Synthesis of Nucleotides

A nucleotide consists of three basic components

  • Nitrogenous base

  • Pentose sugar (deoxyribose or ribose)

  • Phosphate group(s)

Purines

Purines are a type of nitrogenous base that are essential components of nucleotides, characterized by a two-ring structure, which includes adenine and guanine.

The two-ring structures are responsible for the unique bonding properties that allow them to pair specifically with pyrimidines in the formation of nucleic acids.

The two rings in purines are pyrimidine and imidazole rings, which contribute to their ability to participate in hydrogen bonding during base pairing.

Adenine:

  • A nitrogenous base: One of the two purine bases used in forming nucleotides of DNA and RNA; pairs with Thymine (T) in DNA or Uracil (U) in RNA.

  • Adenine + pentose sugar + one phosphate (monophosphate) = Adenosine Monophosphate (AMP).

  • If the sugar is deoxyribose, it becomes Deoxyadenosine Monophosphate (dAMP).

Guanine:

  • A nitrogenous base with a carbonyl group: One of the two purine bases found in nucleotides; pairs with Cytosine (C) in DNA and RNA.

  • Guanine + ribose sugar/deoxyribose sugar + monophosphate = Guanosine Monophosphate (GMP) or deoxyguanosine monophosphate (dGMP).

Nitrogenous Bases: Pyrimidines

  • Single-ring structures consisting of three types:

    • Cytosine:

      • Has an amine group: A pyrimidine base that pairs with Guanine (G) in DNA and RNA.

      • Cytosine + pentose sugar + monophosphate = Cytidine Monophosphate (CMP).

      • Deoxycytidine Monophosphate (dCMP) for DNA.

    • Uracil:

      • Has a carbonyl group but no methyl group: A pyrimidine base found in RNA, where it pairs with Adenine (A).

      • Uracil + pentose sugar + monophosphate = Uridine Monophosphate (UMP).

      • Deoxyuridine Monophosphate (dUMP) is used to make deoxythymidine monophosphate.

    • Thymine:

      • Has a carbonyl group and a methyl group: A pyrimidine base present in DNA, where it pairs with Adenine (A).

      • Thymine + pentose sugar + monophosphate = Thymidine Monophosphate (TMP).

      • Deoxythymidine Monophosphate (dTMP).

Pentose Sugar Synthesis

  • The pentose phosphate pathway is used to create pentose sugars: A metabolic pathway parallel to glycolysis, producing NADPH and pentoses.

  • Glucose-6-phosphate

    • Glucose enters a cell and is phosphorylated by hexokinase or glucokinase at the sixth carbon: The first step of glucose metabolism, trapping glucose inside the cell.

    • ATP→ADPATP \rightarrow ADP (phosphate added to glucose).

    • Can proceed through glycolysis or the pentose phosphate pathway.

    • Enzyme: Glucose-6-phosphate dehydrogenase: Catalyzes the first committed step in the pentose phosphate pathway.

  • 6-phosphoglucono-lactone

    • NADP+→NADPHNADP^+ \rightarrow NADPH (reduction via dehydrogenase enzyme): NADPH is essential for reducing power in anabolic reactions.

  • 6-phosphogluconate

    • 6-phosphoglucono-lactone + water via lactonase: Hydrolysis of 6-phosphoglucono-lactone to form 6-phosphogluconate; lactonase enhances this conversion.

  • Ribulose-5-phosphate

    • NADP+→NADPHNADP^+ \rightarrow NADPH via 6-phosphogluconate dehydrogenase.

    • NADPH goes to the glutathione pathway: Important for reducing oxidative stress within the cell.

  • Ribose-5-phosphate

    • Ribulose-5-phosphate (ketone) converted to ribose-5-phosphate (aldehyde) via an isomerase enzyme: Essential for nucleotide synthesis and other cellular processes.

  • Phosphoribosyl Pyrophosphate (PRPP)

    • Ribose-5-phosphate is converted into a ring structure via ribose-phosphate pyrophosphokinase: PRPP is a key regulatory and intermediate molecule in nucleotide biosynthesis.

    • ATP→AMPATP \rightarrow AMP (two phosphates added).

