Amino Acid Metabolism, Protein Degradation, and Urea Cycle Overview

One of the three metabolic circumstances when amino acids undergo oxidative degradation.

Normal protein turnover

One of the three metabolic circumstances when amino acids undergo oxidative degradation.

Starvation or uncontrolled diabetes

One of the three metabolic circumstances when amino acids undergo oxidative degradation.

Excess dietary protein

One of the three functions of protein degradation in cells.

Remove damaged or misfolded proteins

One of the three functions of protein degradation in cells.

Regulate levels of short-lived regulatory proteins

One of the three functions of protein degradation in cells.

Provide amino acids for energy or new protein synthesis

Occurs in the lysosome.

Chaperone-mediated autophagy (CMA)

Occurs during starvation.

CMA increase circumstances

The sequence motif that targets proteins for CMA.

KFERQ motif

The process by which proteins are selected for proteasomal degradation, usually involving 4+ ubiquitin molecules.

Polyubiquitination

Requires ATP for protein unfolding and translocation.

Proteasomal degradation

Acidic compartments with hydrolytic enzymes that degrade long-lived proteins and organelles.

Lysosomes

ATP-dependent protein complexes that degrade misfolded or short-lived proteins tagged with ubiquitin.

Proteasomes

The enzyme class that catalyzes transamination reactions.

Aminotransferases

The coenzyme required for transamination reactions, also known as pyridoxal phosphate or vitamin B6.

PLP

Alanine + α-ketoglutarate → pyruvate + glutamate.

ALT transamination reaction

Aspartate + α-ketoglutarate → oxaloacetate + glutamate.

AST transamination reaction

The enzyme that catalyzes oxidative deamination of glutamate.

Glutamate dehydrogenase

Glutamate + NAD⁺ → α-ketoglutarate + NH₃ + NADH.

Glutamate deamination reaction

To safely detoxify ammonia, which is toxic to the CNS.

Purpose of converting ammonia to urea

Two nitrogen groups are required to form one molecule of urea.

Nitrogen groups for urea

Carbamoyl phosphate (from NH₃) and aspartate.

Nitrogen delivery into the urea cycle

NH₃ + bicarbonate + 2 ATP.

Substrates for carbamoyl phosphate synthesis

Produces fumarate → enters TCA cycle → becomes malate → oxaloacetate (aspartate-argininosuccinate shunt).

Urea cycle connection to citric acid cycle

One that becomes pyruvate or TCA cycle intermediates → can enter gluconeogenesis to form glucose.

Glucogenic amino acid

One that becomes acetyl-CoA or acetoacetyl-CoA → forms ketone bodies or fatty acids.

Ketogenic amino acid

Enter TCA cycle → create ATP + serve as substrates for gluconeogenesis.

Glucogenic amino acids contribution to energy production

Become acetyl-CoA → enter TCA cycle or form ketone bodies (especially during starvation).

Ketogenic amino acids contribution to energy production

Indicates liver damage; these are transaminases that leak into blood when hepatocytes are injured.

Elevated ALT and AST

Leads to hyperammonemia — ammonia cannot be converted to urea.

Defective carbamoyl phosphate synthetase I (CPS-I)

Increases urea production as more amino groups must be removed from excess amino acids.

High-protein diet effect on urea production

Results in proteasomal degradation failure → accumulation of misfolded proteins → cell stress & dysfunction.

Failure to ubiquitinate proteins