WEEK 8 (Amino acid metabolism) Flashcards
What are amino acids?
Amino acids are organic compounds containing an AMINE GROUP, CARBOXYL GROUP, VARIABLE GROUP and a H ATOM around a central carbon atom
What are the major key elements of amino acids?
- Carbon
- Hydrogen
- Nitrogen
- Oxygen
Which amino acids are non-polar?
- Glycine
- Alanine
- Proline
- Valine
- Leucine
- Isoleucine
- Methionine
- Tryptophan
- Phenylalanine
Which amino acids are polar and uncharged?
- Cysteine
- Asparagine
- Glutamine
- Serine
- Threonine
- Tyrosine
Which amino acids are charged?
- Histidine
- Arginine
- Lysine
- Aspartate
- Glutamate
What is the difference between Essential amino acids and Non-essential amino acids?
ESSENTIAL AMINO ACIDS = cannot be synthesised by the body -> must be consumed
NONESSENTIAL AMINO ACIDS = can be synthesised
Which amino acids are essential?
- Leucine (KETOGENIC)
- Lysine (KETOGENIC)
- Phenylalanine (KETOGENIC/GLUCOGENIC)
- Isoleucine (KETOGENIC/GLUCOGENIC)
- Threonine (KETOGENIC/GLUCOGENIC)
- Tryptophan (KETOGENIC/GLUCOGENIC)
- Methionine (GLUCOGENIC)
- Valine (GLUCOGENIC)
- Arginine (GLUCOGENIC)
- Histidine (GLUCOGENIC)
Which amino acids are nonessential?
- Alanine (GLUCOGENIC)
- Asparagine (GLUCOGENIC)
- Aspartate (GLUCOGENIC)
- Glutamate (GLUCOGENIC)
- Glutamine (GLUCOGENIC)
- Glycine (GLUCOGENIC)
- Proline (GLUCOGENIC)
- Serine (GLUCOGENIC)
- Cysteine (GLUCOGENIC)
- Tyrosine (KETOGENIC/GLUCOGENIC)
What differentiates amino acids and proteins from fats and carbohydrates?
Unlike fats and carbohydrates, there is no storage form of amino acids and proteins so any excess/unused amino acids are broken down
What happens in amino acid breakdown?
The amino group is removed forming NH3 + ALPHA-KETO ACID
What are the properties of ammonia?
- Toxic to the body
- Needs to be transferred to LIVER in a NON-TOXIC STRUCTURE
- Converted by liver to UREA (non-toxic) for excretion by kidneys
All amino acids except ________ and _________ participate in transamination at some point in their catabolism
Lysine and Threonine
What are aminotransferases?
Transfer nitrogen from amino acids to glutamate
What do all aminotransferases require?
The prosthetic group PYRIDOXAL PHOSPHATE (PLP) which is derived from PYRIDOXINE (VITAMIN B6)
What is the clinical significance of Aminotransferases?
Aminotransferases are INTRACELLULAR ENZYMES with LOW LEVELS found in the plasma -> represents release of cellular contents during normal cell turnover -> ELEVATED PLASMA LEVELS of aminotransferases indicate DAMAGE to cells rich in these enzymes
When are Plasma AST and ALT levels elevated in hepatic diseases?
In ALL hepatic diseases but particularly high in conditions that cause extensive cell necrosis
EXAMPLES:
- Severe viral hepatitis
- Toxic injury
- Prolonged circulatory collapse
When are Aminotransferases elevated in non-hepatic diseases?
In diseases that cause damage to cardiac or skeletal muscle
What are Oxidative deamination reactions and where do they occur?
Oxidative deamination reactions result in the liberation of the amino group as FREE AMMONIA and occur in the LIVER and KIDNEY
What are the two mechanisms that are available for the transport of ammonia from peripheral cells to liver for detoxification?
- GLUTAMINE SYNTHETASE to combine glutamate with ammonia
- TRANSAMINATION of pyruvate to Alanine
(used primarily by muscle)
Describe transport of ammonia using Glutamine synthetase
GLUTAMINE SYNTHETASE combines ammonia with glutamate to form GLUTAMINE (nontoxic transport form of ammonia) -> GLUTAMINE is transported in blood to the LIVER where GLUTAMINASE cleaves it into GLUTAMATE and AMMONIA -> Glutamate is OXIDATIVELY DEAMINATED to ammonia and a-ketoglutarate by GDH
Describe the transport of ammonia using Transamination
ALANINE is transported in the blood to the liver where it is TRANSAMINATED by ALT to PYRUVATE -> Glutamate product of ALT can be deaminated by GDH generating AMMONIA -> Both alanine and glutamine carry ammonia to the liver
What are the properties of the Urea cycle?