Deoxyribose vs. Ribose

  • Difference lies on the second carbon of the sugar:

    • Ribose: Hydroxyl group (OH) on the second carbon: Found in RNA nucleotides.

    • Deoxyribose: Hydrogen (H) on the second carbon: Found in DNA nucleotides.

Pyrimidine Synthesis

  • Synthesized from glutamine, bicarbonate, and ATP.

  • Carbamoyl Phosphate

    • Glutamine + Bicarbonate + 2 ATP + Water via Carbamoyl Phosphate Synthetase Type II: The first committed step in pyrimidine biosynthesis, occurring in the cytosol.

  • Carbamoyl Aspartate

    • Carbamoyl Phosphate + Aspartate via Aspartate Transcarbamoylase: A key regulatory step where the enzyme is inhibited by CTP, the end product of the pathway.

  • Orotate

    • Carbamoyl Aspartate dehydrated via dihydratase into a ring structure: The initial ring structure formed in pyrimidine synthesis.

  • Orotidine Monophosphate (OMP)

    • Orotate + PRPP via Orotate Phosphoribosyl Transferase (releases a phosphate group): This step links the pyrimidine base to a ribose-phosphate moiety.

  • Uridine Monophosphate (UMP)

    • OMP is decarboxylated (loses CO2CO_2) via UMP Synthase: UMP is the parent pyrimidine nucleotide from which other pyrimidine nucleotides are derived.

  • Uridine Triphosphate (UTP)

    • UMP converted via nucleoside diphosphate kinase by adding a pyrophosphate group (two phosphates).

  • Cytidine Triphosphate (CTP)

    • UTP + Glutamine (amine group) loses a carbonyl group.

  • Cytidine Monophosphate (CMP)

    • CTP loses a pyrophosphate.

  • Deoxycytidine Diphosphate (dCDP)

    • CMP + phosphate group changed from a hydroxyl group to a hydrogen group via Ribonucleotide Reductase: Ribonucleotide Reductase is crucial for converting ribonucleotides to deoxyribonucleotides.

  • Deoxycytidine Monophosphate (dCMP)

    • dCDP loses a phosphate group and can now incorporated into DNA.

  • Deoxyuridine Diphosphate (dUDP)

    • UMP + phosphate group changed from a hydroxyl group to a hydrogen group via Ribonucleotide Reductase.

  • Deoxyuridine Monophosphate (dUMP)

    • dUDP loses a phosphate group off in that process.

  • Deoxythymidine Monophosphate (dTMP)

    • dUMP + methyl group (from tetrahydrofolate) via Thymidylate Synthase: Thymidylate Synthase is a target for cancer chemotherapy drugs.

Purine Synthesis

When the base adenine combines with ribose and phosphate group, adenosine is produced. When adenine combines with deoxyribose

  • Involves PRPP, glutamine, bicarbonate, formate, glycine, and aspartate through a series of 10 steps.

  • Inosine Monophosphate (IMP)

    • Synthesized from PRPP, glutamine, bicarbonate, formate, glycine, and aspartate: IMP is a branch-point molecule; the precursor to both AMP and GMP.

    • Precursor to AMP and GMP.

  • Hypoxanthine Monophosphate

    • IMP via Inosine Monophosphate Dehydrogenase (NAD+ to NADH) adding a hydroxyl group producing NADH.

  • Guanosine Monophosphate (GMP)

    • Hypoxanthine Monophosphate + Glutamine to make Guanosine Monophosphate via Guanosine Monophosphate Synthase.

  • Deoxyguanosine Diphosphate (dGDP)

    • GMP is turned to deoxy form and gains a phosphate via Ribonucleotide Reductase.

  • Deoxyguanosine Monophosphate (dGMP)

    • dGDP loses a phosphate used to synthesize DNA.

  • Adenosuccinate

    • IMP + Aspartate via Adenosuccinate Synthase.

  • Adenosine Monophosphate (AMP)

    • Adenosuccinate loses Fumarate via Adenosuccinate Lyase.

  • Deoxyadenosine Diphosphate (dADP)

    • AMP to deoxy form and gains a phosphate via Ribonucleotide Reductase.

  • Deoxyadenosine Monophosphate (dAMP)

    • dADP loses a phosphate used to synthesize DNA.