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. The
monomer itself from ribonucleotides forms the basic building blocks for RNA. However, the reduction of
ribonucleotide, by enzyme ribonucleotide reductase (RNR), forms deoxyribonucleotide, which is the essential
building block for DNA.[1] There are several differences between DNA deoxyribonucleotides and RNA
ribonucleotides. Successive nucleotides are linked together via phosphodiester bonds by 3'-5'.

Ribonucleotides are also utilized in other cellular functions. These special monomers are utilized in both cell
regulation and cell signaling as seen in adenosine-monophosphate (AMP). Furthermore, ribonucleotides can
be converted to adenosine triphosphate (ATP), the energy currency in organisms. Ribonucleotides can be
converted to cyclic adenosine monophosphate (cyclic AMP) to regulate hormones in organisms as well.[1] In
living organisms, the most common bases for ribonucleotides are adenine (A), guanine (G), cytosine (C), or
uracil (U). The nitrogenous bases are classified into two parent compounds, purine and pyrimidine.

Contents
Structure
General structure
DNA deoxyribonucleotides versus RNA
ribonucleotides
Linking successive nucleotides
Function
Precursors of deoxyribonucleotides
Ribonucleotide discrimination
Synthesis
Ribonucleotide synthesis General Ribonucleotide Structure: phosphate group,
Ribose, Nucleobase.
Prebiotic synthesis of ribonucleotides
History
See also
References

Structure

General structure

The general structure of a ribonucleotide consists of a phosphate group, a ribose sugar group, and a
nucleobase, in which the nucleobase can either be adenine, guanine, cytosine, or uracil. Without the phosphate
group, the composition of the nucleobase and sugar is known as a nucleoside. The interchangeable
nitrogenous nucleobases are derived from two parent compounds, purine and pyrimidine. Nucleotides are
heterocyclic compounds, that is, they contain at least two different chemical elements as members of its rings.
Both RNA and DNA contain two major purine bases, adenine (A) and
guanine (G), and two major pyrimidines. In both DNA and RNA, one of
the pyrimidines is cytosine (C). However, DNA and RNA differ in the
second major pyrimidine. DNA contains thymine (T) while RNA
contains uracil (U). There are some rare cases where thymine does occur
in RNA and uracil in DNA.[1]

Here are the 4 major ribonucleotides (ribonucleoside 5'-monophosphate)

which are the structural units of RNAs.

Nucleotide Symbols Nucleoside Structure of adenosine 5'-

monophosphate (AMP)
Adenylate (adenosine 5'-monophosphate) A, AMP Adenosine
Guanylate (guanosine 5'-monophosphate) G, GMP Guanosine
Uridylate (uridine 5'-monophosphate) U, UMP Uridine
Cytidylate (cytidine 5'-monophosphate) C, CMP Cytidine

DNA deoxyribonucleotides versus RNA

ribonucleotides
Structure of guanosine 5'-
In ribonucleotides, the sugar component is ribose while in monophosphate (GMP)
deoxyribonucleotides, the sugar component is deoxyribose. Instead of a
hydroxyl group at the second carbon in the ribose ring, it is replaced by a
hydrogen atom.[2]

Both types of pentoses in DNA and RNA are in their β-furanose (closed
five-membered ring) form and they define the identity of a nucleic acid.
DNA is defined by containing 2'-deoxy-ribose nucleic acid while RNA
is defined by containing ribose nucleic acid.[1]

In some occasions, DNA and RNA may contain some minor bases.
Methylated forms of the major bases are most common in DNA. In viral
DNA, some bases may be hydroxymethylated or glucosylated. In RNA, Structure of uridine 5'-
minor or modified bases occur more frequently. Some examples include monophosphate (UMP)
hypoxanthine, dihydrouracil, methylated forms of uracil, cytosine, and
guanine, as well as modified nucleoside pseudouridine.[3] Nucleotides
with phosphate groups in positions other than on the 5' carbon have also
been observed. Examples include ribonucleoside 2',3'-cyclic
monophosphates which are isolatable intermediates, and ribonucleoside
3'-monophosphates which are end products of the hydrolysis of RNA by
certain ribonucleases. Other variations include adenosine 3',5'-cyclic
monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate
(cGMP).[4]

