Amino Acid Metabolism

• dietary intake

• Proteolysis

• Degradation of select molecules

• De novo synthesis within the body

The sources of amino acids within the body

They are catabolized as AA’s are not stored within the body. Excess AA’s are only used for protein synthesis when protein is needed

What happens to excess AA’s in the body

• N theme: where ammonia contained in AA’s is turned to non toxic urea for excretion

• C theme: where the AA’s carbon skeleton enters the kerbs cycle and combined gluconeogenesis to form glucose

The two breakdown pathways of AA’s and what they are fed by

Both N and C themes within the liver

Where does AA metabolism occur

1. Removal of primary amino group from AA (deamination)

2. Synthesis of a alpha-keto acid

3. Detoxification of ammonia

The steps of AA metabolism N theme

Specifically used for the delamination of glutamate but plays a role in delaminating almost all AA’s. converts glutamate to alpha-ketoglutarate removing ammonia from the structure

Glutamate dehydrogenase

Catalyze the reversible reaction of switching R groups between a amino acid and alpha-keto acid forming a new amino acid and alpha-keto acid

The function of transaminases

alpha-ketoglutarate with AA 1 to then from keto acid 1 and glutamate

Almost all transaminases use the amino acid and keto acid

Pyridoxal phosphate which is Vit B6 (pyridoxine) with a phosphate group

Transaminases require prosthetic groups

The glutamate-aspartate transporter as it shuttles AA’s between the inter membrane space and matrix to allow conversion between aspartate and glutamate with the use of keto acids oxaloacetate and alpha-ketoglutarate from the coupled malate-alpha-ketoglutarate transporter

The section of the malate-aspartate shuttle that has transaminase activity

Aspartate aminotransferase

The glutamate-aspartate transporter uses enzyme that is a transaminase

ALT and AST

The two transaminases that are clinical measures of liver damage

They are in equal levels in 1:1 ratio

AST and ALT in the liver are equimolar meaning

They are released into the blood, but AST is released twice as fast

Usually AST and ALT are in the blood at low levels but during liver damage

Liver damage by alcohol, cancer or hepatitis infections

If blood AST:ALT ratio is >2 this is caused by

Non liver sources

If blood AST:ALT ratio is > 5 this is caused by

• serine dehydratase and threonine dehydratase

• Pyridoxal phosphate

Serine and threonine are deaminated by enzymes … which require …

The urea cycle

The detoxification step of AA metabolism occurs through

Mostly in the cytosol, some steps in the mitochondria

The detoxification of AA metabolism occurs

Bicarbonate

ATP to ADP

CPS1

Carboxyphosphate

Irreversible

Step 1 A of Carbamoyl phosphate synthesis: reactant, enzyme reaction, enzyme, product, reversibility

Carboxyphosphate

NH3 added and phosphate removed

CPS1

Carbamic acid

Irreversible

Step 1 B of Carbamoyl phosphate synthesis: reactant, enzyme reaction, enzyme, product, reversibility

Carbamic acid

ATP to ADP

CPS1

Carbamoyl phosphate

Irreversible

Step 1 C of Carbamoyl phosphate synthesis: reactant, enzyme reaction, enzyme, product, reversibility

Ornithine + carbamoyl phosphate

Phosphate removed

Orithine transcarbamoylase

Citrulline

Irreversible

Step 2 condensation: reactant, enzyme reaction, enzyme, product, reversibility

Citrulline + aspartate

ATP to AMP + PPi

Argininosuccinate Synthetase

Argininosuccinate

Irreversible

Step 3: synthesis of argininosuccinate: reactant, enzyme reaction, enzyme, product, reversibility

Argininosuccinate

N/A

Argininosuccinase

Arginine + fumarate

Step 4: reactant, enzyme reaction, enzyme, product, reversibility

Arginine

H2O added

Arginase

Ornithine + urea

• ornithine travels back into mito matrix to continue cycle

Step 5: reactant, enzyme reaction, enzyme, product, reversibility

• malate-aspartate: at step 3 where aspartate is a reactant

• Kerbs cycle: at step 4 where fumarate is formed

The urea cycle is linked to:

• where AA’s are stabilized in the muscles

• The ammonia produced needs to be detoxified before entering the blood stream in this cycle then travels to the liver

• Only occurs during the starvation state

The glucose-alanine cycle

1: muscle proteins are broken down through the N theme to from glutamate

2: using pyruvate (a keto acid) from the concurrent glycolysis in the muscle and enzyme alanine aminotransferase AA alanine and alpha-ketoglutarate are formed

3: alanine travels through the blood to the liver where its transformed back to pyruvate by enzyme alanine aminotransferase which enters gluconeogenesis which provides glucose back to the muscles

4: glutamate is also reformed when pyruvate is were it goes through the rest of N theme to from urea

The stages of the glucose-alanine cycle

Glutamate

CO2 removed

Glutamate decarboxylase

PLP

GABA

Irreversible

GABA synthesis: reactant, enzyme reaction, enzyme, cofactor product, reversibility

Histidine

CO2 removed

Histidine decarboxylase

PLP

histamine

Irreversible

Histamine synthesis: reactant, enzyme reaction, enzyme, cofactor, product, reversibility

1: tryptophan is converted to nicotinate (NAD and NADP precursor) through a multi-step process

2: tryptophan is converted to serotonin through a 2 step process that requires PLP as a cofactor

Serotonin and nicotinate synthesis: