Purine Salvage Pathway in Biochemistry

Nucleotide Metabolism 1 & 2

• Nucleotides are the building blocks of nucleic acids (DNA & RNA)
• They are non-essential nutrients, as they can be synthesized in the body
• Nucleotides are crucial components of ATP, the primary energy source in cells
• They are also part of coenzymes like NAD, NADP, and FAD
• Nucleotides form cAMP and cGMP, which function as secondary messengers for hormones
• Nucleotides act as regulatory molecules for various metabolic pathways

Nucleotide Synthesis

• Nucleotides can be synthesized through two pathways:
  • De novo synthesis: Starts with metabolic precursors like amino acids, ribose-5-phosphate, CO2, and one-carbon units. Enzymes involved are found in the cytosol, liver, and small intestine/thymus.
  • Salvage pathways: Recycles free bases or nucleosides from degraded RNA and DNA.

Purine Synthesis

• Purine ring atoms are supplied by various compounds
• Synthesis involves a series of reactions adding carbons and nitrogens to ribose-5-phosphate
• Most de novo synthesis occurs in the liver
• A key step is the production of 5-phosphoribosyl-1-pyrophosphate (PRPP) from ribose-5-phosphate
• Another crucial step is the synthesis of 5'-phosphoribosylamine catalyzed by glutamine phosphoribosylpyrophosphate amidotransferase (GPAT)

Pyrimidine Synthesis

• Unlike purines, pyrimidine bases are synthesized first, then attached to the ribose-5-phosphate sugar.
• Amine nitrogen (from glutamine) and carbon atoms (from aspartate) are incorporated.

Nucleosides

• Addition of a pentose sugar (ribose or deoxyribose) to a base forms a nucleoside through N-glycosidic linkage
• Examples include adenosine, guanosine, cytidine, and deoxythymidine.

Nucleotides

• Adding one or more phosphate groups to a nucleoside produces a nucleotide
• Nucleotides consist of a base, a pentose sugar (ribose or deoxyribose), and one or more phosphate groups
• Phosphate groups are attached to the 5' carbon of the pentose sugar via ester linkages.

Naming Nucleotides

• Nucleosides are named based on the base (e.g., adenosine)
• Nucleotides are named by adding the suffix '-phosphate' to the nucleoside name (e.g., adenosine monophosphate (AMP))

Unusual Bases

• Some organisms have unusual modified bases in their DNA and RNA, such as viral DNA and tRNA methylation or acetylation

Synthesis of Deoxyribonucleotides

• Two essential enzymes involved are Adenylate kinase and Guanylate kinase.
• The enzymes are involved in the conversion of nucleoside monophosphates to diphosphates and triphosphates.

Regulation of Deoxyribonucleotide Synthesis

• Ribonucleotide reductase is responsible for generating the correct deoxyribonucleotide needed for DNA synthesis
• Regulation is complex and involves allosteric sites, which are influenced by ATP(activator) and dATP (inhibitor) that also influence the substrate-specificity sites within the synthesis pathways

Purine Degradation

• In the small intestine, RNA and DNA are degraded into oligonucleotides which are broken down into mononucleotides
• Mononucleotides are converted into nucleosides by removal of phosphate groups
• Inside cells, purine bases are oxidized to uric acid, which is excreted in the urine.

Pyrimidine Degradation

• Pyrimidine nucleotides are dephosphorylated to nucleosides
• These nucleosides are cleaved to free pyrimidine bases and ribose-1-phosphate
• Pyrimidine bases are deaminated into different products or further metabolized such as cytosine to uracil, which are then metabolized to different substances

Diseases Associated with Purine Degradation

• Gout: high uric acid levels from either overproduction or underexcretion result in deposition of monosodium urate crystals in joints/kidney

Adenosine Deaminase Deficiency (ADA)

• ADA enzyme is crucial for converting adenosine into inosine
• Deficiency leads to an accumulation of adenosine, which inhibits ribonucleotide reductase
• This leads to a combined immunodeficiency disease (SCID)

Pyrimidine Salvage Pathways

• Pyrimidine bases like uracil, cytosine, and thymine are salvaged by phosphorylase to form nucleosides, which are converted into nucleotides by nucleoside kinases.

Diagnosis of Gout

• Definitive diagnosis involves aspirating and inspecting fluid from inflamed joints
• Polarized microscopy verifies the presence of needle-shaped monosodium urate crystals (MSU crystals).

Treatment of Gout

• Acute attacks are treated with anti-inflammatory drugs
• Uric acid synthesis inhibitors like allopurinol block xanthine oxidase to reduce uric acid production.

Test your knowledge on the purine salvage pathway with this quiz. Answer questions about key enzymes, substrates, and the role of nucleotides in cellular processes. Dive deep into the essentials of biochemistry and see how well you understand the significance of nucleotides.