Linking successive nucleotides

Structure of cytidine 5'-
monophosphate (CMP)
Ribonucleotides are linked together to form RNA strands via
phosphodiester bonds. The 5'-phosphate group of one nucleotide is
linked to the 3'-hydroxyl group of the next nucleotide, creating a
backbone of alternating phosphate and pentose residues. There is no phosphodiester bond at each end of the
polynucleotide.[5] Phosphodiester bonds are formed between ribonucleotides by the enzyme RNA
polymerase. The RNA chain is synthesized from the 5' end to the 3' end as the 3'-hydroxyl group of the last
ribonucleotide in the chain acts as a nucleophile and launches a hydrophilic attack on the 5'-triphosphate of the
incoming ribonucleotide, releasing pyrophosphate as a by-[6] product. Due to the physical properties of the
nucleotides, the backbone of RNA is very hydrophilic and polar. At neutral pH, nucleic acids are highly
charged as each phosphate group carries a negative charge.[7]

Both DNA and RNA are built from nucleoside phosphates, also known as mononucleotide monomers, which
are thermodynamically less likely to combine than amino acids. Phosphodiester bonds, when hydrolyzed,
release a considerable amount of free energy. Therefore, nucleic acids tend to spontaneously hydrolyze into
mononucleotides. The precursors for RNA are GTP, CTP, UTP and ATP, which is a major source of energy in
group-transfer reactions.[8]

Function

Precursors of deoxyribonucleotides

Scientists believe that RNA was developed before DNA.[9]

The reduction of ribonucleotides to deoxyribonucleotides is catalyzed by ribonucleotide reductase.

Ribonucleotide reductase (RNR) is an essential enzyme for all living organisms since it is responsible for the
last step in the synthesis of the four deoxyribonucleotides (dNTPs) necessary for DNA replication and
repair.[10] The reaction also requires two other proteins: thioredoxin and thioredoxin reductase. Ribonucleoside
diphosphate (NDP) is reduced by thioredoxin to a deoxyribonucleoside diphosphate (dNTP).

The general reaction is: Ribonucleoside diphosphate + NADPH + H+ -> Deoxyribonucleoside diphosphate +
NADP+ + H2 O [11]

To illustrate this equation, dATP and dGTP are synthesized from ADP and GDP, respectively. They are first
reduced by RNR and then phosphorylated by nucleoside diphosphate kinases to dATP and dGTP.
Ribonucleotide reductase is controlled by allosteric interactions. Once dATP binds to ribonucleotide reductase,
the overall catalytic activity of the enzyme decreases, as it signifies an abundance of deoxyribonucleotides.
This feedback inhibition is reversed once ATP binds.[12]

Ribonucleotide discrimination

During DNA synthesis, DNA polymerases must select against ribonucleotides, present at much higher levels
compared with deoxyribonucleotides. It is crucial that there is selectivity as DNA replication has to be accurate
to maintain the organism's genome. It has been shown that the active sites of Y-family DNA polymerases are
responsible for maintaining a high selectivity against ribonucleotides.[13] Most DNA polymerases are also
equipped to exclude ribonucleotides from their active site through a bulky side chain residue that can sterically
block the 2'-hydroxyl group of the ribose ring. However, many nuclear replicative and repair DNA
polymerases incorporate ribonucleotides into DNA,[14][15] suggesting that the exclusion mechanism is not
perfect.[16]

Synthesis

Ribonucleotide synthesis
Ribonucleotides can be synthesized in organisms from smaller molecules through the de novo pathway or
recycled through the salvage pathway. In the case of the de novo pathway, both purines and pyrimidines are
synthesized from components derived from precursors of amino acids, ribose-5-phosphates, CO2, and
NH3.[17][18]

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)

De novo biosynthesis of purine nucleotides is fairly complex, consisting The synthesis of IMP. The color
scheme is as follows: enzymes,
of several enzymatic reactions. Utilizing the five-ring sugar structure as a
coenzymes, substrate names,
base, the purine ring is built a few atoms at a time in an eleven-step
metal ions, inorganic
process that leads to the formation of inosinate (IMP). Essentially, IMP is
molecules
converted into the purine nucleotides required for nucleic acid
synthesis.[17]

The pathway begins with the conversion of Ribose-5-Phosphate(R5P) to phosphoribosyl pyrophosphate

