Nucleoside- Definition, Types, Structure, Functions
A nucleoside is a type of biomolecule that consists of two components: a pentose sugar and a nitrogenous base. The pentose sugar can be either ribose or deoxyribose, depending on whether the nucleoside is part of RNA or DNA, respectively. The nitrogenous base can be one of the four main bases found in nucleic acids: adenine, guanine, cytosine, or thymine (in DNA) or uracil (in RNA). Alternatively, the nitrogenous base can be a modified or minor base that occurs in some nucleic acids.
The pentose sugar and the nitrogenous base are linked by a glycosidic bond, which is a covalent bond formed between the anomeric carbon atom of the sugar (C1`) and a nitrogen atom of the base (N9 for purines and N1 for pyrimidines). The glycosidic bond determines the orientation of the base relative to the sugar, which can be either syn or anti. In most nucleosides, the anti conformation is preferred, as it allows for more stable stacking interactions between adjacent bases in nucleic acids.
A nucleoside can be distinguished from a nucleotide by the absence of a phosphate group attached to the sugar. A nucleotide is formed when one or more phosphate groups are added to the hydroxyl group at the C5` position of the sugar. Nucleotides are the building blocks of nucleic acids, such as DNA and RNA, which store and transmit genetic information in living cells.
Nucleosides have various functions in biological systems. They serve as precursors for nucleotides, as well as signaling molecules that regulate cellular processes. Some nucleosides also have medical applications as antiviral or anticancer drugs, as they can interfere with the synthesis or function of nucleic acids in pathogens or tumor cells. Nucleosides can also be transported across membranes by specialized proteins called nucleoside transporters, which facilitate their uptake or efflux in different tissues.
In summary, a nucleoside is a molecule composed of a pentose sugar and a nitrogenous base, linked by a glycosidic bond. It differs from a nucleotide by lacking a phosphate group. Nucleosides are involved in various biological roles, such as precursors for nucleotides, signaling molecules, and therapeutic agents.
Nucleosides can be classified into two major types based on the type of nitrogenous base they contain: purine nucleosides and pyrimidine nucleosides.
Purine nucleosides are composed of a pentose sugar and a purine base. Purines are heterocyclic compounds that have a double-ring structure with four nitrogen atoms. The two most common purine bases in nucleic acids are adenine (A) and guanine (G).
In RNA, the purine nucleosides are adenine and guanine, which are abbreviated as A and G respectively. In DNA, the purine nucleosides are deoxyadenosine and deoxyguanosine, which are abbreviated as dA and dG respectively. The deoxy prefix indicates that the pentose sugar is 2`-deoxyribose, which lacks an -OH group at the 2` position.
The purine bases are attached to the pentose sugar at the 1` position by a N-β-glycosidic bond. The bond is formed between the 9th nitrogen atom of the purine ring and the 1` carbon atom of the sugar ring.
Some examples of purine nucleosides are:
- Adenosine: A pentose sugar and an adenine base
- Deoxyadenosine: A 2`-deoxyribose sugar and an adenine base
- Guanosine: A pentose sugar and a guanine base
- Deoxyguanosine: A 2`-deoxyribose sugar and a guanine base
Pyrimidine nucleosides are composed of a pentose sugar and a pyrimidine base. Pyrimidines are heterocyclic compounds that have a single-ring structure with two nitrogen atoms. The three most common pyrimidine bases in nucleic acids are cytosine (C), thymine (T), and uracil (U).
In RNA, the pyrimidine nucleosides are cytidine and uridine, which are abbreviated as C and U respectively. In DNA, the pyrimidine nucleosides are deoxycytidine and thymidine or deoxythymidine, which are abbreviated as dC and dT or T respectively. The deoxy prefix indicates that the pentose sugar is 2`-deoxyribose, which lacks an -OH group at the 2` position.
The pyrimidine bases are attached to the pentose sugar at the 1` position by a N-β-glycosidic bond. The bond is formed between the 1st nitrogen atom of the pyrimidine ring and the 1` carbon atom of the sugar ring.
Some examples of pyrimidine nucleosides are:
- Cytidine: A pentose sugar and a cytosine base
- Deoxycytidine: A 2`-deoxyribose sugar and a cytosine base
- Uridine: A pentose sugar and an uracil base
- Thymidine or Deoxythymidine: A 2`-deoxyribose sugar and a thymine base
A nucleoside is composed of two main components: a pentose sugar and a nitrogenous base. The pentose sugar is a five-carbon ring structure that can be either ribose or deoxyribose. The nitrogenous base is a heterocyclic compound that contains nitrogen atoms and can be either a purine or a pyrimidine.
