Amino acid catabolism

- During times of starvation, amino acids are used to replenish TCA cycle intermediates and as precursors for gluconeogenesis

- Organisms with a diet rich in proteins can oxidize excess amino acids as fuels

- Amino acids are not stored

- In animals, amino acids (in the form of polypeptides) are the major source of nitrogen.

- What is the key difference between amino acids and the other 2 types of oxidizable molecules?

Transamination (in liver):

Universal amino group acceptor

PLP : pyridoxal phosphate

Deamination (oxidative deamination) - in liver:

Dehydrogenation (oxidation)

deamination

Transamination + Deamination = Transdeamination

urea

Glutamate Dehydrogenase

How do non-hepatic tissues remove ammonia?

Amino group

Amide group

Transport of glutamine to liver:

Removal of excess ammonia from muscle

The Urea Cycle In liver cells:

Formation of carbomoyl phosphate

Argininosuccinate synthase reaction:

Transamination

Lyase

Arginase

Links between the urea cycle and the TCA cycle

Cytosolic fumarase

transamination

fumarase

OAA

“Kreb Bicycle”

Oxidation of the carbon skeletons in amino acids

Amino acids giving rise to -ketoglutarate: Glutamate, Glutamine, Histidine

Histidine ammonia lyase

Methyl group transfer

(oxidative deamination)

Amino acids giving rise to -ketoglutarate: Arginine and Proline

α-Ketoglutarate

Aspartate and Asparagine

(Asp)

(Asn)

aspartate aminotransferase

Amino acids giving rise to oxaloacetate:

asparaginase

Amino acids giving rise to pyruvate: Cysteine, tryptophan, threonine, serine, glycine and alanine

pyruvate

glutamate α-ketoglutarate

5, 10-Methylene THF

THF

H2O

Amino acids giving rise to succinyl-CoA: Methionine, threonine

Succinyl-CoA

Cystathionine

α-Ketobutyrate

dehydrogenase

Propionyl-CoA + CO2

NAD+ NADH

Branched chain amino acid (BCAA) catabolism: Valine, Isoleucine, Leucine

Aromatic amino acid metabolism: Phenylalanine and tyrosine

Phenylalanine hydroxylase

O2 H2O

NAD+ NADH + H+

X

Phenylketonuria (1 in 10,000 newborns)

CH2

COO-

Phenylacetate

CH2

CH

COO-

HO

Phenyllactate

CO2

H2O

Phenylpyruvate

CH2

C

COO-

O

Accumulates in phenylketonuria patients

Aspartame -Artificial sweetener -Dipeptide of phenylalanine methyl ester and aspartate

“phenylketonurics: contains phenylalanine”

Amino Acid Biosynthesis

The Nitrogen Cycle

Plants, bacteria, fungi

[N2 as electron acceptor]

Bacteria (symbiotic in legume plants)

Nutrifying bacteria

Denitrification

Nitrogen fixation by the nitrogenase complex:

N2 + 8 H+ + 8 e- + 16 ATP 2NH3 + H2 + 16 ADP + 16 Pi

Nitrogen-fixing bacteria in root nodules of legume plants

Ammonia Assimilation

- Entry point for ammonia: glutamate (Glu) and glutamine (Gln)

Glutamate

synthase

- Plants and bacteria: an additional pathway

NAD(P)H + H+ NAD(P)+

Essential and Non-essential Amino Acids (in mammals)

Essential Amino Acids: Histidine, Isoleucine, Leucine, Lysine, Methionine Phenyalanine, Tryptophan, Threonine, Valine

Non-essential amino acids (precursor): Glutamate, glutamine, proline, arginine (-ketoglutarate) Alanine (pyruvate) Aspartate, asparagine (OAA) Serine, glycine (3-Phophoglycerate) *Cysteine (Methionine) *Tyrosine (Phenylalanine) *Conditional essential

Biosynthesis of Amino Acids

TRANSAMINATIONS

Example:

Glu-ala aminotransferase

Glu α-KG

Aspartate and Asparagine Biosynthesis

Purine and pyrimidine biosynthesis

Asparagine synthetase amide group

amide group

α

β

α

β

α

β

PPi

Proline Biosynthesis

Glutamate kinase

1 2 3 4 5

α β γ

5

Glutamate Glutamate-5-P

Glutamate 5-P

Dehydrogenase

1-Pyrroline-5-

carboxylate reductase

NAD(P)H + H+ NAD(P)+

Proline Δ1-Pyrroline-5-

carboxylate

ATP ADP

NAD(P)H + H+

NAD(P)+

Pi

Glutamate-5-semialdehyde

Spontaneous

cyclization

C

O

-O

CH2 CH2 CH

NH3+

COO-

C

O

O

CH2 CH2 CH

NH3+

PO

-

-O

O

COO-

C

O

H

CH2 CH2 CH

NH3+

COO-

CH2H2C

HC

N

CH COO-

CH2H2C

H2C

HN

CH COO-

Arginine Biosynthesis (related to urea cycle)

(Acetyl-CoA) N-acetyl group

Glutamate acetylglutamate synthase

N-Acetylglutamate

N-Acetyl-γ-glutamyl phosphate

N-Acetylglutamate kinase

N-Acetylglutamate dehydrogenase

1 2 3 4 5

α β γ

1 2 3 4 5

α β γ

1 2 3 4 5

α β γ

1 2 3 4 5

α β γ

1 2 3 4 5

α β γ

argininosuccinase

Fumarate

N-Acetylornithine

+

Serine and Glycine Biosynthesis

Glutamate

-Ketoglutarate

Phosphoserine

transaminase

Phosphoserine

phosphatase

H2O Pi

H2O

Tyrosine synthesis from phenylalanine

Phenylalanine

Tyrosine

tetrahydrobiopterin Phenyalanine hydroxylase

Mixed function oxidase (mechanism similar to fatty acid desaturase)

(defective in phenylketonurics)

CH2 CH COO-

NH3+

HO

CH2 CH COO-

NH3+

O2

H2O

NADH + H+

NAD+

Methionine cylce

(SAM)

(SAH)

Cysteine synthesis from methionine [ Plants and bacteria: SO4

2- cysteine ] assimilation

Cysteine synthesis

(from diet)

(From methionine cycle)

(CBS)

Homocystinuria - Genetic defect in CBS - Homocysteine level in blood stream - Risks of heart diseases

Cysteine Biosynthesis