- Occurs only in liver
- Toxic ammonia (urea) is excreted in urine
- Urea is synthesised from AMMONIA, CO2 and ASPARTATE
What is the first stage of amino acid breakdown?
Removal of nitrogen by TRANSAMINATION [NH2 group is accepted by a-ketoglutarate forming GLUTAMATE]
What are the properties of N-acetylglutamate?
- Regulates UREA CYCLE
- In the 1st step, N-ACETYLGLUTAMATE is an allosteric activator of CARBAMOYL PHOSPHATE SYNTHETASE I
- Synthesised from glutamate and acetyl CoA
Glutamate and ammonia exist in a chemical equilibrium with glutamine, mediated by which enzyme?
GLUTAMINE SYNTHETASE
Glutamate serves as a substrate for glutamate decarboxylase to form _______
GABA
[This mechanism controls GABA concentration and GABAergic tone]
What is Hyperammonemia?
Hyperammonemia is a metabolic condition characterised by the raised levels of ammonia
Elevated serum ammonia levels disrupt the balance between GLUTAMINE, GLUTAMATE, A-KETOGLUTARATE and GABA through the actions of GLUTAMATE DEHYDROGENASE and GLUTAMINE SYNTHETASE -> Results in INCREASED GLUTAMINE and DECREASED GLUTAMATE levels -> low GABA synthesis and GABAergic tone
TYPICAL FEATURES OF HYPERAMMONEMIC ENCEPHALOPATHY:
- Excess glutamine -> Osmotic damage to ASTROCYTES -> Cellular swelling and dysfunction -> CEREBRAL EDEMA
- Imbalance of neurotransmitters -> INHIBITION of excitatory neurotransmission and ACTIVATION of inhibitory neurotransmission
- Low A-KETOGLUTARATE -> Inhibition of TCA cycle
SYMPTOMS:
- Flapping tremor (ASTERIXIS - inability to maintain sustained posture with brief, shock-like, involuntary movements)
- Slurring of speech
- Vomiting
- Somnolence (drowsiness)
- Vomiting
- Blurring of vision
- Can progress to coma
Where are brief, low frequency, rhythmless tremor of the hand that occurs when the arm is outstretched and the wrist is extended seen most commonly?
Hepatic Encephalopathy
What is Ornithine Transcarbamylase (OTC) deficiency?
Ornithine Transcarbamylase deficiency is the most common, X-linked recessive Urea cycle disorder which interferes with the body’s ability to eliminate ammonia. Excess CARBAMOYL PHOSPHATE is converted to OROTIC ACID (part of pyrimidine synthesis pathway).
(OTC deficiency is often evident in the first few days but may present later)
EFFECTS:
- Increased orotic acid in blood & urine
- Decreased BUN (Blood Urea Nitrogen)
- Symptoms of Hyperammonemia
SYMPTOMS:
- Cerebral edema
- Lethargy
- Convulsions
- Coma
- Death
Describe Orotic Aciduria
Orotic Aciduria is the inability to convert OROTIC ACID to UMP (used in de novo pyrimidine synthesis pathway) because of defect in UMP SYNTHASE. Autosomal recessive.
SYMPTOMS:
Presents in children as
- Failure to thrive
- Developmental delay
- Megaloblastic anemia resistant to FOLATE and B12
- No hyperammonemia
Describe Orotic Aciduria
Orotic Aciduria is the inability to convert OROTIC ACID to UMP (used in de novo pyrimidine synthesis pathway) because of defect in UMP SYNTHASE. Autosomal recessive.
SYMPTOMS:
Presents in children as
- Failure to thrive
- Developmental delay
- Megaloblastic anemia resistant to FOLATE and B12
- No hyperammonemia
Describe Carbamoyl Phosphate Deficiency
Carbaryl Phosphate Deficiency is an autosomal recessive deficiency that does not produce orotic acuduria and causes ammonia to accumulate in the blood (hyperammonemia).
[Least common deficiency of the urea cycle]
EFFECTS:
- Increase in ammonia (hyperammonemia)
- Blood glutamine is increased
- BUN is decreased
- No OROTIC ACIDURIA
SYMPTOMS:
- Cerebral edema
- Lethargy
- Convulsions
- Coma
- Death
