Chapter 30: Protein Turnover and Amino Acid Catabolism

Main purpose of Chapter 30

Protein degradation and amino acid recycling.

Three big questions of the chapter

Which proteins are degraded, where nitrogen goes, what happens to carbon.

Main idea of protein degradation

Selective and regulatory, not random.

Why protein half-life matters

Controls pathway activity.

Example of short-lived protein

Ornithine decarboxylase (~11 min).

Example of long-lived protein

Lens crystallins (lifetime).

Main protein degradation system

Ubiquitin-proteasome system (UPS).

UPS steps

Tag → recognize → destroy → recycle.

Small protein used as tag

Ubiquitin.

Size of ubiquitin

76 amino acids.

Why ubiquitin is important

It acts as a signaling code.

Most important ubiquitin linkage

K48.

Meaning of K48 linkage

Proteasomal degradation.

Other important linkage

K63.

Meaning of K63 linkage

DNA repair and signaling.

Minimum ubiquitins for degradation

4 K48-linked ubiquitins.

Three enzymes in ubiquitination

E1, E2, E3.

Function of E1

Activates ubiquitin (uses ATP).

Function of E2

Carries ubiquitin.

Function of E3

Selects target protein.

Where specificity comes from

E3 ligases.

Bond attaching ubiquitin

Isopeptide bond.

N-end rule

First amino acid determines protein half-life.

Very unstable N-terminal residues

Arg, Lys, His, Phe, Tyr, Trp, Leu, Ile.

Stable N-terminal residues

Met, Gly, Ala, Ser, Thr.

Main protein destruction machine

26S proteasome.

Proteasome components

19S cap and 20S core.

Function of 19S cap

Recognizes, unfolds, and feeds protein.

Function of 20S core

Degrades protein into peptides.

Length of peptide products

~4–9 amino acids.

Clinical use of proteasome inhibitors

Cancer therapy (multiple myeloma).

Example drug

Bortezomib.

NF-κB regulation

IκB degraded → NF-κB activated.

Key idea of UPS signaling

Destroys inhibitors to activate pathways.

HIF-1α regulation

Degraded in normoxia, stable in hypoxia.

Why HIF-1α accumulates in hypoxia

No hydroxylation → no ubiquitination.

Main nitrogen removal process

Transamination and deamination.

Transamination reaction

AA + α-KG → α-keto acid + glutamate.

Cofactor for transamination

PLP (vitamin B6).

Nitrogen hub

Glutamate.

Oxidative deamination enzyme

Glutamate dehydrogenase.

Product of deamination

NH4+.

ALT function

Alanine aminotransferase.

AST function

Aspartate aminotransferase.

Clinical meaning of high AST/ALT

Liver damage.

Muscle nitrogen transport

Glucose-alanine cycle.

Alanine role

Transports nitrogen from muscle to liver.

Glutamine function

Safe nitrogen transport in blood.

Glutamine synthesis enzyme

Glutamine synthetase.

Urea cycle purpose

Convert toxic ammonia to urea.

Location of urea cycle

Liver.

Compartments of urea cycle

Mitochondria and cytosol.

Rate-limiting enzyme

CPS I.

CPS I reaction

NH4+ + HCO3- → carbamoyl phosphate.

Second enzyme

OTC.

OTC function

Citrulline formation.

Nitrogen sources in urea

NH4+ and aspartate.

Energy cost of urea cycle

3 ATP (4 high-energy bonds).

Connection to TCA cycle

Fumarate production.

Krebs bicycle

Urea cycle + TCA integration.

Hyperammonemia definition

High ammonia in blood.

Why ammonia is toxic

Causes brain swelling and excitotoxicity.

OTC deficiency result

Hyperammonemia + high orotic acid.

Inheritance of OTC deficiency

X-linked.

Treatment of urea cycle disorders

Nitrogen scavengers and diet.

7 entry points for amino acids

Pyruvate, Acetyl-CoA, Acetoacetyl-CoA, α-KG, Succinyl-CoA, Fumarate, OAA.

Glucogenic amino acids

Can form glucose.

Ketogenic amino acids

Form ketones/fat.

Purely ketogenic amino acids

Leucine and lysine.

Mixed amino acids

Ile, Phe, Thr, Trp, Tyr.

PKU enzyme defect

Phenylalanine hydroxylase.

PKU treatment

Low Phe diet + Tyr.

MSUD enzyme defect

BCKDC.

MSUD symptom

Maple syrup odor.

Alkaptonuria enzyme defect

Homogentisate oxidase.

Alkaptonuria symptom

Black urine.

Big idea of amino acid catabolism

Nitrogen is toxic, carbon is useful.