10.3 Urea cycle and nitrogen excretion in animals

The urea cycle is a crucial process in nitrogen metabolism, converting toxic ammonia into urea for safe excretion. It's a complex series of reactions occurring in the liver, involving both mitochondrial and cytosolic enzymes. This cycle is vital for maintaining nitrogen balance in the body.

Animals have evolved different strategies for nitrogen excretion based on their environments. While aquatic animals can directly excrete ammonia, terrestrial animals use the urea cycle or produce uric acid to conserve water. These adaptations showcase the diverse ways organisms handle nitrogen waste.

The Urea Cycle: Nitrogen Excretion in Animals

Urea Cycle Overview and Function

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• Urea cycle (ornithine cycle) removes excess nitrogen from the body in mammals and some aquatic animals
• Converts toxic ammonia into less toxic, water-soluble urea for excretion in urine
• Maintains nitrogen balance and prevents ammonia toxicity which causes severe neurological damage
• Involves five enzymatic reactions (two in mitochondria, three in cytosol)
• Links to other metabolic pathways (amino acid catabolism and citric acid cycle)
• Net reaction consumes three ATP molecules and produces one urea molecule from two ammonia molecules and one bicarbonate molecule
  • Balanced equation: $2 NH_3 + CO_2 + 3 ATP \rightarrow H_2N-CO-NH_2 + 2 ADP + AMP + 2 P_i + PP_i$

Cycle Reactions and Cellular Localization

• Mitochondrial reactions
  • Carbamoyl phosphate formation from ammonia and bicarbonate
  • Citrulline formation from carbamoyl phosphate and ornithine
• Cytosolic reactions
  • Argininosuccinate formation from citrulline and aspartate
  • Arginine formation from argininosuccinate (releases fumarate)
  • Urea formation from arginine hydrolysis (regenerates ornithine)
• Cycle completion regenerates ornithine for continued ammonia detoxification
• Interconnection with citric acid cycle through fumarate production

Key Enzymes and Intermediates of the Urea Cycle

Enzymes and Their Functions

• Carbamoyl phosphate synthetase I (CPS I) catalyzes first, rate-limiting step
  • Converts ammonia and bicarbonate to carbamoyl phosphate
  • Requires N-acetylglutamate (NAG) as allosteric activator
• Ornithine transcarbamylase (OTC) catalyzes reaction between carbamoyl phosphate and ornithine
  • Forms citrulline
• Argininosuccinate synthetase (ASS) catalyzes formation of argininosuccinate
  • Combines citrulline and aspartate
• Argininosuccinase (ASL) cleaves argininosuccinate
  • Produces arginine and fumarate
• Arginase catalyzes final step
  • Hydrolyzes arginine to form urea and regenerate ornithine

Key Intermediates and Regulatory Molecules

• Carbamoyl phosphate initiates cycle
  • High-energy compound formed from ammonia and bicarbonate
• Ornithine acts as cycle carrier
  • Regenerated in final step for continued ammonia detoxification
• Citrulline first urea precursor formed in mitochondria
  • Transported to cytosol for further reactions
• Argininosuccinate links urea cycle to aspartate metabolism
  • Incorporates second nitrogen atom into urea molecule
• Arginine immediate precursor of urea
  • Hydrolyzed by arginase to produce urea
• N-acetylglutamate (NAG) essential allosteric activator of CPS I
  • Regulates entry of nitrogen into cycle
  • Synthesized by N-acetylglutamate synthase (NAGS) from glutamate and acetyl-CoA

Regulation of the Urea Cycle by Dietary Protein

Substrate Availability and Allosteric Modulation

• Urea cycle regulated primarily by substrate availability and allosteric modulation
• N-acetylglutamate synthase (NAGS) produces NAG
  • Activates CPS I in response to increased amino acid catabolism
• Increased protein intake elevates amino acid catabolism
  • Results in higher ammonia levels and increased urea cycle activity
• Urea cycle enzyme activities coordinated with amino acid-catabolizing enzymes
  • Maintains overall nitrogen balance in body

Hormonal and Dietary Influences

• Glucagon and glucocorticoids upregulate urea cycle enzyme expression
  • Occurs during periods of increased protein catabolism (fasting, stress)
• Insulin suppresses urea cycle activity
  • Happens during periods of protein synthesis and anabolism (after meals)
• Long-term adaptation to high-protein diets involves
  • Increased expression of urea cycle enzymes (CPS I, OTC, ASS, ASL, arginase)
  • Upregulation of amino acid transporters in liver cells
• Protein-restricted diets lead to decreased urea cycle enzyme expression
  • Conserves nitrogen for essential protein synthesis

Nitrogen Excretion Strategies: Animal Groups Compared

Ammonotelism and Ureotelism

• Ammonotelism involves direct excretion of ammonia
  • Primarily used by aquatic animals (most fish, aquatic invertebrates)
  • Requires high water availability for dilution of toxic ammonia
  • Energy-efficient but limited to aquatic environments
• Ureotelism converts ammonia to urea through urea cycle
  • Used by mammals, amphibians, and some fish (sharks, coelacanths)
  • Allows for less toxic nitrogen excretion in water-limited environments
  • Requires more energy than ammonotelism but conserves water

Uricotelism and Adaptive Strategies

• Uricotelism involves excretion of uric acid
  • Used by birds, reptiles, and insects
  • Allows for significant water conservation in terrestrial environments
  • Highest energy cost among nitrogen excretion strategies
• Choice of excretion strategy influenced by
  • Habitat (aquatic vs. terrestrial)
  • Water availability (abundant vs. scarce)
  • Evolutionary history (ancestral adaptations)
• Some animals switch between excretion strategies
  • Amphibians use ammonotelism as aquatic larvae, ureotelism as terrestrial adults
  • Certain fish species adapt excretion based on environmental salinity
• Energy cost increases from ammonotelism to ureotelism to uricotelism
  • Reflects increasing metabolic complexity of each strategy
• Adaptations in kidney function and excretory organs accompany different strategies
  • Maintain osmotic balance
  • Conserve water in terrestrial environments (loop of Henle in mammalian kidneys)