BICH441 Exam Notes

Course Introduction and Introduction to Metabolism

  • Course Introduction and Introduction to Metabolism (Chapter 14)
  • Glycolysis (Chapter 15)
  • Gluconeogenesis and Glycogen Metabolism (Chapter 16)
  • Pentose Phosphate Pathway (Chapter 15)
  • Citric Acid Cycle (Chapter 17)
  • Electron Transport Chain and Oxidative Phosphorylation (Chapter 18)
  • Photosynthesis (Chapter 19)
  • Lipid Metabolism (Chapter 20)
  • Amino Acid Metabolism (Chapter 21)
  • Nucleotide Metabolism (Chapter 23)
  • Metabolic Integration and Organ Specialization (Chapter 22)

Essential and Nonessential Amino Acids

  • Humans can synthesize only 10 of the 20 common amino acids.
  • Essential Amino Acids:
    • Arginine*
    • Histidine*
    • Isoleucine
    • Leucine
    • Lysine
    • Methionine
    • Phenylalanine
    • Threonine
    • Tryptophan
    • Valine
    • Tyrosine*
  • Nonessential Amino Acids:
    • Alanine
    • Asparagine
    • Aspartate
    • Cysteine
    • Glutamate
    • Glutamine
    • Glycine
    • Proline
    • Serine
  • *Arginine and Histidine are conditionally essential. Tyrosine can be synthesized from phenylalanine.

Amino Group Derivation and Transamination

  • Amino groups for amino acids are derived from glutamate in transamination reactions.
  • Glutamate-dependent transamination of α-keto acid carbon skeletons is a primary mechanism for amino acid synthesis.

Amino Acid Families

  • Amino acids are grouped into families according to the metabolic intermediates that serve as their progenitors.
  • α-Ketoglutarate Family:
    • Glutamate
    • Glutamine
    • Proline
    • Arginine
    • Lysine*
  • Oxaloacetate Family:
    • Aspartate
    • Asparagine
    • Methionine
    • Threonine
    • Isoleucine
    • Lysine*
  • Pyruvate Family:
    • Alanine
    • Valine
    • Leucine
  • 3-Phosphoglycerate Family:
    • Serine
    • Glycine
    • Cysteine
  • Phosphoenolpyruvate and Erythrose-4-P Family:
    • Phenylalanine
    • Tyrosine
    • Tryptophan
  • Histidine is derived from PRPP (5-phosphoribosyl-1-pyrophosphate) and ATP.
  • *Different organisms use different precursors to synthesize lysine.

Aspartate Biosynthesis

  • Aspartate biosynthesis occurs via transamination of oxaloacetate by glutamate.
  • The oxaloacetate family of amino acids includes Asp, Asn, Met, Thr, and Iso.

Alanine Biosynthesis

  • The pyruvate family of amino acids includes Val, Ala, and Leu.
  • Transamination of pyruvate, with glutamate as amino donor, gives Ala.
  • Pyruvate+Glutamate→Alanine+α−KetoglutaratePyruvate + Glutamate \rightarrow Alanine + α-Ketoglutarate

Serine Biosynthesis

  • 3-Phosphoglycerate dehydrogenase (1), an NAD+NAD^+ -dependent enzyme, diverts 3-phosphoglycerate from glycolysis, yielding 3-phosphohydroxpyruvate.
  • The 3-phosphoglycerate family of amino acids includes Ser, Cys, and Gly.

Serine Biosynthesis Steps

  • Transamination of 3-phosphohydroxypyruvate by glutamate gives 3-phosphoserine (2).
  • Serine phosphatase (3) then generates serine.

Nitrogen Excretion

  • NH4+NH_4^+ is toxic, leading to lethargy and retardation.
  • Organisms excrete excess NH4+NH_4^+.
    • Fish
    • Mammals
    • Birds and reptiles

Urea Cycle

  • Overview of the Urea Cycle:
    • Ammonia is converted to urea for excretion.
    • Occurs in the liver.
    • Linked to the TCA cycle by fumarate.