The pentose sugar and the nitrogenous base are linked by a glycosidic bond, which is a covalent bond formed between the anomeric carbon of the sugar (C1`) and the nitrogen atom of the base. The glycosidic bond can have two possible configurations: alpha (α) or beta (β). In nucleosides, the β configuration is more common and stable.
The pentose sugar can have different conformations depending on the position of the hydroxyl groups attached to the ring. The most common conformation is the furanose form, which resembles a flattened five-sided figure. The furanose form can exist in two anomeric forms: alpha (α) or beta (β). In nucleosides, the β form is more prevalent.
The nitrogenous base can be either a purine or a pyrimidine. Purines have a double-ring structure with nine atoms, while pyrimidines have a single-ring structure with six atoms. The most common purines are adenine (A) and guanine (G), and the most common pyrimidines are cytosine (C), thymine (T), and uracil (U). Thymine is only found in DNA, while uracil is only found in RNA.
The nitrogenous base is attached to the pentose sugar at a specific position depending on its type. Purines are attached at the N9 position, while pyrimidines are attached at the N1 position. The attachment site determines the orientation of the base relative to the sugar. Purines are perpendicular to the sugar plane, while pyrimidines are parallel to it.
The structure of nucleosides can vary depending on the type of pentose sugar and nitrogenous base involved. For example, in DNA, the pentose sugar is deoxyribose, which lacks a hydroxyl group at the 2` position. This makes DNA more stable and resistant to hydrolysis. In RNA, the pentose sugar is ribose, which has a hydroxyl group at the 2` position. This makes RNA more flexible and prone to degradation.
The structure of nucleosides can also be modified by adding functional groups to the pentose sugar or the nitrogenous base. These modifications can alter the properties and functions of nucleosides. For example, some nucleosides have methyl groups attached to their bases, such as 5-methylcytidine and N6-methyladenosine. These methylated nucleosides can regulate gene expression and cellular differentiation.
The structure of nucleosides determines their role in biological processes. Nucleosides are precursors for nucleotides, which are the building blocks of nucleic acids such as DNA and RNA. Nucleic acids store and transmit genetic information in cells. Nucleosides can also act as signaling molecules that regulate cellular activities such as metabolism, growth, and differentiation. Furthermore, some nucleosides have medical applications as antiviral and anticancer agents.
Nucleosides are molecules that consist of a pentose sugar and a nitrogenous base. They have several important functions in biological systems, such as:
- Precursors for nucleotides: Nucleosides can be phosphorylated by kinases to form nucleotides, which are the building blocks of nucleic acids (DNA and RNA). Nucleic acids store and transmit genetic information in cells and organisms. Nucleotides also participate in various metabolic pathways, such as energy production (ATP), signal transduction (cAMP), and coenzyme synthesis (NAD+).
- Signaling molecules: Some nucleosides act as signaling molecules that regulate cellular processes, such as cell growth, differentiation, apoptosis, and immune response. For example, adenosine is a nucleoside that binds to specific receptors on the cell surface and modulates the activity of various enzymes and ion channels. Adenosine also has anti-inflammatory and neuroprotective effects. Another example is cyclic adenosine monophosphate (cAMP), which is a nucleotide derived from adenosine. cAMP is a second messenger that mediates the effects of hormones and neurotransmitters on target cells.
- Role in regulating genetic information: Some nucleosides have modified or unusual bases that can affect the stability, structure, and function of nucleic acids. For example, 5-methylcytosine is a nucleoside that is present in DNA and is involved in epigenetic regulation of gene expression. Epigenetics refers to the changes in gene activity that are not caused by changes in DNA sequence, but by chemical modifications or interactions with other molecules. 5-methylcytosine can silence or activate genes by affecting the binding of transcription factors or chromatin remodeling enzymes. Another example is pseudouridine, which is a nucleoside that is present in RNA and is involved in enhancing the folding and stability of RNA molecules. Pseudouridine can also affect the translation efficiency and accuracy of mRNA.
Nucleosides and their analogs have been widely used in the medical field for the treatment of various diseases, especially malignancies, tumors, and viral infections. Nucleoside analogs are molecules that resemble natural nucleosides in structure but have some modifications in the pentose sugar or the nitrogenous base. These modifications can affect the synthesis, metabolism, and function of nucleic acids in cells, and thus interfere with the replication and growth of pathogens or cancer cells.
Some examples of nucleoside analogs that are used as anticancer drugs are:
- Cytarabine (cytosine arabinoside): This is a pyrimidine nucleoside analog that inhibits DNA polymerase and DNA synthesis. It is used to treat acute myeloid leukemia, acute lymphoblastic leukemia, and some types of lymphoma.
