Amino Acid Metabolism Flashcards
1
Q
Amino acids
A
- Monomeric units for proteins; therefore important for growth, metabolism
2
Q
Amino acids are a precursor for what?
A
- biologically important nitrogen containing compounds: haem, creatine, purines and pyrimidines
3
Q
Dietary intake of amino acids
A
- Dietary protein intake is main source of nitrogen
- Excess dietary AA’s not required for protein synthesis can’t be stored (in mammals) & aren’t excreted
- Converted to energy metabolites
4
Q
Amino acids as source of energy
A
- Glucose and fatty acids are the major metabolic fuels
- Oxidation of aa’s play a role in energy requirements of organisms when there is excessive protein in the diet
when the normal metabolic fuels are unavailable due to starvation or disease - Most humans normally get 10-25% of their energy requirements from amino acids
- In carnivores it can be up to 50%
5
Q
Sources of amino acids
A
- dietary protein digestion (60-100gm/day)
- Synthesis of non-essential amino acids
- tissue protein synthesis/ catabolism (~400gm/day)
6
Q
Utilisation of amino acids
A
- amino acid catabolism: ammonia → urea, carbon skeleton: glucose/lipid synthesis
- Synthesis of nitrogen containing compounds: haem, neurotransmitters, creatine, purines, pyrimidines
7
Q
Essential and Non-essential Amino Acids
A
- Essential: cannot be synthesized by the body; obtained via diet
- Non-essential: can be synthesized by the body
8
Q
Glucogenic amino acids
A
- catabolism yields pyruvate or an intermediate of the citric acid cycle –> Substrates for gluconeogenesis
- carbon skeletons broken down to glucose precursors
9
Q
Ketogenic amino acids
A
- yields acetoacetate, acetyl CoA or acetoacetyl CoA –> not substrates for gluconeogenesis
- carbon skeletons broken down to ketone body or fatty acid precursors
10
Q
Major site of amino acid catabolism
A
- liver
11
Q
3 main stages of amino acid catabolism
A
- Deamination/Transamination– removal and conversion of amino group to ammonia or amino group of aspartate
- Incorporation of nitrogen from ammonia/aspartate to urea
- Conversion of amino acid carbon skeletons (a-keto acids) to one of the 7 common metabolic intermediates
12
Q
Enzymes involved in deamination/transamination
A
- Aminotransferases – these are specific for each amino acid
- Enzyme requires pyridoxal phosphate (Vit B6) as coenzyme
13
Q
Pyridoxine in deamination/transamination
A
- in the form of pyridoxal-5’-phosphate (PLP) is required to help carry the amino group
- PLP is covalently attached to enzyme via Schiff base formation through condensation of the PLP’s aldehyde group with the amino group
14
Q
Other products of transamination
A
- remaining carbon skeleton of the amino acid exists as a keto acid - fate depends on the amino acid, but is either glucose or ketone/FA precursor
- Reactions also form glutamate (or aspartate) which feeds excess NH4+ to the urea cycle
15
Q
Deamination
A
- involves the release of free NH3 from glutamate by Glutamate dehydrogenase and Glutamine synthetase
16
Q
Additional minor mechanism involving L-AA’s and D-AA’s
A
- two isomeric forms L- or D-
- Animals only utilse L-AA’s
- D-AA’s are found in bacterial cell walls, but are present in the human body where they have passed through the bloodstream from bacteria in the colon
- D-AA’s can interfere with metabolism of L-aa’s
- Defence mechanism is therefore to remove them
The enzyme D-amino acid oxidase (D-AAO) does this
17
Q
Products of glucogenic amino acid catabolism
A
- pyruvate
- oxaloacetate
- a-ketoglutarate
- fumerate
- or succinyl-CoA
18
Q
Alanine
A
- converted to pyruvate via transamination
- Enzyme is Alanine aminotransferase (ALT)
- Enzyme requires PLP (pyridoxal phosphate) (Vit B6)
- a-Ketoglutarate acts as an amino acceptor - Glutamate
19
Q
Aspartate
A
- converted to oxaloacetate via transamination – Aspartate aminotransferase (AST)
- Reaction similar to alanine i.e. formation of glutamate
- Enzyme also requires PLP (pyridoxal phosphate) (Vit B6)
- Oxaloacetate can be used in gluconeogenesis or TCA cycle
- Reaction is reversible – produce aspartate from oxaloacetate
20
Q
Asparagine
A
- firstly deaminated to aspartate by Asparaginase, produces ammonium
- Therefore ultimately asparagine is converted to oxaloacetate
- used for synthesis of Asparagine – Asparagine synthetase.
- Glutamine is the N-donor (not free ammonia (NH3))
- used in the treatment of some leukaemia patients
- Reduced availability of asparagine to the tumour cells inhibits growth/proliferation of leukemic cells
21
Q
Glutamate
A
- required for the Urea Cycle
- special aa - can be formed or degraded by aminotransferases or by glutamate dehydrogenase (mitochondrial enzyme)
- Both reactions are reversible
- Aminotransferases need pyridoxal phosphate (PLP) (Vit B6) as cofactor, and glutamate dehydrogenase needs either NAD+ or NADPH
22
Q
Oxidative deamination by Glutamate dehydrogenase
A
- readily reversible
- Requirement for NAD+ or NADP+ depends on the direction of the reaction
- Glutamate DH is key for both disposal and synthesis of aa’s
- In humans, its one of three enzymes capable of incorporating free ammonia into an organic compounds
23
Q
Glutamine
A
- non-toxic, transport form of ammonia from the peripheral tissues (especially important in brain)
- In peripheral tissues glutamate is converted to glutamine – Glutamine synthetase
- Requires ATP and free ammonia
- converted back to glutamate by Glutaminase, releases ammonia
24
Q
Catabolism of both glutamine and glutamate
A
- produces a-ketoglutarate
- Combined actions of: Glutamate dehydrogenase, Glutaminase
25
Q
Methionine and cysteine
A
- Share a common catabolic pathway
- Methionine converted to homocysteine via SAM & SAH intermediates
26
Q
2 fates of homocysteine
A
- Conversion back to methionine by methionine synthase via reaction requiring Vit B12 as a coenzyme & THF substrate
- Transfer of sulphur group to serine by Cystathionine-b synthase with cofactor PLP
27
Q
Products of homocysteine reactions
A
- cystathionine is converted to cysteine and a- ketobutyrate by Cysthionase with cofactor PLP
- Subsequently, a-ketobutyrate is converted to succinyl-CoA for use in TCA cycle
28
Q
Final stage of cysteine catabolism
A
- converted to sulphate
- Pathway produces glutamate and pyruvate
- End product of sulphate can be excreted or combined with ATP to produce PAPS (3’-phosphoadenosine 5’-phosphosulfate).
