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Amino Acid metab.
Biochem and medical genetics
| Question | Answer |
|---|---|
| Overview of AA metabolism | Turnover of 300g a day 100g intake via diet and 100g excreted Bodies are in a nitrogen balance - what is take in is excreted as CO2 and urea Don't store protein as an energy source Amino acid pool is filled by diet and body protein |
| Classification of AA by availability | Essential - cannot make so must come from diet Non essential - synthesis de novo Semi essential - can be made but can also be taken in if excess is needed |
| Essential amino acids | Histidine Isoleucine Leucine Lysine Methionine Phenylalanine Threonine Tryptophan Valine |
| Conditionally essential AA | Arginine Cystine Glutamine Glycine Proline Serine Tyrosine |
| Non-essential AA | Alanine Asparagine Aspartic acid Glutamic acid |
| Dietary absorption of AA | Pepsin - non specific maximally active at pH 2 Proteolytic enzymes of the pancreas - display a wide array of specificity in intestinal lumen Aminopeptidases - digest proteins from the amino terminal end |
| Active Na linked AA transport | AA Na cotransporter - uses Na gradient This is maintained by Na K ATPase Not used by branched chain or aromatic AAs |
| Protein turnover | Many cellular proteins are degraded and resynthesized constantly Damaged/incorrectly folded/produced proteins Signalling proteins need to be removed as needed Enzymes are often up/down regulated as a regulatory mechanism Mostly in skeletal muscle |
| How do we know which proteins to break down | Proteins that need to be broken down are tagged with ubiquitin Broken down by a proteasome-internal catalytic band and regulatory particle to recognise ubiquitin Ubiquitin ligases attach this - E1 pick up ubiquitin transfers to E2 which combines with E3 |
| How does E3 recognise proteins to be degraded | Can recognise damaged/ misfolded proteins Can recognise certain n-terminal residues that signal the half life of a protein E.g. Alanine = half life > 20 hours Arginine = half life 2-30 mins |
| Angelman's syndrome | Genetic disease with severe motor and intellectual disability Caused by mutations in ubiquitin ligase Lack of ability to turnover proteins |
| Overall regulation of protein metabolism | Insulin - net anabolic effect from stimulation of chain initiation effects on transcription and inhibition of breakdown Thyroid hormones and cortisol have catabolic effect Other steroids have anabolic effects |
| Classification of amino acids by side chain | Hydrophobic alkyl Hydrophobic aromatic Hydrophilic acidic Hydrophilic neutral Hydrophilic basic |
| Hydrophobic alkyl AA | Glycine Alanine Valine Leucine Isoleucine Methionine Proline |
| Hydrophobic aromatic AA | Phenylalanine Tryptophan |
| Hydrophilic neutral AA | Tyrosine Serine Threonine Cysteine Glutamine Asparagine |
| Hydrophilic acidic AA | Glutamic acid Aspartic acid |
| Hydrophilic basic AA | Lysine Histidine Arginine |
| Deamination | Presence of amine group prevents oxidative breakdown This must be removed before catabolism can proceed Nitrogen incorporated into other compounds or excreted |
| Types of deamination | Oxidative e.g. glutamate dehydrogenase Non-oxidative e.g. serine and threonine Hydrolytic e.g. asparagine and glutamine |
| Oxidative deamination | Amino acid converted to alpha keto acid coupled with conversion of NAD to NADH or NADP to NADPH Glutamate is the only amino acid using this - glutamate dehydrogenase Glutamate - alpha ketoglutarate |
| Glutamate dehydrogenase | Mostly liver and kidney Can used NAD or NADP as a coenzyme - NAD in oxidative deamination and NADP is reductive amination Direction of reaction depends on substrate availability |
| Allosteric regulation of GDH | Anabolic - ATP and GTP upregulate Catabolic - ADP and GDP upregulate |
| Funnelling of AA into glutamate | Via transamination AAs are converted to alpha keto acids which can be metabolised - aminotransferases catalyse This is coupled with alpha ketoglutarate being converted to glutamate This can then undergo deamination to release NH3 |
| Examples of transamination | Alanine transaminase - alanine + alpha ketoglutarate = pyruvate + glutamate Aspartate transaminase - asparagine + alpha ketoglutarate = oxaloacetate + glutamate |
| Use of pyridoxal phosphate | Used by all transaminases Derived from pyridoxine and Vit B6 Forms a Schiff base with a lysine residue in the active site of the transaminase Can alternate between PLP and pyridoxamine phosphate - can temporarily accept amine groups |
| Mechanism of transamination | Amino acid forms a Schiff base with PLP - displaces enzyme Alpha keto acid is removed - amine left bound to PMP Alpha ketoglutarate then comes in and bind to this to form a Schiff base with PLP This dissociates to form glutamate |
| Non-oxidative transamination | Serine and threonine are directly deaminated as they have an OH group Serine - pyruvate and NH3 via serine dehydratase Threonine - alpha ketobutyrate and NH3 via threonine dehydratase |
| Hydrolytic deamination | Glutamine to glutamate via glutaminase (H2O to NH4) Asparagine to aspartate via asparaginase (H2O in, NH4 out) |
