Nitrogen Metabolism Summary

Nitrogen Balance

  • Nitrogen intake vs. nitrogen loss.

    • Positive balance: intake > (greater) need (protein synthesis > degradation).

    • Negative balance: intake < need (lower) (protein synthesis < degradation).

  • Adults: generally in equilibrium.

  • Essential amino acids: PVT TIM HALL (Phe, Val, Thr, Trp, Iso, Met, His, Arg, Leu, Lys).

    • Arg is only essential in positive nitrogen balance.

Amino Acid Fate

  • Amino acids are either used for:

    • Biosynthesis of proteins.

    • Degradation into urea and carbon skeletons.

  • Carbon skeletons:

    • Energy production via pyruvate, acetyl CoA, etc.

    • Synthesis of purines, pyrimidines, porphyrins.

Deamination and Transamination

  • Deamination: Removal of nitrogen from amino acids (e.g., by asparaginase).

  • Transamination: Transfer of amino group to α-ketoglutarate, forming glutamate.

Ammonia Toxicity

  • Ammonia is toxic; normal levels are age-dependent (reference ranges provided).

  • Symptoms of high ammonia: confusion, delirium, coma, death.

  • Toxicity mechanism:

    • Depletion of α-ketoglutarate, reducing ATP production.

    • Increased glutamine, causing cell swelling.

    • Neurosignaling interference, free radical production.

Nitrogen Excretion

  • Ammonia excreted by the kidney, trapped in urine.

  • Urea: primary nitrogen excretion product (>95%).

    • Ureotelic: excrete urea (mammals).

    • Uricotelic: excrete uric acid (birds, insects).

    • Ammonotelic: excrete ammonium ion (fish).

Urea Cycle

  • First metabolic cycle discovered.

  • Converts ammonia to urea.

Urea Cycle Regulation

  • First step regulated by N-acetylglutamate, activated by arginine.

Diseases of Urea Cycle

  • Hereditary enzyme deficiencies lead to hyperammonemia.

  • Total enzyme lack is lethal.

  • Treatment: depends on deficient enzyme; may include alternate excretion routes, supplements, liver transplant.

  • Common deficiency: ornithine transcarbamoylase (OTC).

    • Treat with Na benzoate/phenylacetate to drive alternate nitrogen excretion.

Ammonia-Scavenging Medications

  • Benzoate and phenylacetate.

  • Promote excretion of nitrogen through alternative pathways.

Other Nitrogen Metabolism

  • Creatine.

  • Nitric oxide (NO).

  • Bases.

  • Neurotransmitters.

Creatine and Creatinine

  • Creatine synthesized from arginine and glycine; phosphorylated to phosphocreatine (energy store).

  • Creatinine: breakdown product of phosphocreatine, used to measure kidney function.

Nitric Oxide (NO)

  • Signaling molecule involved in various physiological processes.

  • Activates guanylyl cyclase, increasing cGMP.

  • Drugs like nitroglycerin and sildenafil (Viagra) increase vasodilation via NO.

Purine Synthesis

  • Complex pathway starting from α-D-Ribose 5-phosphate and utilizing glutamine, glycine, aspartate, and formyltetrahydrofolate.

Pyrimidine Synthesis

  • Involves carbamoyl phosphate, aspartate, and PRPP.

Uric Acid and Gout

  • Excess uric acid leads to gout.

  • Uric acid crystals accumulate in joints.

Monoamine Oxidase (MAO)

  • Involved in neurotransmitter breakdown (serotonin, dopamine).

  • Variations in MAO gene (VNTR) affect enzyme expression and aggression risk.

    • Reduced activity alleles linked to increased aggression.