- Serine, Glycine and Threonine also generate pyruvate (Threoine also acetyl-CoA)
29
Q
Products of ketogenic amino acid catabolism
A
- Acetyl-CoA
- Acetoacetate
- Acetoacetyl-CoA
30
Q
Lysine
A
- Converted to acetoacetate by a multi-step reaction.
- Includes standard reactions of fatty acyl-CoA oxidation (reactions 6,8,9) and ketone body formation (reactions 10, 11)
31
Q
Phenylalanine and Tyrosine
A
- Phenylanine and tyrosine share a common catabolic pathway
- Phenylalanine converted to tyrosine – Phenylalanine hydroxylase (tetrahydrobiopterin (BH4) required)
32
Q
Utilisation and regeneration of tetrahydrobiopterin (BH4)
A
- In cyclic series of reactions BH4 is regenerated after use in the phenylalanine hydroxylase reaction
- BH4 is also formed in a priming reaction by dihydrofolate reductase, but utilising a different form of 7,8-Dihydrobiopterin
33
Q
Tyrosine to homogentisate
A
- Tyrosine transaminated by Tyrosine aminotransferase (PLP required)
- Glutamate and p-Hydroxyphenylpyruvate is produced
- Decarboxylation by Hydroxyphenylpyruvate decarboxylase produces Homogentisate
34
Q
Homogensitate to fumarate and acetoacetate
A
- Oxidation followed by hydrolysis produces fumarate and acetoacetate
- Enzymes are Homogentisate oxidase and fumarylacetoacetate hydrolase
- End products: fumerate (TCA Cycle) and acetoacetate (ketone body)
35
Q
Phenylketonuria (PKU)
A
- Autosomal recessive, occurs 1/10000 in UK
- Deficiency of Phenylalanine hydroxlase
- Elevation in serum phenylalanine and reduction in tyrosine
- Metabolized to phenylpyruvate, phenylacetate & phenyllactate (excreted in urine) resulting in mousey/musty odour of urine
- Tyrosine becomes and essential amino acid
36
Q
Effects of PKA
A
- Decreased pigmentation of skin and hair as tyrosine conversion to melanin is inhibited by the elevated phe levels (inhibits tyrosinase)
- Infants appear normal until a few months old. If untreated, leads to permanent intellectual disability, seizures, delayed development, behavioural problems, & psychiatric disorders
37
Q
PKU treatment
A
- amino acid restriction via low-protein diet avoiding high-protein foods(i.e. meat, eggs, dairy)
- avoid aspartame (artificial sweetener) which is converted to phenylalaine
- supplementation w/Tyrosine
- regular monitoring of blood phenylalaine
38
Q
PKU in pregnancy
A
- If women with PKU have high phenylalanine during pregnancy this can harm the fetus or cause miscarriage
39
Q
PKU complications at birth
A
- Low birth weight
- Delayed development
- Facial abnormalities
- Abnormally small head
- Heart defects and other heart problems
- Intellectual disability
- Behavioural problems
40
Q
Tetrahydrobiopterin (BH4) deficiency
A
- Rare, autosomal recessive disorder – 600 cases worldwide
- Deficiency of dihydrobiopterin reductase
- Elevation in serum phenylalanine
- Treatment: BH4 supplementation (2-20mg/kg per day) or diet
41
Q
BH4 deficiency complications
A
- Mild: temporary low muscle tone
- Severe: intellectual disability, movement disorders, difficulty swallowing, seizures, behavioural problems, progressive problems with development, inability to control body temperature
42
Q
Branched chain amino acids
A
- Valine, Leucine, Isoleucine: branched, non-polar, glucogenic and/or ketogenic
- First is transamination
- Oxidative decarboxylation: pyruvate dehydrogenase (PDH) complex
- Generation of acyl-CoA derivatives
- 3rd step, dehydrogenation: C=C bond formation
43
Q
Maple Syrup Urine disease (MSUD)
A
- Rare, autosomal recessive disorder - 1/185 000 worldwide
- Deficiency in Branched-chain a-ketoacid dehydrogenase
- Accumulation of BCAA & associated a-ketoacids.
44
Q
Symptoms of MSUD
A
- first symptom: Ketosis and the characteristic odour of maple syrup in urine
- metabolic crisis: lack of energy, vomiting, irritability, breathing difficulties
- cause brain damage and death if untreated
45
Q
Treatment of MSUD
A
- dietary restriction of branched chain amino acids
- Problems: Very difficult to treat, BCAA are very abundant in most protein sources, 3 BCAA are all essential
- Supplementation of dietary thiamine (coenzyme) may be useful in patients that have an enzyme with low coenzyme affinity