| Glutaminase | Tissue specific isozymes Mitochondrial Expressed in liver to generate urea Expressed in kidneys to generate NH4 to help in acid base balance Expressed in neurons to assist in neurotransmission |
| Why is amino acid release from muscle important | Largest store of protein in the body - 5-7Kg of 10-11 Kg total During starvation glucose continues to be oxidised, especially by the brain Glucose must come from non-glucose sources These sources are glycerol and amino acids |
| Amino acid metabolism in muscles | All AAs go through transamination to make alanine and glutamine Alanine - freely transported Glutamine - 2 amines in one molecule |
| Glucose-Alanine cycle | In the liver, alanine undergoes transamination to form pyruvate This forms glucose via gluconeogenesis Glucose goes to muscle where it forms pyruvate in glycolysis This then undergoes transamination to form alanine again |
| Conversion between glutamine and glutamate | Glutamate to glutamine via glutamate synthetase (uses NH4 and ATP) Glutamine to glutamate via glutaminase (uses water and releases ammonia) |
| Urea cycle | Humans excrete 90% of waste nitrogen as urea Ammonia is toxic and limited excretion is involved in acid base balance Urea provides a safe, non-toxic means to excrete the nitrogen |
| Overview of urea cycle | Carbamoyl phosphate combines with ornithine in mitochondria to form citrulline Transported out and forms aspartate Forms Arginosuccinate Fumarate is released to form arginine Urea released to reform ornithine |
| Carbamoyl phosphate synthetase 1 | HCO3 + NH3 = carbamoyl phosphate This uses 2ATP Catalysed by carbamoyl phosphate synthetase 1 Mitochondrial Allosterically activated by N-acetyl glutamate |
| Links between Urea and TCA cycle | Arginosuccinate forms arginine - stays in urea cycle Also forms fumarate, which enters TCA cycle to form malate etc Reforms aspartate to enter urea cycle again |
| Regulation of urea cycle | Enzymatic capacity is high compared with flux, so any increase in AA oxidation will be dealt with Enzymes are co-ordinately upregulated by glucagon and glucocorticoids (activity increases with catabolism) |
| Cerebral ammonia metabolism | NH3 is able to cross blood brain barrier Both astrocytes and neurons have endogenous NH3 production Glutamine synthase plays a critical role - combines glutamate and NH3 to form glutamine |
| Hyperammonaemia and neurotoxicity | Elevated NH3 leads to neurotoxicity Cell membrane - acts like k to increase resting potential and give depolarisation block Neurotransmitters - altered glutamine and glutamate influence GABA Metabolism - high lactate, reduced phosphocreatine |
| Defects of urea cycle | Blockage of carbamoyl phosphate synthesis/any step leads to increased ammonia May present early or later in life - depends on severity Lethargy, poor feeding, hypothermia, vomiting, hyperventilation. respiratory distress etc - leads to brain damage |
| Argininosuccinase deficiency | Partly bypassed by providing surplus of arginine and reducing total protein intake Arginine split into urea and ornithine, which forms citrulline This condenses to form arginosuccinate - can be excreted |
| CPS or ornithine transcarbamoylase deficiency | Treated by supplementing with benzoate and phenylacetate Benzoate activated to benzoyl CoA with reacts with glycine to form Hippurate and phenylacetate to form phenylacetyl CoA This forms phenylacetylglutamine |
| Classification of AAs by metabolism | Glucogenic - Ala, Arg, Asn, Asp, Cyc, Glu, Gln, Gly, His, Met. Pro. Ser, Thr, Val Ketogenic - Leu, Lys Both - Ile, Phe, Trp, Tyr |
| What can the carbon skeleton form | Glucogenic - pyruvate, fumarate, oxaloacetate, succinyl CoA, alpha ketoglutarate Ketogenic - acetyl CoA and acetoacetyl CoA |
| Formation of pyruvate | 2 carbon AAs Tryptophan - alanine - pyruvate via alanine transaminase Glycine - serine (serine hydroxymethyl transferase) - pyruvate (serine dehydratase) Cystine - pyruvate (cystathionase) |
| Formation of fumarate | 4 Carbon AAs Phenylalanine - tyrosine (phenylalanine hydroxylase) - fumarate and acetoacetate (tyrosine aminotransferase homogentisate oxidate) |
| Phenylketonuria | Caused by blockage of phenylalanine hydroxylase Causes build up of phenylalanine |
| Formation of oxaloacetate | Asparagine to aspartate (asparaginase) To oxaloacetate via aminotransferase (coupled with alpha ketoglutarate to glutamine) |
| Formation of succinyl CoA | Branched chain AAs Leucine - alpha ketoisocaproic acid - isovaleryl CoA - acetoacetate and acetyl CoA Valine - alpha ketoisovaleric acid - isobutyryl CoA - Succinyl CoA Isoleucine - a-keto-b-methyl valeric acid - a-methyl butyryl CoA - Succinyl CoA |
| Formation of succinyl CoA from methionine | Methionine - homocysteine via s-adenosyl methionine To a-ketobutyrate via homocysteine desulphydratase Threonine also forms this via serine dehydratase This then forms Succinyl CoA |
| Formation of Alpha Ketoglutarate | Arginine - ornithine (arginase) - a-KG Proline - glutamate (oxidation) - a-KG (aminotransferase) Histidine - N-formimino glutamate (histidase) - glutamate - a-KG Glutamine - glutamate (aminotransferase) - a-KG |
| Ketogenic amino acids | Leucine and isoleucine Leucine + OAA - acetoacetyl CoA |
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