Urea Cycle Enzymes

  • Carbamoyl P synthase I:
    • 2ATP+HCO<em>3−+NH</em>3→carbamoylP+2ADP+2Pi2ATP + HCO<em>3^- + NH</em>3 \rightarrow carbamoyl P + 2ADP + 2Pi
    • (Note: CPSII is different)
  • Ornithine transcarboxylase:
    • carbamoyl P + ornithine → citrulline
  • Arginosuccinate synthase:
    • Citrulline + Asp → arginosuccinate
  • Argininosuccinase:
    • Arginosuccinate → Arg + fumarate
  • Arginase:
    • Arginine → urea + ornithine

Metabolic Roles of Ornithine

  • Serves as a precursor to arginine.
  • Functions as an intermediate in the Urea cycle.
  • Acts as an intermediate in arginine degradation.
  • The urea cycle acts to excrete excess N through Arg breakdown.
  • Breakdown of Arg in the urea cycle releases two N and one C as urea.
  • Important N excretion mechanism in livers of terrestrial vertebrates.
  • Urea cycle is linked to TCA by fumarate.

Amino Acid Catabolism and Energy Production

  • Amino acids from protein provide only ~10% energy (Rest 90% comes from carbs and fats).
  • Dietary amount of free amino acids is negligible in most cases.
  • Protein degradation can be an important source of energy during starvation or during a defect in carbohydrate metabolism (diabetes mellitus).
  • The 20 common amino acids are degraded by 20 different pathways to produce just 7 metabolic intermediates.

Common Amino Acid Degradation Products

  • Amino acids can be gluconeogenic (→ glucose) or ketogenic (→ acetyl CoA) or both.

Degradation of Branched-Chain Amino Acids

  • Valine, leucine, and isoleucine are degraded not only in the liver, but also in adipose tissue and skeletal muscle.
  • The first three reactions are identical:
    • Transamination
    • Oxidative decarboxylation
    • Dehydrogenation
  • Hereditary defects in the branched chain α-keto acid dehydrogenase (BCKDH) causes maple syrup urine disease.
  • Maple syrup urine disease causes mental retardation and is fatal unless branched-chain amino acid intake is restricted.

Common Pathway

  • The first three steps for degradation of Val, Ile, and Leu follow a common pathway.

Ketogenic Amino Acids

  • Leucine and Lysine are two purely ketogenic amino acids that are degraded into acetoacetate.

Phenylalanine and Tyrosine Degradation

  • Phenylalanine and tyrosine are degraded to acetoacetate and fumarate.
  • The first reaction in phenylalanine degradation is the hydroxylation reaction of tyrosine biosynthesis.
  • Both these amino acids share a common degradative pathway.
  • Transamination of Tyr yields p-hydroxyphenylpyruvate.
  • A vitamin C-dependent dioxygenase then produces homogentisate.
  • Ring opening and isomerization gives 4-fumaryl-acetoacetate, which is hydrolyzed to acetoacetate and fumarate.

Phenylketonuria (PKU)

  • Phenylalanine tyrosine phenylpyruvate TCA cycle
  • Phehydroxylase+αKGGluXPhe hydroxylase + αKG Glu X
  • Phenyl Ketone Uria
    • Normally a minor product, it accumulates in PKU.
    • Mental retardation unless a low Phe diet is followed.

Phenylketonuria (PKU) cont.

  • The urine of phenylketonurics contains excessive amounts of phenylpyruvate due to a deficiency of phenylalanine hydroxylase.
  • In such individuals, the excess Phe that accumulates is transaminated to phenylpyruvate.
  • Phenylketonurics must be placed on a low phenylalanine diet immediately after birth to avoid severe mental retardation.
  • Hereditary defects in Phe catabolism underlie phenylketonuria.

Phenylalanine and Tyrosine Degradation (Recap)

  • Phenylalanine and tyrosine are degraded to acetoacetate and fumarate.

Alkaptonuria

  • Hereditary defects in Phe/Tyr catabolism underlie alkaptonuria.
  • Alkaptonuria and phenylketonuria are two human genetic diseases arising from specific enzyme defects in Phe degradation.
  • Alkaptonuria is characterized by urinary excretion of large amounts of homogentisate and results from a deficiency in homogentisate dioxygenase.
  • Air oxidation of homogentisate causes urine to turn dark on standing.
  • Patients with Alkaptonuria have a tendency for arthritis later in life.