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MEH Sem 1 > Lecture 4: Alcohol+ Protein Metabolism > Flashcards

Lecture 4: Alcohol+ Protein Metabolism Flashcards

1
Q

Case study: Pesticide Poisoning. Guy has continued exposure to aromatic weak acids (e.g. DNC).
Symptoms = Low body temp, no subcutaneous fat. Explain symptoms.

A
  • aromatic weak acids readily penetrate the mitochondrial membrane & act as uncoupling agents
  • collapses p.m.f and uncontrolled metabolism occurs
  • large amount of metabolic fuel (fatty acids) + O2 used
  • less ATP, more heat = high body temp = sweating to cool down
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2
Q

Ketogenic a/a

A

Lysine, Leucime

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3
Q

Both glucogenic and ketogenic

A

Tyrosine, Threonine, Phenylalanine

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4
Q

Which a/a do pregnant women and children need more of? (Conditionally essential)

A

Arginine, thyrosine, cysteine

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5
Q

Where do carbon atoms for non-essential a/a come from?

A
  • intermediates of glycolysis (C3)
  • PPP (C4&C5)
  • Krebs Cycle (C4&C5)
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6
Q

Why is removal of nitrogen from a/a important?

A

To allow carbon skeleton of a/a to be metabolised

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7
Q

How is NH3 toxic (Hyperammonaemia) and state symptoms.

A
  • associated with blurred vision, tremors, coma, death
  • Disrupts energy supply to brain
  • affects pH and interferes with neurotransmitter release n synthesis
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8
Q

Which aminotransferase enzyme is routinely measured to test for liver damage?

A
  • ALT (Arginine Aminotransferase)

- AST (Aspartate Aminotransferase)

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9
Q

What is the difference between homocysteine and homocystine

A
  • Homocystine is two homocysteine molecules joint by a disulphide bond.
  • Homocystine is the oxidised form of homocysteine
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10
Q

What is the mode of inheritance of homocystinuria?

A

Autosomal recessive

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11
Q

How would PKU disrupt blood brain barrier?

A
  • Phenylalanine is a large neutral amino acid (LNAA) and competes for transport across the blood brain barrier via LNAAT.
  • Excess phenylalanine saturate this transporter
  • Inhibiting protein/neurotransmitter synthesis = brain development affected.
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12
Q

Briefly explain how the metabolism of alcohol can cause damage to the liver.

A
  • Intermediate metabolite, acetaldehyde is a toxic metabolite.
  • Increased acetyl coA, more fat synthesized, converted to triacylglycerol. Decreased NAD/NADH ratio. No oxidation of FA.
  • Less lipoproteins formed. Unable to transport fat out of liver. Results in ‘fatty’ liver.
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13
Q

Desc. the metabolism of alcohol

A

Ethanol —> Acetaldehyde —> Acetate
[alcohol dehydrogenase] [aldehyde dehydrogenase]
- Acetate –> acetyl CoA (enter TCA or FA synthesis)

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14
Q

What is the recommended limit of alcohol for both men and women in a week? What is the kinetics displayed by alcohol removal?

A
  • 14 units spread over 3 days in a week

- Exhibits zero-order kinetics (eliminated in linear fashion) = undergo constant removal regardless of plasma conc.

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15
Q

Which compound formed in alcohol metabolism is toxic and what keeps its effects to a minimum?

A
  • Acetaldehyde

- Aldehyde dehydrogenase has a very low Km

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16
Q

How does alcohol damage affect liver?

[3 disease]

A
  • Fatty liver
  • Alcoholic hepatitis
  • Alcoholic cirrhosis (damage)
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17
Q

What is the response to chronic alcohol consumption?

A
  • Decrease NAD+ –> lactate X converted to pyruvate –> lactate ⬆️ –> lactic acidosis + kidney ability to excrete uric acid ⬇️–> monosodium urate crystals form –> phagocytes remove, die –> release lysosomal enzyme –> cell lysis & inflammation –> gout
  • Decrease NAD+ –> X glycerol metabolism –> ⬇️gluconeogenesis –> hypoglycaemia
  • Increased acetyl~CoA –> ⬆️FA + ketone bodies + TAG –> lower lipoprotein synthesis –> fatty liver
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18
Q

Explain the mechanism of action of Disulfiram

A
  • Inhibit aldehyde dehydrogenase –> acetaldehyde accumulate –> ‘hangover’
  • Used with other methods to stop drinking
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19
Q

What diseases are oxidative stress linked to?

A
  • Cardiovascular disease
  • Alzheimer’s disease
  • Rheumatoid arthritis
  • Multiple sclerosis
  • Cancer
  • COPD
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20
Q

What are free radicals?

