Amino Acids Flashcards
Describe the catabolism of amino acids
1) Transamination or Deamination to remove amino group
2) Nitrogen can be excreted as urea or incorporated into other compounds
3) Remaining C-Skeleton can be converted into:
- Pyruvate
- Oxaloacetate
- Fumarate
- Ketoglutarate
- Succinate
- Acetyl~CoA
What is transamination?
-chemical reaction that replaces an amine functional group with another amine.
two substrates:
- amino acid
- keto acid, (contains a keto (=O) group)
- In transamination, the NH2 group on one molecule is exchanged with the =O group on the other.
- The original amino acid converts to a keto acid, and the keto acid converts to an amino acid.
What is deamination?
- liberates amino group as free ammonia
- mainly occurs in liver and kidney
- kept acids can be utilised for energy
- also important in deamination of dietary D-amino acids (found in plants and microorganisms)
Discuss phenylalanine metabolism defects
Phenylketonuria (PKU) is an inherited disorder in which the urine contains large amounts of phenylketones produced from phenylalanine.
1) Phenylalanine is oxidised to tyrosine by the enzyme phenylalanine hydroxylase. This enzyme is defective in most PKU cases. As a result, phenylalanine accumulates in tissues and blood. It is metabolised by other pathways to produce various products including phenylpyruvate that is excreted in the urine.
Diagnosis:
PKU is diagnosed by the detection of phenylketones in the urine or high phenylalanine blood concentration
Failure to diagnose and treat PKU at birth can lead to mental retardation due to failure of brain to uptake and utilise glucose.
What is homocystinuria?
autosomal recessive defect in methionine metabolism,
Type 1: caused by a deficiency in the cystathionine -synthase (CBS) enzyme.
- CBS normally converts homocysteine to cystathionine, which is further converted to cysteine.
- If CBS is deficient, homocysteine increases in the blood and some homocysteine can be converted to methionine.
- The condition is detected by elevated levels of homocysteine and methionine in plasma.
- Causes disorders of connective tissue. Similar symptoms to Marfan’s Syndrome in children
How is ammonia removed from the body?
- Urea synthesis
- Occurs in liver and involves 5 enzymes
- NH2 groups of urea comes from deamination of amino acids as well as aspartate
- also from gut bacteria that enters the liver via portal circulation
Why does ammonia cause problems in the body?
- ammonia (and ammonium ions) are very toxic
- at physiological pH, ammonia is rapidly converted to ammonium ions (NH4+)
- peripheral blood concentration of 25-40 uM
How is the urea cycle regulated?
- Not regulated
- Inducible
- high protein diet induces enzyme levels, low protein diet or starvation represses levels
Describe the clinical consequences of defects in the urea cycle?
- autosomal recessive genetic disorders caused by deficiency of one of the enzymes in the urea cycle
- occur in 1 of 30,000 live births
Severity depends on:
- nature of defect
- amount of protein eaten
- severe urea cycle disorders show symptoms within 1 day of birth. If untreated, child will die. Mild urea cycle enzyme deficiencies may not show symptoms until early childhood
symptoms:
- Vomiting
- lethargy
- irritability
- mental retardation
- seizures
- coma
Management:
- low protein diet
- replace amino acids in diet with keto acids
What is refeeding syndrome?
- can occur when nutritional support given to severely malnourished patients
- ammonia toxicity is a significant factor (urea cycle down regulated)
- refeed at 5 to 10 kcal per kg per day (raised gradually to fulfill needs within a week)
How does transamination occur in the body?
- amino acids converted into glutamate or aspartate
- aminotransferase enzymes utilised
- alpha- ketoglutarate is keto acid used
- Exception: aspartate aminotransferase which uses oxaloacetate to funnel amino group of glutamate to aspartate
- All aminotransferases require the coenzyme pyridoxal phosphate which is a derivative of vitamin B6
What are the main aminotransferase enzymes and what is their clinical significance?
- Alanine aminotransferase (ALT)- converts alanine to glutamate
- Aspartate aminotransferase (AST)- Converts glutamate to aspartate
Plasma ALT and AST levels measured routinely as part of liver function test. Levels particularly high in conditions that cause cellular necrosis such as:
Viral Hepatitis
Autoimune liver diseases
Toxic injury
How are protein reserves mobilised?
Occurs during extreme stress (starvation)
Under hormonal control:
- insulin and growth hormone increase protein synthesis and decrease protein degradation
- glucocorticoids e.g. cortisol, decrease protein synthesis and increase protein degradation
What are glucogenic and ketogenic amino acids?
- Amino acids that produce acetyl~CoA are described as ketogenic as the acetyl~CoA can be used to synthesise ketone bodies.
- (e.g. leucine, lysine)
- Amino acids that produce other products are described as glucogenic as they can be used for glucose synthesis by gluconeogenesis. (tyrosine, tryptophan)
- Some AAs are both ketogenic and glucogenic (isoleucine, threonine, phenylalanine)
What is the biochemical basis for the toxicity of ammonia?
-readily diffusible and extremely toxic to the brain
Potential side effects:
- interference with amino acid transport and protein synthesis
- disruption of cerebral blood flow
- alkaline interference with metabolism of excitatory amino acid neurotransmitters
- alteration of the blood-brain barrier
- interference with TCA cycle (reacts with alpha-ketoglutarate to form glutamate in mitochondria via glutamate dehydrogenase)
