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Nucleotide

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Definition

noun

plural: nucleotides

nu·cle·o·tide, [ˈnjuːklɪəˌtaɪd]


The basic building block of nucleic acid polymers; an organic compound made up of a nitrogenous base, a sugar, and a phosphate group

Details

Overview

A nucleotide is regarded as the basic building block of nucleic acid polymers (e.g. DNA and RNA). A nucleic acid is one of the major groups of biomolecules (the others are carbohydrates (especially, polysaccharides), proteins, and amino acids. Nucleic acids are involved in the preservation, replication, and expression of hereditary information.


Characteristics

Nucleotide is an organic compound made up of three subunits: a nitrogenous base, a five-carbon sugar, and a phosphate group. The sugar component may either be ribose or deoxyribose. The ribose sugar is the sugar component of the nucleotides that make up RNA. The deoxyribose sugar is the sugar component of DNA. Each phosphate group connects the sugar rings of two adjacent nucleotide monomers. The phosphate groups and the sugar moieties form the backbone of a nucleic acid. The directionality of the chain runs from 5'-end to 3'-end. In DNA, the orientation of the two strands is in opposite directions. This is to allow complementary base pairing between nucleobase constituents. Apart from the long chain of nucleic acids, nucleotides also occur in cyclic forms. Cyclic nucleotides form when the phosphate group is linked twice to the sugar moiety, particularly to the two hydroxyl groups of the constituent sugar.


Nucleosides vs. Nucleotides

Nucleotides should not be confused to nucleosides, which are also 5-carbon sugar with a nitrogenous base. However, nucleosides do not have a phosphate group. When a nucleoside is bound to a phosphate group, it yields a nucleotide. Thus, a nucleotide is also referred to as nucleoside monophosphate (if with only one phosphate group), nucleoside diphosphate (with two phosphate groups), or nucleoside triphosphate (when with three phosphate groups). Depending on the pentose sugar component, a nucleoside may be a ribonucleoside or a deoxyribonucleoside. A ribonucleoside is a nucleoside with a ribose sugar component. Based on the nucleobase component, the ribonucleoside may be adenosine, guanosine, cytidine, uridine, or 5-methyluridine. A deoxyribonucleoside is a nucleoside with a deoxyribose sugar. Similarly, based on the nucleobase component, a deoxyribonucleoside may be deoxyadenosine, deoxyguanosine, deoxycytidine, thymidine, or deoxyuridine. Also, depending on the nucleobase component, the nucleosides may be grouped into either the "double-ringed" purine or the "single-ringed" pyrimidine.


Classification

The fundamental nucleotides are divided into purines and pyrimidines based on the structure of the nitrogenous base. In DNA, the purine bases include adenine and guanine while the pyrimidine bases are thymine and cytosine. RNA includes adenine, guanine, cytosine, and uracil instead of thymine (thymine is produced by adding a methyl to uracil).


While both purines and pyrimidines are heterocyclic aromatic compounds, they can be differed from each other based on the chemical structure. A purine has two carbon rings whereas a pyrimidine has one carbon ring. The purine has a pyrimidine ring fused to an imidazole ring. The pyrimidine has only a pyrimidine ring. Thus, the purine has four nitrogen atoms whereas the pyrimidine has two.


Purines include adenine and guanine whereas pyrimidines include cytosine, thymine, and uracil. These five nitrogenous bases are regarded as primary or canonical since they are the fundamental units of the genetic code. The nucleobases that make up the nucleic acid are used to distinguish DNA from RNA molecules. In DNA, thymine complementary pairs with adenine whereas in RNA, uracil matches with adenine. The thymine differs from uracil in having a methyl group, which the uracil lacks. The pairings of nucleobases C-G and A-T (or A-U in RNA) are referred to as base complements.


Types

Examples of nucleotides with only one phosphate group:


Nucleotides with two phosphate groups:

  • adenosine diphosphate (ADP)
  • guanosine diphosphate (GDP)
  • cytidine diphosphate (CDP)
  • uridine diphosphate (UDP)
  • deoxyadenosine diphosphate (dADP)
  • deoxyguanosine diphosphate (dGDP)
  • deoxycytidine diphosphate (dCDP)
  • (deoxy)thymidine diphosphate (dTDP)


Nucleotides with three phosphate groups:


Common biological reactions

Nucleotide synthesis

Nucleotides are produced naturally by de novo synthesis pathway or by salvage pathways. In humans, the de novo synthesis pathway of the fundamental nucleotides occurs mainly in the liver.


