Nucleotide Metabolism and Purine Synthesis

Nucleotide Metabolism

• Nucleotides are the fundamental building blocks of nucleic acids (DNA and RNA)
• They are non-essential nutrients, meaning the body can synthesize them.
• Nucleotides play a crucial role in energy transfer (ATP), coenzyme function (NAD, NADP, FAD), and as secondary messengers (cAMP, cGMP).
• They also act as regulatory molecules in metabolic pathways.
• Purines and pyrimidines are the two classes of nitrogenous bases in nucleotides.

Purine Synthesis

• Purines are synthesized from amino acids, ribose-5-phosphate, CO₂, and one-carbon units.
• The process begins with the production of 5-phosphoribosyl-1-pyrophosphate (PRPP) from ribose-5-phosphate using ATP by the enzyme phosphoribosyl pyrophosphate synthetase (PRPP synthetase)
• This step is crucial but not the commitment step in purine synthesis.
• The next step is the synthesis of 5'-phosphoribosylamine from PRPP by glutamine phosphoribosyl pyrophosphate amidotransferase (GPAT)
• This is the committed step in purine synthesis.
• Other steps involve adding carbons and nitrogens to form the purine ring
• Most de novo synthesis takes place in the liver.

Purine Salvage Pathway

• This pathway recycles pre-formed purines (nucleosides or bases) released from the break down of DNA or RNA.
• Two enzymes, HGPRT and APRT, are involved in this pathway.
• These are irreversible reactions, dependent on PRPP as a source of ribose-5-phosphate, coupled to the release of pyrophosphate.
• The deficiency of HGPRT causes Lesch-Nyhan Syndrome.

Pyrimidine Synthesis

• Pyrimidine synthesis differs from purine synthesis as the base is constructed first, followed by attachment to the ribose-5-phosphate sugar.
• The sequence starts with the synthesis of carbamoyl phosphate from glutamine, ATP, and CO₂
• This sequence requires the enzyme carbamoyl phosphate synthetase II (CPS II).
• The pyrimidine ring is then constructed through several steps, involving aspartate.
• The biosynthesis of the pyrimidine ring precedes attachment to the ribose sugar.

Pyrimidine Degradation

• Pyrimidine bases are deaminated or cleaved (broken down) to simple components
• These components (CO₂, ammonia, and simple amino acids) are then further metabolized and excreted.

Deoxyribonucleotide Synthesis

• Deoxyribonucleotides are required for DNA synthesis, using ribonucleoside-diphosphates and Ribonucleotide reductase enzyme.
• The process utilizes hydrogen atoms provided by an enzyme, Thioredoxin, which is reduced by NADPH + H+

Regulation of Deoxyribonucleotide Synthesis

• The enzyme Ribonucleotide reductase is complex, with regulatory sites in addition to the catalytic site.
• ATP activates, and dATP inhibits the enzyme.
• Different NTPs (ATP, dATP, dTTP etc) regulate the specific nucleoside reductions.

Nucleotide Metabolism Diseases

• Gout: A disorder caused by high uric acid levels in the blood, leading to crystal deposition in joints and kidneys.
• Treatment involves anti-inflammatory drugs and inhibiting uric acid synthesis.
• Lesch-Nyhan Syndrome: A rare genetic disorder caused by a deficiency of HGPRT, characterized by high uric acid, and self-mutilation.