11.4 Nucleotide metabolism and salvage pathways

Nucleotide metabolism is crucial for making DNA and RNA building blocks. Cells use two main ways to get nucleotides: making them from scratch (de novo synthesis) or recycling existing ones (salvage pathway).

Understanding these processes helps us grasp how cells maintain their genetic material. We'll look at key enzymes, purine and pyrimidine metabolism, and related disorders like gout and Lesch-Nyhan syndrome.

Nucleotide Biosynthesis Pathways

De Novo Synthesis and Salvage Pathway

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Top images from around the web for De Novo Synthesis and Salvage Pathway

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  Frontiers | Large-Scale de novo Oligonucleotide Synthesis for Whole-Genome Synthesis and Data ... View original

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  Frontiers | Targeting Future Pandemics, a Case for De Novo Purine Synthesis and Basic Research View original

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• De novo synthesis pathway synthesizes nucleotides from simple precursor molecules like amino acids, carbon dioxide, and tetrahydrofolate derivatives
• Consists of a series of enzymatic reactions that build the purine or pyrimidine ring system step by step
• Energy-intensive process consumes a significant amount of ATP and GTP
• Salvage pathway recycles preformed nucleobases and nucleosides from the breakdown of nucleic acids and nucleotides
• Involves the attachment of a ribose-5-phosphate unit to a nucleobase using phosphoribosyltransferase enzymes (hypoxanthine-guanine phosphoribosyltransferase and adenine phosphoribosyltransferase)
• More energy-efficient than de novo synthesis as it bypasses the energy-consuming steps of ring synthesis

Key Enzymes in Nucleotide Biosynthesis

• Ribonucleotide reductase catalyzes the reduction of ribonucleotides to deoxyribonucleotides
• Essential for the synthesis of DNA precursors (dATP, dGTP, dCTP, and dTTP)
• Allosterically regulated by the binding of nucleoside triphosphates to ensure a balanced supply of dNTPs for DNA replication
• Nucleoside kinases phosphorylate nucleosides to form nucleoside monophosphates
• Includes adenosine kinase, guanosine kinase, cytidine kinase, and thymidine kinase
• Plays a crucial role in the salvage pathway by converting nucleosides to nucleotides

Purine and Pyrimidine Metabolism

Purine Metabolism

• Purine nucleotides (AMP and GMP) are synthesized de novo from phosphoribosyl pyrophosphate (PRPP) and amino acids (glycine, glutamine, and aspartate)
• Inosine monophosphate (IMP) is the first fully formed purine nucleotide and serves as a branch point for AMP and GMP synthesis
• Purine nucleotides are degraded to uric acid via a series of enzymatic reactions involving purine nucleoside phosphorylase, xanthine oxidase, and urate oxidase
• Uric acid is excreted in urine or further degraded to allantoin in some species (humans lack urate oxidase)

Pyrimidine Metabolism

• Pyrimidine nucleotides (CTP and UTP) are synthesized de novo from carbamoyl phosphate, aspartate, and PRPP
• Orotate is a key intermediate in the de novo synthesis of pyrimidines
• Pyrimidine nucleotides are degraded to β-alanine (from CTP and UTP) and β-aminoisobutyrate (from TTP) via a series of enzymatic reactions
• Phosphoribosyltransferases (orotate phosphoribosyltransferase and uracil phosphoribosyltransferase) catalyze the formation of pyrimidine nucleotides in the salvage pathway
• Nucleotidases (5'-nucleotidase and cytosolic 5'-nucleotidase) hydrolyze nucleoside monophosphates to nucleosides and inorganic phosphate, regulating nucleotide pool sizes

Disorders of Nucleotide Metabolism

Hyperuricemia and Gout

• Uric acid is the final product of purine degradation in humans
• Hyperuricemia refers to elevated blood uric acid levels (>6.8 mg/dL) due to increased production or decreased excretion of uric acid
• Can lead to the formation of uric acid crystals in joints, causing painful inflammation and swelling (gout)
• Risk factors for hyperuricemia and gout include genetics, high-purine diet (red meat, seafood, and alcohol), obesity, and certain medications (diuretics and cyclosporine)
• Treatment involves lifestyle modifications, anti-inflammatory drugs (NSAIDs and colchicine), and uric acid-lowering agents (allopurinol and febuxostat)

Other Disorders of Nucleotide Metabolism

• Lesch-Nyhan syndrome is a rare X-linked disorder caused by a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
• Characterized by hyperuricemia, neurological abnormalities (dystonia and self-mutilating behavior), and intellectual disability
• Orotic aciduria is an autosomal recessive disorder caused by defects in the de novo synthesis of pyrimidines
• Results in the accumulation of orotic acid in urine and can lead to megaloblastic anemia and growth retardation