In pyrimidine biosynthesis, the ring forms by a series of steps that begins in the formation of carbamoyl phosphate. First, carbamoyl phosphate is produced from biochemical reaction involving bicarbonate, glutamine, ATP (for phosphorylation), and water molecule. The enzyme that catalyzes the reaction is carbamoyl phosphate synthetase II located in the cytosol. Next, the carbamoyl phosphate is converted into carbamoyl aspartate by the enzyme aspartate transcarbamylase. Then, the ring closes through intramolecular condensation, converting carbamoyl phosphate into dihydroorotate by the enzyme dihydroorotase. Lastly, the dihydroorotate is oxidized by dihydroorotate dehydrogenase (an integral membrane protein in the inner mitochondrial membrane) to convert into orotate. After the pyrimidine ring forms, 5-phospho-α-D-ribosyl 1-pyrophosphate (PRPP), a ribose phosphate, reacts to orotate to form orotidine-5-monophosphate (OMP). OMP is then decarboxylated by the enzyme OMP decarboxylase to yield uridine monophosphate (UMP). Eventually, uridine diphosphate (UDP) and uridine triphosphate (UTP) are produced down the biosynthetic pathway by kinases and dephosphorylation of ATPs. UTP can be converted into cytidine triphosphate (CTP) by amination of UTP via the enzyme CTP synthetase.[1]


Pyrimidine biosynthesis differs from purine biosynthesis in a way that purines are synthesized as a nucleotide first whereas pyrimidines form initially as a free base. Purines are derived from the nucleotide inosine monophosphate (IMP). IMP, in turn, is produced from a pre-existing ribose phosphate that forms mainly from the amino acids glycine, glutamine, and aspartic acid. Ribose 5-phosphate reacts with ATP to produce 5-Phosphoribosyl-1-pyrophosphate (PRPP). PRRP has a role in both purine and pyrimidine synthesis; it is also involved in NAD and NADP formation and salvage pathways. PRRP though becomes committed particularly to purine biosynthesis when PRRP is converted into 5-phosphoribosyl amine by having the pyrophosphate of PRRP replaced by the amide group of glutamine. IMP is then converted into either adenosine monophosphate (AMP) or guanosine monophosphate (GMP).


Nucleotide degradation and salvage

Purines guanine and adenine may be degraded as follows:

  • Guanine (via guanase) » xanthine (via xanthine oxidase) » uric acid
  • Adenosine »» inosine (via purine nucleoside phosphorylase) » hypoxanthine (via xanthine oxidase) » xanthine (via xanthine oxidase) » uric acid


In humans and other vertebrates, the exogenous purines are degraded in the liver. As a result of purine degradation, uric acid is produced as a waste product. The uric acid is released from the liver into the bloodstream through which it reaches the kidney. It is then excreted from the body via the urine. Purines from catabolism may be salvaged and re-used as follows:

  • Adenine is salvaged by the enzyme adenine phosphoribosyltransferase (APRT)
  • Guanine and hypoxanthine are salvaged by the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT)


Pyrimidines that are degraded can be recycled by a salvage pathway. Nucleobases are recovered for re-use post-RNA and DNA degradations. Pyrimidine salvage pathways are as follows:

  • Cytosine is converted into uracil by deamination. By uridine phosphorylase, uracil is converted into uridine by reacting with ribose-1-phosphate. Through the enzyme nucleoside kinase, uridine is converted into uridine monophosphate (UMP).
  • Thymine is converted into thymidine by reacting with deoxyribose-1-phosphate and by the enzyme thymidine phosphorylase. Thymidine is then converted into thymidine monophosphate by the enzyme nucleoside kinase.


Biological functions

Aside from serving as precursors of nucleic acids, nucleotides also serve as important cofactors in cellular signaling and metabolism. These cofactors include CoA, flavin adenine dinucleotide (FAD), flavin mononucleotide, adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide phosphate (NADP). The nucleoside triphosphates, in particular, carry packets of chemical energy that is used in many cellular activities demanding energy, e.g. amino acid synthesis, protein synthesis, cell division, internal and intercellular movements, etc.



Supplementary

Etymology

  • nucleo- ("nucleus") + -ide (chemical suffix)

Derived term(s)

  • Nucleotide pyrophosphate transferase
  • Nucleotide deletion
  • Triphosphopyridine nucleotide
  • Long interspersed nucleotide element


Further reading

See also


Reference

  1. Charma, K. & Somani, D. (2015). Pyrimidine Biosynthesis. Retrieved from Slideshare.net website: [Link]



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