Lecture 2- Protein and amino acid metabolism Flashcards
1
Q
Major nitrogen containing compounds:
A
- Amino acids
- Proteins
- Purines and pyrimidines (DNA/RNA)
- Creatine phosphate
- Neurotransmitters (dopamine)
- Some hormones (adrenaline)
2
Q
Nitrogen balance
A
Nitrogen balance is a measure of nitrogen input minus nitrogen output. Nitrogen Balance = Nitrogen intake - Nitrogen loss
3
Q
Nitrogen equilibrium
A
Intake = outake
- No change in total body protein
- Normal state in adult
4
Q
Positive N balance
A
Intake >output
- Increase in total body protein
- Normal state in growth and pregnancy or in adult recovering from malnutrition
5
Q
Negative N balance
A
Intake < output
- Net loss of body protein
- Never normal
- Trauma
- Infection
- malnutrition
6
Q
creatinine can be used to estimate
A
muscle mass
Creatinine urine excretion over 24h proportional to muscle mass
7
Q
creatinine is also a useful indicator of
A
renal function
- raised levels when nephron are dmaage
8
Q
creatinine is the breakdown product of
A
creatine & creatine phosphate in muscle
- Usually produced at constant rate depending on muscle mass (unless muscle is wasting)
- Filtered via kidneys into urine
9
Q
reference range of creatinine
A
10
Q
amino acid structure
A
11
Q
how many different types of amino acid
A
20
- 20 different side chains
12
Q
essential amino acids
A
Isoleucine
Leucine
Threonine
Histidine
Lycine
Methionine
Phenylalanine
Tryptophan
Valine
13
Q
Conditionally essential aa =
A
arginine, tyrosine and cysteine (children and pregnant women- high rate of protein synthesis)
14
Q
Animal origin protein=
A
high qual
15
Q
Plant origin =
A
low qual
16
Q
What contributes to free amino acids
A
- Dietary protein gets broken down into free amino acids
- Some amino acids produced de novo
- Some muscle protein broken down into amino acids via proteolysis
17
Q
Free amino acids are transporter to the liver and :
A
- Either lose their amino group (-NH2) à urea à urine
- Uses carbon skeleton (carboxyl group (COOH) and R groups)
- R groups determine if the amino acid is:
- Glucogenic
- Ketogenic amino acids
- R groups determine if the amino acid is:
18
Q
glucogenic
A
glucoseneogenesis
19
Q
ketogenic
A
ketone bodies
20
Q
glucoseneogensiss and ketone bodies both used tod erive nergy
A
21
Q
Glucogenic amino acids used in gluconeogenesis
A
- Glutamine
- Arginine
- Proline
- Histidine
22
Q
Ketogenic amino acids used to form ketone bodies
A
• lysine and leucine (provide acetyl CoA)
23
Q
Both glucogenic and ketogenic
A
- Threonine
- Tryptophan
24
Q
mobilisation of protein reserve
A
during extreme stress (starvation)
- under hromonal control
25
insuilin and growth hormone
both increase the rate of protein synthesis and decrease the rate of protein degradation
26
**Glucocorticoids (e.g. cortisol)**
decrease protein synthesis and increase protein degradation
27
**Cushing’s syndrome**
* Excessive breakdown of proteins can occur (excess cortisol)
* Weakens skin structure leading to striae formation
28
what sort of amino acids can the body synthesie
non-essential AA
29
Carbon for non-essential amino acid synthesis come from
* Intermediates of glycolysis (C3)
* Pentose phosphate pathway (C4 &C5)
* Kreb cycle (C4 7C5)
30
Amino group provided by
other amino acids by process transamination or from ammonia
31
In addition to **protein synthesis** (requires all 20 amino acids) amino acids also required for synthesis of **other important compounds** (requires **specific** amino acids).
32
**Removal of nitrogen from amino acids**
Allow carbon skeleton of amino acids to be utilised in oxidative metabolism
33
Once removed N can be
incorporated into other compounds or excreted from body as **urea**
34
Two main pathways facilitate removal of nitrogen from amino acids:
1. transamination
2. deamination
35
transamtionation
* Most aminotransferase enzyme use alpha-ketoglutarate to funnel the amino group to glutamate
* Exception to rule is aspartate aminotransferase which uses oxaloacetate to funnel amino groups to aspartate
36
All aminotransferase requires is
the coenzyme pyridoxal phosphate which is a derivative of vitamin B6
37
**Key aminotransferase enzymes**
**1) Alanine aminotransferase (ALT)**
Converts alanine to glutamate
**2) Asparate aminotransferase (AST)**
Converts glutamate to aspartate
38
Plasma ALT and AST
Measured routinely as part of liver function test. Levels high in conditions that cause extensive cellular necrosis:
* Viral hepatitis
* Autoimmune liver damage
* Toxic injury
39
amanita phalloides
death cap mushrooms which cause acute liver failure if ingested (plasma ALT levels up 20x normal)
40
**Deamination**
* Liberate amino group as free ammonia
* Mainly occurs in liver and kidney
41
Ammonia very toxic and must be removed...
