Nitrogen Recycling

Enzymes in Glutamine-TCA Flux

Glutaminase (GLS)
Anaplerosis

Glutamine Synthetase (GS)
Cataplerosis

Glutamine flux through the TCA cycle involves two key opposing processes, anaplerosis (filling up intermediates) and cataplerosis (drawing out intermediates), which are primarily regulated by the enzymes glutaminase (GLS) and glutamine synthetase (GS).

This relationship is defined by the balance between anaplerosis (filling) and cataplerosis (emptying), mediated by key enzymes that facilitate nitrogen recycling and carbon flux.

Anaplerosis: The process of replenishing TCA cycle intermediates. Glutamine is a primary anaplerotic substrate, especially in proliferating cells. It enters the cycle as (\alpha )-ketoglutarate ((\alpha )-KG).Cataplerosis: The removal of TCA cycle intermediates to fuel biosynthesis (e.g., lipids, amino acids, and nucleotides).

Anaplerosis replenishes TCA cycle intermediates, crucial for biosynthesis, often using glutamine (via glutaminase to glutamate, then α-ketoglutarate) or pyruvate (via pyruvate carboxylase to oxaloacetate). Glutamine synthetase (GS) is vital for cataplerosis, converting glutamate back to glutamine, balancing the cycle, and fueling nucleotide/protein synthesis.

Anaplerosis: Reactions that replenish TCA cycle intermediates (like OAA, α-KG) that are siphoned off for biosynthesis (amino acids, lipids, nucleotides).

Glutamine Metabolism: Glutamine (Gln) provides both carbon and nitrogen.

Glutaminase (GLS): Converts Gln to glutamate (Glu).

Glutamine Synthetase (GS): Converts Glu to Gln, a key step in recycling nitrogen and supporting biosynthesis (cataplerosis).

Nitrogen Recycling (Cataplerosis): When cells need to build proteins or nucleotides, they use TCA intermediates. To maintain TCA levels and nitrogen balance, GS converts glutamate back to glutamine, effectively removing carbon/nitrogen from the cycle and directing it to biosynthesis (e.g., purines).

Glutamine synthetase (GS) is the central enzyme linking nitrogen recycling and anaplerosis by regulating the synthesis of glutamine from ammonia and glutamate. This process is critical for maintaining nitrogen homeostasis and fueling the Tricarboxylic Acid (TCA) cycle in various organisms, including humans and plants.

Cancer Metabolism: Many cancers, such as pancreatic ductal adenocarcinoma (PDAC) and glioblastoma, upregulate GS to sustain growth in nutrient-poor environments by recycling internal nitrogen.

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Nitrification (Ammonia to Nitrite): Ammonia-oxidizing bacteria (like Nitrosomonas) convert ammonia into nitrite, a toxic intermediate.

Nitrification (Nitrite to Nitrate): Nitrite-oxidizing bacteria (like Nitrospira) convert nitrite into nitrate.

Assimilation: Plants absorb nitrate (or ammonium) from the soil and use it to build organic molecules, including amino acids, proteins, and DNA.

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In ruminant digestion, the nitrogen from sources like nitrates in grass is converted to ammonia in the rumen (the first stomach compartment) by microbes. These microbes then use the ammonia, along with energy, to synthesize their own amino acids and microbial protein.