The components used in de novo nucleotide synthesis are derived from biosynthetic precursors of carbohydrate and 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 and pyrimidine nucleotides are carried out by several enzymes in the cytoplasm of the cell, not within a specific organelle. Nucleotides undergo breakdown such that useful parts can be reused in synthesis reactions to create new nucleotides.

In vitro, protecting groups may be used during laboratory production of nucleotides. A purified nucleoside is protected to create a phosphoramidite, which can then be used to obtain analogues not found in nature and/or to synthesize an oligonucleotide.

Pyrimidine ribonucleotide synthesis

The synthesis of UMP.

The color scheme is as follows: enzymes, coenzymes, substrate names, inorganic molecules

Main article: Pyrimidine metabolism

The synthesis of the pyrimidines CTP and UTP occurs in the cytoplasm and starts with the formation of carbamoyl phosphate from glutamine and CO₂. Next, aspartate undergoes a condensation reaction with carbamoyl-phosphate to form orotic acid. In a subsequent cyclization reaction, the enzyme Aspartate carbamoyltransferase forms N-carbamoyl-aspartate which is converted into dihydroorotic acid by Dihydroorotase. The latter is converted to orotate 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 unit, which contains a pyrophosphate, and N₁ of the pyrimidine ring. Orotate phosphoribosyltransferase (aka "PRPP transferase") catalyzes the net reaction yielding orotidine monophosphate (OMP):

Orotate + 5-Phospho-α-D-ribose 1-diphosphate (aka. "PRPP") = Orotidine 5'-phosphate + Pyrophosphate

Orotidine-5-phosphate 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 form 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 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 + P_i

Cytidine monophosphate (CMP) is derived from cytidine triphosphate (CTP) with subsequent loss of two phosphates.^{[4] [5]}

Purine ribonucleotide synthesis

Main article: Purine metabolism

The atoms which are used to build the purine nucleotides come from a variety of sources:

The synthesis of IMP. The color scheme is as follows: enzymes, coenzymes, substrate names, metal ions, inorganic molecules

The biosynthetic origins of purine ring atoms N1 arises from the amine group of Asp C2 and C8 originate from formate N3 and N9 are contributed by the amide group of Gln C4, C5 and N7 are derived from Gly C6 comes from HCO3- (CO2)

The de novo synthesis 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, the nucleotide of the base 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 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 that activates R5P, which is formed primarily by the pentose phosphate pathway, to PRPP by reacting it with 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 Trp, His, 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 group (PP_i) by an amide nitrogen donated from either glutamine (N), glycine (N&C), aspartate (N), 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 a glutamine to the first carbon of the glycine unit. A carboxylation of the second carbon of the glycin unit is concomittantly added. This new carbon is modified by the additional 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 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 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).

Length unit

Nucleotide (abbreviated nt) is a common length unit for single-stranded RNA, similar to how base pair is a length unit for double-stranded DNA.

Abbreviation codes for degenerate bases

Main article: Nucleic acid notation

The IUPAC has designated the symbols for nucleotides.^[6] 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.

IUPAC nucleotide code	Base
A	Adenine
C	Cytosine
G	Guanine
T (or U)	Thymine (or Uracil)
R	A or G [puRine]
Y	C or T (U) [pYrimidine]
S	G or C
W	A or T (U)
K	G or T (U)
M	A or C
B	C or G or T (U)
D	A or G or T (U)
H	A or C or T (U)
V	A or C or G
N	any base
. or -	gap

See also

• Nucleoside
• Nucleobase
• Chromosome
• Gene
• Genetics
• Biology
• Nucleic acid analogues

References

1. ^ ^{a b} Alberts B, Johnson A, Lewis J, Raff M, Roberts K & Wlater P (2002). Molecular Biology of the Cell (4th ed.). Garland Science. ISBN 0-8153-3218-1. pp. 120-121.
2. ^ Coghill, Anne M.; Garson, Lorrin R., ed. (2006). The ACS style guide: effective communication of scientific information (3rd ed.). Washington, D.C.: American Chemical Society. p. 244. ISBN 9780841239999. 
3. ^ Zaharevitz, DW; Anerson, LW; Manlinowski, NM; Hyman, R; Strong, JM; Cysyk, RL.. Contribution of de-novo and salvage synthesis to the uracil nucleotide pool in mouse tissues and tumors in vivo. 
4. ^ Jones, ME (1980). "Pyrimidine nucleotide biosynthesis in animals: Genes, enzymes, and regulation of UMP biosynthesis". Ann. Rev. Biochem 49 (1): 253–79. doi:10.1146/annurev.bi.49.070180.001345. PMID 6105839. 
5. ^ McMurry, JE; Begley, TP (2005). The organic chemistry of biological pathways. Roberts & Company. ISBN 9780974707716. 
6. ^ IUPAC nucleotide code

External links

• Abbreviations and Symbols for Nucleic Acids, Polynucleotides and their Constituents (IUPAC)
• Provisional Recommendations 2004 (IUPAC)
• Chemistry explanation of nucleotide structure

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v d e Nucleic acid constituents Nucleobase Purine (Adenine, Guanine, Purine analogue) · Pyrimidine (Uracil, Thymine, Cytosine, Pyrimidine analogue) Nucleoside Ribonucleoside Adenosine · Guanosine · 5-Methyluridine · Uridine · Cytidine Deoxyribonucleoside Deoxyadenosine · Deoxyguanosine · Thymidine · Deoxyuridine · Deoxycytidine Nucleotide (Nucleoside monophosphate) Ribonucleotide AMP, GMP, m5UMP, UMP, CMP Deoxyribonucleotide dAMP, dGMP, dTMP, dUMP, dCMP Cyclic nucleotide cAMP, cGMP, c-di-GMP, cADPR Nucleoside diphosphate ADP, GDP, m5UDP, UDP, CDP  · dADP, dGDP, dTDP, dUDP, dCDP Nucleoside triphosphate ATP, GTP, m5UTP, UTP, CTP  · dATP, dGTP, dTTP, dUTP, dCTP biochemical families: proteins (amino acids/intermediates) · nucleic acids (constituents/intermediates) · carbohydrates (glycoproteins, alcohols, glycosides) lipids (fatty acids/intermediates, phospholipids, steroids, sphingolipids, eicosanoids) · tetrapyrroles/intermediates

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