Chapter 30 - Amino Acid Degradation and the Urea Cycle

What are the metabolic challenges in storing amino acids?

Cells do not have a mechanism for it

• Excess nitrogen is toxic

• Side chains are chemical diverse

Where are excess amino acids degraded?

Primarily in the liver

• branched chain AA are an exception, they are used as an energy source in muscle

Nitrogen is the first step in degrading AA

How is nitrogen removed while degrading an AA?

Enzymes remove it to generate a-keto acids

• Aminotransferases (transaminases)

• Dehydrogenase (glutamate)

• Dehydratase (serine and threonine)

transaminations are reversible

What do aminotransferases do?

• Usually transfer NH3 to a-ketoglutarate to make glutamate

  • NH3 then removed producing NH4+ and a-ketoglutarate

What does alanine aminotransferase do?

• Converts alanine to pyruvate

  • reversible

What does aspartate aminotransferase do?

• Converts aspartate to oxaloacetate

  • reversible

How is ammonium (NH4) produced?

Excess nitrogen gets converted to ammonium in the mitochondria

• deamination of most AA results in production of glutamate

• Nitrogen in glutamate is released as NH4 by glutamate dehydrogenase

  • requires NAD/NADP

  • occurs in the liver mitochondria

  • GD responds to energy charge

    • ATP/GTP inhibiting

    • ADP/GDP activating

What is the glucose alanine cycle?

Because branched chains: Leu, Val, Ile are used for fuel in muscle tissue

• cannot assimilate nitrogen in muscle

• gets transported to the liver

What does glutamine synthetase do?

Converts NH4 and glutamate to glutamine

• glutamine gets transported to the liver and is processed to urea

An overview of the urea cycle

Most terrestrial vertebrates dispose of excess NH4 using urea

• Urea is made from

  • Free ammonium (NH4)

  • Bicarbonate (HCO3)

  • Aspartate (source of NH3)

cycle beings in mitochondria, with CPS I combing with NH4 and bicarbonate

What happens when CPS I combines with NH4 and bicarbonate in the mitochondria?

• Product is carbamoyl phosphate

• Requires hydrolysis of two ATP molecules

  • makes it irreversible

• carbamoyl phosphate is transferred to ornithine, creating citrulline

  • O and C → noncanonical AA, not apart of genetic code

What happens are citrulline is created?

It gets transported to cytoplasm in exchange for ornithine

• arginosuccinate synthetase combines citrulline and aspartate

  • ATP cleaved to AMP

  • driven via hydrolysis of PPi

• arginosuccinase then produces arginine and fumarate

What happens to the arginine that arginosuccinase creates?

Gets cleaved by arginase to make urea and ornithine

• regenerates ornithine used in condensation with carbamoyl phosphate

• transported into mitochondria in exchange for citrulline

What are the energetics of nitrogen removal?

Incorporation of two NH4, including aspartate, in urea costs four phosphate bonds

• three ATP converted into two ADP and one AMP

fumata can enter CTA for conversion into oxaloacetate

• then the oxaloacetate can be converted to glucose for gluconeogenesis

• or converted into aspartate by transamination

What happens to the carbon skeletons?

Can be processed ito metabolic intermediates

• pyruvate

• acetyl CoA

• a-ketoglutarate

• Succinyl CoA

• Fumarate

• Oxaloacetate

some can be used to make glucose

What happens if there is direct conversion of AA?

Action of an aminotransferase leads directly to usable intermediates

• Alaine aminotransferase converts alanine to pyruvate

• Aspartate aminotransferase converts aspartate to oxaloacetate

products can be used in general carbon metabolism

remember, transaminations are readily reversible

What can three carbon AAs and tryptophan can used for?

To generate pyruvate

What can some five carbon AA be converted into?

Converted into glutamate

• glutamate then converted into a-ketoglutarate for entry into TCA

• conversion of histidine requires tetrahydrofolate cofactor from folic acid

What happens to branched AA in muscle tissue?

Get degraded into acetyl CoA, acetoacetate, and succinyl CoA

• transamination forms a-ketoacid

• then the a-ketoacid is oxidatively decarboxylated

• isovaleryl CoA is formed then dehydrogenated

• the product is carboxylated at the cost of one ATP

• then that’s hydrated to form 3-hydroxy-3-methylglutary CoA

• which is then cleaved to produced acetyl CoA and acetoacetate

What happens when aromatic AA are degraded?

Requires molecular oxygen for ring breaking

• phenylalanine hydroxylase uses O2 to convert phenylalanine to tyrosine

  • which is then converted to acetoacetate and fumarate in 5 steps, using additional O2

What causes the defect phenylketonuria?

Defect in phenylalanine hydroxylase, the conversion to tyrosine