Nucleotide Metabolism in Medicine School

Nucleotide Functions

• Nucleotides function as energy carriers (ATP, FAD)
• They are structural components of enzyme cofactors (NAD)
• They act as second messengers in signal transduction (cAMP)
• They are carriers of activated intermediates in the synthesis of carbohydrates, lipids, and conjugated proteins (UDP-glucose)

Nucleic Acid Functions

• They store genetic information (DNA)
• They transmit genetic information (mRNA)
• They process genetic information (ribozymes)
• They are involved in protein synthesis (tRNA and rRNA)

Nucleotide Structure

• Nucleotides are composed of a nitrogenous base, a pentose monosaccharide, and one to three phosphate groups
• Modifications such as methylation, acetylation, and glycosylation can be added to nucleotides

Synthesis of Purine Nucleotides

• Purine ring is built on ribose-5-phosphate in the liver
• Ribose-5-phosphate is produced in the hexose monophosphate shunt of carbohydrate metabolism
• 5-Phosphoribosyl-1-pyrophosphate (PRPP) is an activated pentose that participates in the synthesis and salvage of purines
• Glutamine transfers its amide nitrogen to PRPP to produce 5-phosphoribosylamine, a committed step of synthesis
• The enzyme PRPP glutamyl amidotransferase is controlled by feedback inhibition of nucleotides AMP, GMP, and IMP

Synthesis of Deoxyribonucleotides

• 2'-Deoxyribonucleotides are synthesized from ribonucleoside diphosphates by a reduction of C2 of ribose moiety
• Thioredoxin is a peptide coenzyme of ribonucleotide reductase
• Regulation of deoxyribonucleotide synthesis is controlled by catalytic site and allosteric site
• dATP inhibits the enzyme and prevents synthesis of any four nucleoside diphosphates

Degradation of Purine Nucleotides

• Occurs in the small intestine
• Nucleic acids are hydrolyzed to nucleotides
• Purine bases are not used for the synthesis of nucleic acids
• They are converted to uric acid

Diseases Associated with Purine Degradation

• Lesch-Nyhan syndrome: characterized by excessive uric acid production, neurological abnormalities, and self-mutilation

Synthesis of Pyrimidine Nucleotides

• Pyrimidine ring is synthesized before being attached to a ribose-5-phosphate
• Carbamoyl phosphate is formed from ATP, GLUTAMINE, and CO2
• Pyrimidine ring is converted to the nucleotide orotidine monophosphate (OMP)
• PRPP is the ribose-phosphate donor

Degradation and Salvage of Pyrimidines

• Pyrimidine ring is opened and degraded to highly soluble products, beta-alanine, and beta-aminoisobutyrate
• The pyrimidines can also serve as precursors in the salvage pathway to be converted to the respective nucleotides via phosphorylation