Ultimately converted to urea or excreted directly in urine
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important deamination enzymes
* Amino acids oxidases
* Glutaminase
* Glutamate dehydrogenase
43
At physiological pH, NH3 is rapidly converted to
ammonium (NH4+)
44
urea
* High nitrogen content
* Non-toxic
* Extremely water soluble
* Chemically inert in humans
* Most urea is excreted in the urine via the kidneys
* Also performs useful osmotic role in kidney tubules
45
urea cycle
* Occurs in the liver and involves 5 enzymes
* Amount of urea cycle enzymes normally related to need to dispose of ammonia
* High protein diet induces enzyme levels
* Low protein diet or starvation represses levels
* Cycle is inducible but not regulated
46
refeeding syndrome
* can occur when nutiritonal support is given to severly malnourished patient
* ammonia toxicity significant factor (urea cycle down regulated)
* re-feed @ 5 to 10 kcal/kg/day
* raid gradually to full needs withing a week
47
**Defects in the urea cycle**
* Autosomal recessive genetic disorder caused by a deficiency of one of the 5 enzymes in the cycle
* Occurs in 1 in 30,000 live births
* Mutation cause partial loss of enzyme function
48
**Defects in the urea cycle can lead to**
* Hyperammonaemia
* Accumulation/excretion of urea cycle intermediates
49
clinical severity resulting from defects in the urea cycle depend on
* Nature of defect
* Amount of protein eaten
50
Severe urea cycle disorders show
* within 1 day of birth- if untreated child will die
51
Mild urea cycle enzyme deficiencies may
not show symptoms until early childhood
52
symptoms of urea cycle enzyme deficiency
* Vomiting
* Lethargy
* Irritability
* Mental retardation
* Seizures
* Coma
53
**Management of urea cycle enzyme deficiency**
* Low protein diet
* Replace amino acids in diet with keto acids
54
biochemical basis of ammonia toxicity
* Readily diffusible and extremely toxic to brain
* Blood level needs to be kept low (25-40 umol/l)
* Several potential toxic effects
55
Several potential toxic effects of ammonia toxicity
* Interference with amino acid transport and protein synthesis
* Disruption of cerebral blood flow
* pH effects (alkaline)
* interference with metabolism of excitatory amino acid NT (glutamate and aspartate)
* alteration of BBB
* interference with TCA cycle
56
transport of amino acid nitrogen from tissues to liver for safe disposal
two transport mechanisms utilised
1) Glutamine
2) Alanine
57
Transport mechanisms utilised
1) Glutamine
* Ammonia combined with glutamate to form glutamine
* Glutamine transported in blood to liver or kidneys where it is cleaved by glutaminase to reform glutamate and ammonia
* In liver ammonia fed into urea cycle
* In kidneys excreted directly into urine
58
Transport mechanisms utilised
2) Alanine
* Amine groups transferred to glutamate by transamination
* Pyruvate then transaminase by glutamate to form alanine
* Alanine transported in blood to liver where it is converted back to pyruvate by transamination
* Amino group fed via glutamate into urea cycle for disposal as urea whereas pyruvate is used to synthesise glucose which can be fed back to tissues
59
60
**Clinical problems of amino acid metabolism**
* Over **50** inherited diseases involving defects in amino acid metabolism
* Either total, or more commonly partial loss of **enzyme activity**
* **Rare** (many diseases \<1:250,000) although **collectively as a group** constitute a **significant** portion of paediatric genetic disease
61
if untreated those with probelsm of amino acid emtbaolism
are intellectually impaired
62
treatment of those with problems of aminoa acid metabolism
restricting amino acids in diet
63
how are problems of aminoa acid metabolism diagnosed
heel prick test
64
what does the heel prick test test for
* Sickle cell
* CF
* Congenital hypothyroidism
* Inborn errors of metabolism:
* Phenylketonuria (PKU)
* Homocystinuria
65
Inborn errors of metabolism:
* Phenylketonuria (PKU)
* Homocystinuria
66
Phenylketonuria (PKU)
* Moss common inborn error of amino acid metabolism (1 in 15,000 births)
* Deficiency in phenylalanine hydroxylase
* Autosomal recessive (chromosome 12)
* Accumulation of phenylalanine in tissue, plasma and urine
* **Phenylketones in urine**
* **Musty smell**
67
treatment of phenylketonuria (PKU)
* Low phenylalanine diet enriched with tyrosine
* Avoid artificial sweeteners (contain phenylalanine)
* Avoid high protein foods such as meat, milk, and eggs
68
homocystinuria
* Problem breaking down methionine
* Excess homocysteine (oxidised form of homocysteine) excreted in urine
* Autosomal recessive disorder
* 1 in 344,000 incidence
* Defect in cystathionine B-synthase (CBS)
* Affects connective tissue, muscle, CNS and CVS
69
70
treatment of homocysti uria
**Treatment**
* Low methionine diet
* Avoid milk, meat, fish, cheese, eggs, nuts
* Cysteine, Vit B6, Betaine, B12 and folate supplement
71
homocystinuria is often confused with
Marfans
* Some of the clinical features of homocystinuria such as – lens dislocation, skeletal deformities are similar to Mar fans
72
High levels of homocysteine affect connective tissue and bone
* Excess homocysteine causes damage to **collagen** and **elastin** fibres in connective tissue by binding to lysine residues in proteins
73
74
Metabolites of methionine are toxic to
neurones and cause neurological dysfunction
75