(PRPP) by enzyme ribose-phosphate diphosphokinase (PRPS1). PRPP is then converted to 5-
phosphoribosylamine (5-PRA) as glutamine donates an amino group to the C-1 of PRPP. In a condensation
reaction, enzyme GAR synthetase, along with glycine and ATP, activates the glycine carboxylase group of 5-
PRA to form Glycinamide ribonucleotide (GAR). Co-enzyme N10-formyl-THF, along with enzyme GAR
transformylase, then donates a one-carbon unit to the amino group onto the glycine of GAR, followed by
glutamine addition by enzyme FGAR amidotransferase, leading to the formation of formylglycinamidine
ribonucleotide (FGAM). Dehydration of FGAM by enzyme FGAM cyclase results in the closure of the
imidazole ring, as 5-aminoimidazole ribonucleotide (AIR). A carboxyl group is attached to AIR by N5-CAIR
synthetase to form N5-Carboxyaminoimidazole ribonucleotide (N5-CAIR), which is then converted to
Carboxyamino-imidazole ribonucleotide (CAIR) with enzyme N5-CAIR mutase. Enzyme SAICAR
synthetase, along with amino group from aspartate forms an amide bond to create N-succinyl-5-
aminoimidazale-4-carboxamide ribonucleotide (SAICAR). Continuing down the pathway, the removal of the
carbon skeleton of aspartate by SAICAR lyase results in 5-aminoimidazole-4-carboxamide ribonucleotide
(AICAR). Enzyme AICAR transformylase assists in the final carbon transfer from N10-
formyltetrahydrofolate, forming N-formylaminoimidazole-4-carboxamide ribonucleotide (FAICAR). Lastly,
closure of the second ring structure is carried out by IMP synthase to form IMP, where IMP fate would lead to
the formation of a purine nucleotide.[17]

Synthesis of pyrimidine nucleotides is a much simpler process. The formation of the pyrimidine ring begins
with the conversion of Aspartate to N-Carbamoylaspartate by undergoing a condensation reaction with
carbamoyl phosphate. Dihydroorotase and dihydroorotase dehydrogenase then converts N-
Carbamoylaspartate to orotate. Orotate is covalently linked with phosphoribosyl pyrophosphate (PRPP) by
orotate phosphoribysol-transferase yielding orotidine monophosphate (OMP). OMP follows with the
decarboxylation by orotidylate decarboxylase to form the Uridylate (UMP) ribonucleotide structure. UMP can
then be converted to Uridine-5’-trisphosphate (UTP) by two kinases reaction. Formation of Cytidine-5’-
trisphosphate (CTP) from UTP can be achieved by cytidylate synthetase by an acyl phosphate
intermediate.[17]
Prebiotic synthesis of ribonucleotides
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. According to the RNA world
hypothesis free-floating ribonucleotides were present in the primitive
soup. These were the fundamental molecules that combined in series
to form RNA. Molecules as complex as RNA must have arisen from
small molecules whose reactivity was governed by physico-chemical
processes. RNA is composed of purine and pyrimidine nucleotides,
both of which are necessary for reliable information transfer, and thus
Darwinian natural selection and evolution. Nam et al.[19]
Pyrimidine de Novo pathway
demonstrated the direct condensation of nucleobases with ribose to
give ribonucleosides in aqueous microdroplets, a key step leading to
RNA formation. Also, a plausible prebiotic process for synthesizing
pyrimidine and purine ribonucleotides using wet-dry cycles was presented by Becker et al. [20]

History
Prior to James Watson and Francis Crick's landmark paper that detailed
the structure of DNA from Rosalind Franklin's X-ray crystallography
image, there were several historical scientists that also contributed to its
discovery.[21] Friedrich Miescher, a Swiss physician, who, in 1869, was
first to isolate and identify nucleic substance from the nuclei of white
blood cells he later called “nuclein”, paving the way for the discovery of
DNA.[22] Following Mieschers work, was the German biochemist,
Albrecht Kossel, who, in 1878, isolated the non-protein components of
“nuclein”, and discovered the five nucleobases present in nucleic acids:
adenine, cytosine, guanine, thymine and uracil.[23] Although some
fundamental facts were known about nucleic acids due to these early
discoveries, its structure and function remained a mystery.

It wasn't until the discovery of nucleotides in 1919 by Phoebus Levene, a

Russian-Lithuanian biochemist that re-opened the gates of the DNA
discovery. Levene first identified the carbohydrate component present in
Phoebus Levene
yeast RNA was in fact ribose. However, it was not until his discovery
that the carbohydrate component in thymus nucleic acid was also a sugar
but lacked one oxygen atom, termed deoxyribose, that his discovery was
widely appreciated by the scientific community. Eventually, Levene was able to identify the correct order of
which the components of RNA and DNA are put together, a phosphate-sugar-base unit, in which he later
called a nucleotide. Although the order of nucleotide components were well understood by Levene, the
structure of nucleotide arrangement in space and its genetic code still remained a mystery during the early
years of his career.[24]

See also
Ribonucleosides or ribosides

References
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