A

An atom/molecule that has unpaired electrons and is very reactive

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21
Q

What are RNS and give some examples

A
  • Superoxide react w NO to form peroxynitrite

- Not a free radical –> powerful oxidant

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22
Q

What are ROS and give some examples

A
  • Superoxide and Hydroxyl radical

- H2O2 X a radical but react with Fe2+ to produce radicals

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23
Q

How does ROS affect DNA?

A
  • Reacts with base: lead to mispairing –> mutation
  • Reacts w sugar: Strand break/mutation
  • Mutation can lead to cancer
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24
Q

How does ROS cause damage to proteins?

A
  • Reacts w proteins –> disulphide bond form –> fragment/ change in protein structure –> loss of function/change of func –> protein degradation
  • Lead to misfolding/crosslinking –> Heinz bodies in RBC
25
Q

What is the function of disulphide bonds?

A
  • Important role in folding and stability of proteins

- Formed between thiol groups of cysteine

26
Q

How does ROS damage lipids? x2

A
  • Lipid peroxidation (atherosclerosis)
  • ROS react w polyunsaturated FA –> lipid radical/ lipid peroxyl radical (after O2) –> chain reaction, react with more FA by extracting H atom –> Lipid bilayer integrity fails
27
Q

What are some sources of biological oxidants?

A

Endo:

  • ETC
  • Peroxidases
  • NADPH oxidases
  • NO oxidases

Exo:

  • Radiation
  • Drugs (Primaquine, anti-malarial)
  • Pollutants
  • Toxins (Paraquat, herbicide)
28
Q

How is the ETC a source of ROS?

A
  • Occasionally electrons escape ETC –> react w O2 –> superoxide
29
Q

What is a respiratory burst?

A
  • Rapid production of superoxide and H2O2 by phagocytes to kill bacteria
  • Neutrophils and monocytes
30
Q

What is chronic granulomatous disease?

A
  • Genetic defect in NADPH oxidase complex –> ⬆️risk to bacterial infections
  • Pneumonia, Impetigo (skin infection), cellulitis (infection in deeper layer of skin)
31
Q

What are some cellular defences against ROS and RNS?

A
  • Superoxide dismutase (SOD):
    i) Converts superoxide to H2O2 and O2
  • Catalase:
    i) Converts H2O2 to H2O & O2
    II) Declining levels associated w grey hair
  • Glutathione:
    i) Thiol group of Cys- donates e- to ROS
    ii) Reacts with another GSH to form disulphide
    [catalysed by glutathione peroxidase]
    *requires selenium
    iii) GSH reduced back by glutathione reductase –> transfer e- to NADPH
32
Q

What vitamins are cellular defences and how?

A
  • Vit E: Prevent peroxidation –> reduce free radical by donating H atom in nonezymatic reaction
  • Vit C: Regenerate reduced form of Vit E

BONUS: Carotenoids, Uric acid, Melatonin

33
Q

What are Heinz bodies?

A
  • Hb in RBC form disulphide bonds –> aggregates
  • Increased mechanical stress when squeezing through capillaries
  • Sign of G6PDH deficiency
  • Removed by spleen
34
Q

How does paracetamol cause damage? How is overdose treated?

A
  • High levels –> NAPQI ⬆️–> Lipid peroxidation, damage to proteins + DNA
  • Acetylcysteine replenish glutathione levels
35
Q

Why is creatinine measured?

A
  • Breakdown product of creatine/creatine.P
  • Produced at a constant rate, proportional to muscle mass
  • Indicator of renal function: raised plasma level + low urine level = damage to nephrons

Bonus: Plot graph of 24hr urine creatinine muscle mass X muscle mass

36
Q

Describe the different types of nitrogen balance

A
  1. N equilibrium: Intake = Loss
    [Normal state, No change in body protein]

2.Positive N balance: Intake > Loss
[Growth/Pregnancy/Recovering from malnutrition, ⬆️in total body protein]

  1. Negative N balance: Intake < Loss
    [Never normal/Trauma/Infection/Malnutrition, ⬇️body protein]
37
Q

Name glucogenic, ketogenic and both a.a & desc. their function

A
  • Glucogenic: Alanine
    (a. a can be used to make glucose)
  • Ketogenic: Lysine, Leucine
    (a. a can be used to make ketone bodies, acetyl CoA)
  • Both: Tyrosine
38
Q

When does mobilisation of protein reserves occur? What inhibits/stimulates it?

A
  • Occurs in liver
  • Extreme stress (starvation)
  • Inhibit: Insulin + GH, Stimulate: Cortisol (glucocorticoid)
39
Q

What are the conditionally essential a.a?

