Amino acid degradation and the urea cycle

Describe how protein turnover contributes to amino acid availability and degradation

Dietary proteins containing both essential and non essential amino acids can broken down via digestion by: pepsin in the stomach and peptidases in the pancreas and surface of intestinal cells,.

Intracellular proteins can be degraded, they are marked for destruction by the covalent attachment of ubiquitin and degraded by the proteosome. This can be due to a change in metabolic demands, misfolding in the ER or damaged proteins.

Both produce amino acids that can be used as building blocks for biosynthesis of proteins and other nitrogenous compounds

Any excess cannot be stored so need to be degraded.

What is an essential amino acid?

Can’t be synthesised in the body so needs to be obtained through duet

Descrie the 2 parts of an amino acid, what happens to them during degradation?

A-amino group can be transferred to an a-keto acid via transamination and then oxidative deamination and then the urea cyle

The carbon skeleton can be converted to metabolic intermediates

Describe the removal of the a-amino group of an amino acid

Main site is the liver in mitochondria

Muscles can degrade branched chain amino acids such as leucine, isoleucine and valine

A-amino group transferred onto a-ketoglutarate (transamination), this forms glutamate and regenerates the a keto acid. Glutamate is oxidatively deaminated, produces NH4+ and NADH

Catalysed by aminotransferases

What do all aminotransferases contain?

Pyridoxal phosphate which is derived from vitamin B6

Describe the oxidative deamination of glutamate by glutamate dehydrogenase

Catalysed by glutamate dehydrogenase - in mammals inhibited allosterically by GTP and stimulated by ADP

Transamination produced glutamate, which h undergoes oxidative deamination - the enzyme lacks specificity (very different), oxidising agent can be NAD+ or NADP+. Releases NH4+ which enters the urea cycle and a-ketoglutarate which is used in the TCA cycle

The reaction is reversible but is driven forward by the rapid removal of NH4+ in the urea cycle, regulated by energy charge, and high pools of GTP is inh9bitory

Describe serine and threonine deamination

• Doesn’t require a-ketoglutarate involvement

• Serine ----> pyruvate + NH4+ (via serine dehydratase)

• Threonine ----> a-ketobutyrate + NH4+ (via threonine dehydratase)

Describe the transport of nitrogen to the liver

High exercise and fasting: Normally try and reserve protein and use glycogen and fats as sources of fuel, may need to use proteins for fuel. Muscles used branched AA as fuel for the TCA cycle and oxidative phosphorylation. Muscles cant use NH4+ in the urea cycle as they lack the enzymes for it, so it is transported to the liver as alanine or glutamine

Alanine and glutamine cycle allows the use of certain branched chain amino acids, transamination occurs in the muscle and is then transferred to the liver for further reactions

 

Describe the conversion of NH4+ to urea (the urea cycle)

• Cyle is split between the mitochondrial matrix and cytoplasm

• Input of CO2 and 2ATP allows you to make carbamoyl phosphate, interacts with ornithine to produce citrulline

• Citrulline and aspartate in the cytoplasm form arginosuccinate, converted to fumarate and arginine, arginine is converted to Orthinine using he input of water and also produces Urea

--> detoxified the ammonium ion

• Urea is made up of: one N from NH4+, one N from aspartate and one c from bicarbonate

• A level of compartmentalism to detoxify the ammonium ion

Describe the formation of carbamoyl phosphate

• Three step reaction

• Initial phosphorylation of HCO3- uses 1ATP to form carboxyphosphate

• This reacts with NH3 to form carbamic acid

• Phosphorylation of carbamic acid using another ATP forms carbamoyl phosphate

Describe the regulation of carbamoyl phosphate synthetase

Allosteric activation by N-acetyl glutamate (NAG) - stimulatory

--> enzyme for synthesis is activated via arginine and requires glutamate as a substrate, indicating amino acids are available, positive effect on the enzyme increases activity for degradation of amino acids

Acetyl CoA + glutamate --> NAG

Covalent modification via acetylation - inhibitory

--> rise in NAD+ in the mitochondria indicates low energy and stimulates A deacetylase enzyme which removes an acetyl group

Describe the date of carbon skeletons of amino acids

• Transformed into metabolic intermediates that can be converted to glucose via gluconeogenesis or oxidised by the TCA cycle

• 20 amino acid skeletons produce 7 intermediates: pyruvate, acetyl CoA, acetoacetyl CoA, a-ketoglutarate, succinyl CoA, fumarate and oxaloacetate

• Depending on where they fall into the pathway, can be glucogenic - give rise o pyruvate or ketogenic - give rise to ketone bodies, amino acids can be glucogenic and ketogenic

• --> only leucine and lysine are solely ketogenic

What is a glucogenic amino acid?

Gives rise to pyruvate

Describe a ketogenic amino acid

Gives rise to ketone bodies