Amino acids

Amino acids

Structure

  • Consists of a carbon atom attached to a/an:
    • Carboxyl group (-COOH)
    • Hydrogen atom
    • Amino group (-NH2)
    • Variable R group (side chain): determines unique properties
  • Only L-form amino acids are incorporated into proteins.
  • There are 20 standard proteinogenic amino acids in humans.

Properties

Essential vs. nonessential and catabolic product

Group Catabolic product Amino acid

Essential amino acids: cannot be synthesized (must be consumed)

  • Leucine
  • Lysine
  • Phenylalanine
  • Isoleucine
  • Threonine
  • Tryptophan
  • Methionine
  • Valine
  • Arginine*
  • Histidine*
Nonessential amino acids: can be synthesized
  • Alanine
  • Asparagine
  • Aspartate
  • Glutamate
  • Glutamine
  • Glycine
  • Proline
  • Serine
  • Cysteine**
  • Tyrosine**
Conditional amino acids

*AAs that may become essential (thus require supplementation) during times of increased demand (e.g., during illness, growth phases like pregnancy or childhood)

**AAs that are synthesized from essential AAs

Hydrophobic and hydrophilic

  • During protein folding, hydrophobic AAs normally settle within the protein core and hydrophilic AAs are on the surface.
  • Hydrophobic AA R groups are nonpolar.
    • Aromatic: Phe, Trp
    • Aliphatic: Gly, Ala, Met, Pro, branched chain AAs (Val, Leu, Iso)
  • Hydrophilic AA R groups are polar.
    • Uncharged: Tyr, Ser, Thr, Cys, Asn, Gln
    • Charged: Asp, Glu, Arg, Lys, His

Acid-base properties

  • Overview
    • The net charge and thus polarity of AAs can change according to the surrounding pH and availability of H+ available for protonation.
    • All AAs have at least two ionizable groups, each with its own acid dissociation constant (pKa).
      • pKa of the α-carboxyl group = 2
      • pKa of the α-amino group = 9–10
    • Acidic/basic AAs have another pKa for their ionizable side chain group, which varies.
  • Acidic amino acids: Side groups are negatively charged at body pH (both have a pKa of ∼ 4).
    • Asp
    • Glu

Aspidic glue!

  • Basic amino acids
    • Weakly basic: Side group has no charge at body pH (∼ 7.4).
      • His: pKa of 6
    • Side groups are positively charged at body pH.
      • Lys: pKa of 10.5
      • Arg: pKa of 12.5

His basic lies argitate me

Amino acid derivatives

Catabolism of amino acids

Overview of amino acid catabolism

Biochemical reactions of amino acid metabolism

Transamination

Since it is involved in most transamination reactions, glutamate is a very important part of AA metabolism.

Deamination

  • Description: reaction in which an amino group from an AA is released as ammonium
  • Examples: of enzymes with their reactions

Glutamate dehydrogenase can use either NAD+ or NADP+ as a cofactor.

Decarboxylation

  • Description: release of the α-carboxyl group of an AA via splitting of CO2
  • Examples: : synthesis of biogenic amines via L-amino acid decarboxylase (also known as DOPA decarboxylase, tryptophan decarboxylase, and 5-hydroxytryptophan decarboxylase), which also uses PLP

Catabolism of the carbon skeleton of amino acids

Overview AA carbon skeleton metabolism

There are 3 different routes for catabolism of the carbon skeleton, depending on the AA.

Metabolism routes Amino acids
Glucogenic amino acids
  • Alanine
  • Asparagine
  • Aspartate
  • Glutamate
  • Glutamine
  • Glycine
  • Proline
  • Serine
  • Cysteine
Mixed glucogenic/ketogenic amino acids
  • Phenylalanine
  • Isoleucine
  • Threonine
  • Tryptophan
  • Tyrosine
Ketogenic amino acids
  • Lysine
  • Leucine

Routes of AA carbon skeleton metabolism

  1. Glucogenic amino acids
  2. Ketogenic amino acids: lysine and leucine are metabolized to acetyl-CoA, then either:
  3. Mixed gluconeogenic/ketogenic amino acids: metabolized to acetyl-CoA and glucogenic byproducts (fumarate, succinyl-CoA)

Lysine and leucine are the only pure ketogenic AAs.

References:[1]

Urea cycle

  • Description:
    • A cycle of reactions that produce urea ((NH2)2CO) from ammonia (NH3), bicarbonate (HCO3), and the amino group of aspartate.
    • Enables the excretion of nitrogen (in urine)
    • Primarily occurs in the cytosol and mitochondria of liver cells, also in kidney cells
    • Requires 3 ATP for energy
    • Measured as blood urea nitrogen (BUN) for clinical use
  • Origin of ammonia: Ammonia develops as a product of various metabolic pathways throughout the body.
Urea cycle reactions
Reaction Substrate Enzyme (+ site of reaction) Product(s) Special features
1. Entering the urea cycle: creation of carbamoyl phosphate from HCO3 and NH3
  • HCO3
  • NH3
  • Carbamoyl phosphate
  • Rate-limiting step!
  • 2 ATP → 2 ADP + phosphate
  • CPS1 is activated by N-acetylglutamate
    • ↑ AA catabolism → ↑ glutamate (+ acetyl-CoA) → ↑ N-acetylglutamate → ↑ CPS1 activity → ↑ urea production
    • Synthesis of N-acetylglutamate is also activated by arginine, which has higher concentrations after eating protein.

2. Creation of citrulline from carbamoyl phosphate and ornithine

  • Carbamoyl phosphate
  • Ornithine
  • Citrulline
3. Creation of argininosuccinate from citrulline and aspartate
  • Argininosuccinate
  • ATPAMP + 2 phosphate
  • Aspartate “donates” its amino group
4. Hydrolysis of argininosuccinate to arginine and fumarate
  • Argininosuccinate
5. Hydrolysis of arginine to urea and ornithine
  • Arginine
  • H2O
  • Urea enters the bloodstream
  • Ornithine is transferred back into the mitochondria

The rate-limiting step of the urea cycle involves CPS1.

The mitochondrial carbamoyl phosphate synthetase 1 of the urea cycle should not be confused with the cytosolic carbamoyl phosphate synthetase 2, which is an important enzyme for pyrimidine synthesis!

From urea, one NH2 group is provided by NH4+ from carbamoyl phosphate, one NH2 group is provided by aspartate, and the -C=O group comes from bicarbonate!

Do not confuse urea with uric acid from purine metabolism!

Synthesis of nonessential amino acids

Overview of nonessential AA synthesis

Amino acids

Development from Responsible enzyme(s)
Glutamate
Glutamine
  • Glutamate through ATP-dependent attachment of an amino group from ammonia
Aspartate
Asparagine
  • Aspartate after the transfer of an amino group from glutamine
Arginine and Proline
  • Reversal of the degradation reaction of glutamate
Cysteine
  • Homocysteine and serine via splitting of α-ketobutyrate (in 2 steps)
Serine
  • 3-phosphoglycerate (in multiple steps)
Glycine
  • PLP-dependent demethylation of serine: Serine + THFGlycine + N5,N10-Methylene-THF + H2O
Alanine

Conditions associated with amino acid metabolism

  • 1. Anand CV, Anand U. Text book error: Threonine is ketogenic too. Biochem Educ. 1992; 20(3): pp. 183–184. doi: 10.1016/0307-4412(92)90073-U.
last updated 11/20/2018
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