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Nitrogen from amino acid ==> urea

  1. transamination w/alpha-ketoglutarate 
  2. oxidative deamination
  • One nitrogen of the urea molecule is supplied by free NH3  and enters the cycle and the other nitrogen is contributed by aspartate.
  • Most amino acids are ultimately funneled to glutamate by means of transamination with α-ketoglutarate.


Entry points for nitrogen into urea cycle

  • NH3 freed from glutamate by glutamate dehydrogenase results in a free NH3 + α ketoglutarate. That NH3 then enter the Urea cycle by combining with CO2 to make Carbamoyl phosphate.
  • The conversion of oxaloacetate to aspartate via transamination supplies the second NH3 for the cycle and enters after citrulline



Rate limiting step of nitrogen entry into urea cycle + regulation

  • Glutamate (Glutamate dehydrogenase) → α ketoglutarate + NH3
  • It is allosterically activated by ADP and GDP.
  • ATP and GTP are allosteric inhibitors of Glu dehydrogenase
  • energy levels are low in the cell, amino acid degradation (by glutamate dehydrogenase) is high, facilitating energy production from the aa carbon skeletons.



Characteristics of control points of urea cycle

  • Carbamoyl phosphate synthetase 1 (CPS1)
    • This is the committed step of the urea cycle.
  • N-acetyl glutamate allosterically  activates CPS1.
    • Arginine is an activator of N-acetylglutamate synthase which forms N-acetyl glutamate.
    • N-acetyl glutamate causes unknown structural change in CPS1 that pushes the reaction forward.



Characteristics of ammonia transport in blood

  • Glutamine carries 2 ammonia molecules through the blood.
    • Most tissues use glutamine synthetase to convert glutamate to glutamine for transport to the liver for entrance into the urea cycle.
  • Glucose-alanine cycle in muscles: allows for ammonia transport in blood as alanine, but it is minor.


Characteristics of glucogenic amino acids

  • Glucogenic: amino acids that can be used as substrates for gluconeogenesis → pyruvate or TCA intermediates
  • Example: Aspartate (aspartate transamination) → oxaloacetate → gluconeogeneis


Characteristics of ketogenic amino acids

  • Ketogenic: amino acids that produce no net production of glucose but instead are fed into TCA cycle for energy.
  • Lysine and leucine are the ketogenic amino acids since breakdown gives Acetyl-CoA  which is only 2 carbons.


Types of diseases related to nitrogen cycle/removal

  • urea cycle disorders (UCDs)
  • hyperammonemia
  • Maple Syrup Urine Disease (MSUD)


Characteristics of hyperammonemia

  • Disorder of elevated ammonia in the blood due to urea cycle enzyme defects
  • Leads to encephalopathy, coma, death


Characteristics of Maple Syrup Urine Disease

  • high concentration of branched amino acids
  • Branched amino acids including valine, isoleucine, and leucine are broken down first by deaminases to their α keto acid forms, then they are decarboxylated.
  • When there is decarboxylate deficiency, there is a buildup of α keto acids in the urine, which is sweet smelling.
  • Several genetic deficiencies have been observed, and this can be fatal if not treated.


Normal breakdown of branched amino acids

  • Valine →  α keto acid  →   Succinyl COA; (glucogenic)
  • Isoleucine   →  α keto acid  →  Acetyl COA / Succinyl COA (ketogenic + glucogenic)
  • Leucine →  α keto acid  → Acetyl CoA → (ketogenic)


Production of thyroxin

  • Thyroglobulin in the thyroid gland has ~140 tyrosines of which only 2-5 are iodinated
  • By cleaving off one of the iodinated tyrosines we can then develop T3/T4.
  • T4 (Thyroxin) is produced from tyrosine
    • Thyroid stimulating hormone (TSH) stimulated iodide uptake and release of T3/T4
    • Thyroid peroxidase oxidizes I- to I2


Thyroxin modification and release

  • T4 (deiodinase) → T3, which is a more active form of Thyroxin and  has 1 less iodine
  • T4 and T3 are transported from thyroid through blood via thyroxin binding globulin (TBG)


Characteristics of heme metabolism

  • Heme metabolism: Pyrole → Bilirubin → Porphyrin (Heme)
  • Heme is produced in liver → part of production is in cytosol, part in mitochondria
  • Four pyrole rings are put together in a cyclic formation
  • Final step in producing heme is the iron addition step with the enzyme ferrochelatase


Porphyrin definition

Porphyrins are cyclic molecules that bind metals


Regulation of porphyrin production

  • Porphyrin production is regulated by end product inhibition, as well as unnatural causes such as lead poisoining.
  • Lead poisoining ==> lead displaces iron or zinc in two important reactions in heme production


Poryphyrias definition

inherited defects in heme synthesis