A
  • Children and pregnant women

- ACT = Arginine, Cysteine, Tyrosine

40
Q

Where does the carbon atoms for a.a synthesis come from?

A
  • TCA cycle
  • PPP
  • Glycolysis
41
Q

Where does the amino group for the synthesis of a.a come from?

A
  • Transamination from other a.a

- Ammonia

42
Q

What is tyrosine, cysteine and tryptophan used to synthesise?

A
  • Tyrosine: T3,T4 & melanin
  • Cysteine: Glutathione
  • Tryptophan: Melanin
43
Q

Why is removal of nitrogen from a.a essential? Which pathways facilitate the removal?

A
  • Allow carbon skeleton of a.a –> oxidative metabolism
  • Nitrogen –> urea
  • Pathways: Transamination & Deamination
44
Q

What is transamination? What enzyme catalyses the reaction, what is their mode of action?

A
  • Transfer amine group from one a.a to another
  • Aminotransferase enzyme use α-ketoglutarate –> trf to glutamate
  • Require coenzyme pyridoxal phosphate (Vit B6)
45
Q

What are some key aminotransferase enzymes? What do they test for?

A
  • Alanine (ALT), Aspartate (AST)
  • Liver function test
  • High in conditions: Viral hepatitis, toxic injury, autoimmune liver disease
46
Q

What is deamination? Where does it occur? Give some examples of enzymes that can perform deamination.

A
  • Changes amino group –> ammonia (very toxic) –> urea
  • Done in liver and kidney
  • Keto acids –> metabolism
  • Enzymes: Glutamate dehydrogenase, glutaminase
47
Q

Features of urea

A
  • High N content

- Inert, water sol, excreted in urea, osmotic role

48
Q

Where does the urea cycle occur? What regulates it?

A
  • Occur in liver & 5 enzymes

- High protein diet activate enzyme, Low represses it

49
Q

What are some consequences and causes of defects in the urea cycle?

A
  • Autosomal recessive genetic disorders deficiency in one of enzymes
  • Leads to: hyperammonaemia, accumulation of urea cycle intermediates
50
Q

What are some symptoms of defects in urea cycle and its treatment?

A
  • Symptoms: Vomiting, Lethargy, Mental retardation, Seizures, Coma
  • Low protein diet, replace a.a with keto acids

N.B Severe case = die, Mild = symptoms show late

51
Q

Why is ammonia toxic?

A
  • Readily diffusible, toxic to brain
  • Affects pH (alkaline)
  • Interfere w TCA cycle/ protein synthesis
52
Q

What are mechanisms used to transport a.a?

A
  1. Glutamine
    - A.a + glutamate –> glutamine
    - Transported in blood, cleaved by glutaminase (form glutamate & a.a –> urine)
  2. Alanine
    - Amine group transfered to glutamate (transamination) –> T. to pyruvate forms alanine
    - Alanine (blood) –> liver convert back to pyruvate –> amino group (urea) + pyruvate (TCA)
53
Q

How are defects in a.a metabolism detected and treated? What are some examples?

A
  • Rare
  • Heel prick test
  • Phenylketonuria (PKU),
  • Homocystinuria
  • Treatment: X a.a in diet, modify diet at early age (effect less)
54
Q

What is phenylketonuria (PKU)? Treatment?

A
  • Deficiency in phenylalanine hydroxylase
  • Accumulation of phenylalanine in tissue –> phenylketones in urine
  • T: Low PhA diet enriched w tyrosine, avoid artificial sweeteners + high protein foods (milk, meat, eggs)
55
Q

What are the affected pathways in PKU and what are its symptoms?

A
  • X phenylalanine hydroxylase –> PhA X converted to tyrosine –> X T3,T4, melanin synthesis
  • S: microcephaly (small head), hypopigmentation, intellectual disability, delayed development

**CAN BE AVOIDED W EARLY INTERVENTION

56
Q

What is homocystinuria? Treatment?

A
  • Problem breaking down methionine –> ⬆️homocystine
  • Autosomal recessive
  • Defect in cystathionine β-synthase
  • T: low methionine diet, avoid high protein foods, X nuts, cysteine/vit B6 supplement
57
Q

Effect of homocystinuria?

A
  • Accumulation of homocysteine due to cystathionine β-synthase deficiency (require vit B6 co-factor)
  • Elevated H.C –> cardiovascular disease
58
Q

How does protein turnover occur?

A
  1. Free amino acids from proteolysis of muscle proteins and digestion (also used for synthesis of muscle proteins)
  2. Free a.a go to the liver –> amino group removed form urea –> urine
  3. Free a.a –> carbon skeleton used (glucogenic + ketogenic) –> energy

MEH Sem 1 (18 decks)

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