Amino Acid Metabolism

Amino acid degradation

• Glucogenic amino acids give rise to pyruvate and Krebs cycle intermediates.
• Ketogenic amino acids give rise to acetoacetate and acetyl-CoA.

• Amino acid	Pyr	Kreb	Acac	CoA
  Threonine	X			X
  Glycine	X
  Serine	X
  Alanine	X
  Cysteine	X
  Tryptophan	X		X	X
  Leucine			X	X
  Lysine			X	X
  Isoleucine		S		X
  Histidine		K
  Glutamine		K
  Glutamate		K
  Arginine		K
  Proline		K
  Methionine		S
  Valine		S
  Phenylalanine		F	X
  Tyrosine		F	X
  Asparagine		O
  Aspartate		F/O

  
  Key: Pyr = Pyruvate, Kreb = Krebs cycle intermediate, Acac = Acetoacetate, CoA = Acetyl-CoA, X = yes, K = αKG, S = Succinyl-CoA, F = Fumarate, O = Oxaloacetate

  Deamination of N-terminal Amine

  • Aminotransferase
    • Takes N-terminal amine of amino acid and places it on αKG to make glutamate. Aka. Transamination.
    • Requires PLP (pyridoxal-5-phosphate), which is derived from pyridoxine (vitamin B₆).
  • Glucose-alanine cycle
    • Amino acids in muscle passes amino group to alanine, which travels to liver and passes the amino group on to glutamate.
  • Glutamate dehydrogenase
    • Accepts either NAD⁺ or NADP⁺.
    • Activated by NAD⁺, ADP, Leucine.
    • Inhibited by NADH, GTP.
    • HI/HA = Hyperinsulinism/Hyperammonemia = mutant GDH too active lead to too much ammonia and αKG, which feed into Krebs cycle increasing oxidative phosphorylation, which lead to increased insulin secretion, hence hypoglycemia.
  • Amino acid oxidase
    • Amino acid → NH₄⁺ + α-keto acid (uses FAD and H₂O)
  • Some amino acids are deaminated non-oxidatively (something other than α-keto acid results)

  Urea Cycle

  • What goes in: NH₄⁺ + HCO₃^- + Aspartate
  • What comes out: Urea + Fumarate
    • Urea gets one amino group from NH₄⁺, the other form aspartate, and the carbon atom from HCO₃^-. Fumarate is derived from the carbon skeleton of aspartate.
  • 3 ATP hydrolyzed: CPS converts 2ATP → 2ADP. AS Synthase converts ATP → AMP.
  • OTC deficiency: X-linked recessive deficiency in OTC, results in build up of carbamoyl phosphate, which is converted to orotic acid (found in blood and urine). Increased ammonia, decreased urea.

  Biosynthesis of amino acids

  Essential and Nonessential Amino Acids

  • Essential amino acids we can't make (or don't make in enough quantities). Plants and microorganisms can make these.
  • Nonessential amino acids we can make.

  • Essential	Nonessential	Derived from
    Histidine		PRPP
    	Serine	3PG
    	Glycine	3PG
    	Cysteine	3PG
    Phenylalanine	Tyrosine	PEP
    Tryptophan		PEP
    Valine	Alanine	Pyruvate
    Leucine		Pyruvate
    Isoleucine		Pyruvate
    Arginine*	Glutamate	αKG
    	Glutamine	αKG
    	Proline	αKG
    Lysine	Aspartate	OA
    Methionine	Asparagine	OA
    Threonine		OA

    
    *We can make arginine in urea cycle, but we need more than we can make, so it's an essential amino acid.

  Nonessential Amino Acid Biosynthesis Pathways

  

  Diseases

  PKU

  
  
  

  Homocystinuria

  
  • Phenylketonuria (PKU): phenylketones (phenylacetate, phenyllactate, phenylpyruvate) in urine because phenylalanine can't be converted to tyrosine (faulty phenylalanine hydroxylase or tetrahydrobiopterin cofactor). Musty body odor, mental and growth retardation, seizures, fair skin (↑ phenylalanine inhibits tyrosine hydroxylation in melanine production), eczema. Maternal PKU causes birth defects and retardation. Treatment: intake tyrosine rather than phenylalanine. Autosomal recessive.
  • Alkaptonuria: homogentisic acid in urine, which turns dark on standing. Arthritis later on in life. Autosomal recessive. Pigmented sclera, dark connective tissue.
  • Homocystinuria: homocysteine (demethylated methionine) in urine. Tall, kyphosis, osteoporosis, lens subluxation, mental retardation and atherosclerosis.
    • Cystathionine synthase deficiency. Treatment: bypass enzyme by eating more cysteine, less methionine. Also eat more B₁₂.
    • Cystathionine synthase don't bind cofactor. Treatment: intake cofactor (B₆)
    • Homocysteine methyltransferase deficiency
  • Cystinuria: cystine (cysteine dimer) in urine because of defective PCT transport for cysteine, ornithine, lysine, and arginine. Cysteine kidney stones. Treat with acetazolamide. Autosomal recessive.
  • Maple syrup urine disease: urine smells like maple syrup because of build up of branched-chain α-keto acids (deficient Branched Chain α-Keto Acid Dehydrogenase / BCKDH). Disease causes CNS defects, mental retardation, and is fatal. Treat by diet low in branched amino acids.