- Gemcitabine (2`-deoxy-2`,2`-difluorocytidine): This is another pyrimidine nucleoside analog that inhibits DNA synthesis and induces apoptosis (cell death) in cancer cells. It is used to treat pancreatic cancer, ovarian cancer, breast cancer, and non-small cell lung cancer.
- Fludarabine (fluorine-ara-adenine): This is a purine nucleoside analog that inhibits DNA synthesis and RNA function. It is used to treat chronic lymphocytic leukemia, non-Hodgkin`s lymphoma, and some types of myeloma.
Some examples of nucleoside analogs that are used as antiviral drugs are:
- Acyclovir (acycloguanosine): This is a guanine nucleoside analog that inhibits viral DNA polymerase and viral DNA synthesis. It is used to treat herpes simplex virus (HSV) infections, varicella-zoster virus (VZV) infections, and cytomegalovirus (CMV) infections.
- Lamivudine (3TC): This is a cytosine nucleoside analog that inhibits reverse transcriptase and viral RNA synthesis. It is used to treat human immunodeficiency virus (HIV) infection and hepatitis B virus (HBV) infection.
- Ribavirin (1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide): This is a purine nucleoside analog that inhibits viral RNA synthesis and viral RNA-dependent RNA polymerase. It is used to treat hepatitis C virus (HCV) infection and respiratory syncytial virus (RSV) infection.
The use of nucleoside analogs as therapeutic agents has some limitations and challenges, such as toxicity, resistance, and delivery. Therefore, researchers are constantly developing new nucleoside analogs with improved efficacy, safety, and specificity. Some of the recent advances in this field include:
- Nucleoside prodrugs: These are molecules that are converted into active nucleoside analogs inside the cells by enzymatic or chemical reactions. This can enhance the bioavailability, stability, and selectivity of the drugs. For example, valacyclovir is a prodrug of acyclovir that has better oral absorption and higher plasma concentration than acyclovir.
- Nucleoside conjugates: These are molecules that have a nucleoside analog attached to another functional group or molecule that can enhance the delivery, targeting, or activity of the drug. For example, troxacitabine is a cytosine nucleoside analog conjugated to a cyclopentane ring that can cross the blood-brain barrier and has potent activity against brain tumors.
- Nucleoside hybrids: These are molecules that combine two different nucleoside analogs or a nucleoside analog and another pharmacophore into one molecule. This can increase the diversity, complexity, and potency of the drugs. For example, elvucitabine is a hybrid of lamivudine and emtricitabine that has dual activity against HIV and HBV.
Nucleosides and their analogs are promising candidates for the development of novel drugs for various diseases. By understanding their structure-function relationships and mechanisms of action, researchers can design more effective and safer drugs for clinical use.
Nucleoside transporters (NTs) are a group of membrane transport proteins that facilitate the movement of nucleosides and their analogs across cellular membranes. Nucleosides are essential for nucleic acid synthesis and cellular metabolism, but they cannot diffuse freely through the lipid bilayer due to their hydrophilic nature. Therefore, NTs play a vital role in the salvage pathway of nucleobases and nucleosides, as well as in the uptake and efflux of nucleoside-based drugs used in anticancer and antiviral therapies.
There are two major types of NTs: concentrative nucleoside transporters (CNTs) and equilibrative nucleoside transporters (ENTs). CNTs are sodium-dependent transporters that use the electrochemical gradient of sodium to drive the active transport of nucleosides against their concentration gradient. CNTs belong to the SLC28 gene family and have three subtypes: CNT1, CNT2, and CNT3. CNT1 and CNT2 are selective for pyrimidine and purine nucleosides, respectively, while CNT3 has a broad substrate specificity.
ENTs are sodium-independent transporters that mediate the passive transport of nucleosides along their concentration gradient. ENTs belong to the SLC29 gene family and have four subtypes: ENT1, ENT2, ENT3, and ENT4. ENT1 and ENT2 are widely expressed in various tissues and have a broad substrate specificity, while ENT3 and ENT4 are more restricted in their expression and substrate preference. ENT3 is mainly found in lysosomes and mediates the efflux of nucleosides from these organelles, while ENT4 is predominantly expressed in the placenta and mediates the uptake of nucleosides from maternal blood.
NTs are important for the pharmacokinetics and pharmacodynamics of nucleoside-based drugs, such as cytarabine, gemcitabine, lamivudine, zidovudine, and others. These drugs rely on NTs for their cellular entry and exit, as well as for their conversion to active metabolites by intracellular kinases. The expression and activity of NTs can affect the efficacy and toxicity of these drugs by modulating their availability and distribution in target cells. Therefore, NTs are potential targets for drug delivery and drug resistance modulation.
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