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Metabolism, Endocrinology and Haemotology > Alcohol Metabolism and Oxidative Stress & Protein Metabolism > Flashcards

Alcohol Metabolism and Oxidative Stress & Protein Metabolism Flashcards

1
Q

Where is >90% of alcohol metabolised and what happens to the rest of it?

A

In the liver.
The remainder is excreted passively in urine and on the breath - negligible amounts are oxidised by CYP2E1 enzyme or by catalase in the brain.

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2
Q

What are the recommended alcohol limits?

A

14 units per week over at least 3 days. 1 unit = 1/2 pint of beer / a small glass of wine = 8g eliminated at a rate of ~ 7g/hr.

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3
Q

In the first step of alcohol metabolism, ethanol —> ________________ (toxic metabolite, accumulation causes hangover) and this reaction is catalysed by ______ ___________. This reaction also involves the reduction of ______ to ______.

A

Acetaldehyde
Alcohol dehydrogenase
NAD+
NADH

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4
Q

The second step of alcohol metabolism converts acetaldehyde to _________, with the help of the enzyme _________ _____________. It also involves the reduction of NAD+. When this product is conjugated to _____ it forms acetyl-CoA, metabolised in the ___ cycle or utilised for ______ _____ synthesis.

A 
Acetate
Aldehyde dehydrogenase
CoA
TCA
Fatty acid
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5
Q

Acetylaldehyde toxicity is kept to a minimum by which property of aldehyde dehydrogenase?

A

It has a low Km.

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6
Q

Prolonged and excessive consumption of alcohol can cause sufficient accumulation which leads to what?

A

Liver damage - excess NADH and acetylCoA lead to a change in liver metabolism: ‘fatty liver’, alcoholic hepatitis and cirrhosis (scaring and fibrosis).

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7
Q

How does chronic alcohol consumption lead to lactic acidosis and gout?

A

Inadequate NAD+ for lactate —> pyruvate, so it accumulates in the blood, resulting in lactic acidosis.
The kidney’s ability to secrete uric acid is reduced by the same method, hence the gout.

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8
Q

How does chronic alcohol consumption lead to hypoglycaemia and fatty liver?

A

Inadequate NAD+ for glycerol metabolism means a deficit in gluconeogenesis, resulting in hypoglycaemia.
Inadequate NAD+ for fatty acid oxidation as well as increased AcetylCoA meaning more fatty acid and ketone body synthesis and so increased synthesis of triacylglycerol and lower lipoprotein synthesis leads to fatty liver.

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9
Q

Name an inhibitor of aldehyde dehydrogenase used as an adjunct in treatment of chronic alcohol dependence and explain its use?

A

Disulfram will mean that there’s a faster build up of acetaldehyde, making the user feel hungover from consuming alcohol.

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10
Q

Cellular damage caused by reactive oxygen/nitrogen species (ROS and RNS) is a significant component in a wide range of disease states. What is a free radical and how does it cause damage?

A

A free radical is an atom or molecule containing 1 or more unpaired electrons and is capable of independent existence.
They are usually very reactive and tend to acquire electrons from other atoms/molecules/ions, typically generating a 2nd free radical, thereby propagating damage.

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11
Q

An oxygen molecule is biradical with 2 _______ electrons in different ________. The addition of an ______ can make it into a O2.- superoxide ion. If you add 2H+ and an e- to superoxide, it become ________ _________, which is not a free radical, but can react with _____ to produce them.

A 
Unpaired
Orbitals
Electron 
Hydrogen peroxide
Fe2+
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12
Q

H2O2 is readily diffusible, how does it go on to produce OH/hydroxyl radical, which is the most reactive and damaging and how is it neutralised?

A

H2O2 + e- + H+ —–> H2O + OH

OH + e- + H+ —-> H2O

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13
Q

Superoxide + nitric oxide —> ONOO-/ ________, which is not itself a free radical, but a powerful _______ which can damage cells.

A

Peroxynitrite

Oxidant

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14
Q

How do ROS damage DNA in a way that could lead to mutations?

A

React with a base (modified base leads to mispairing and mutation) or with a sugar (strand break and mutation on repair).

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15
Q

How is the extent of oxidative damage present in cells damaged?

A

Measuring the amount of 8-oxo-dG present in cells, a product of the oxidative damage.

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16
Q

How may ROS damage proteins?

A

React with the backbone (fragmentation leading to degradation), or to a side chain (chemical modifications e.g. Disulphides bond at cys residue, meaning a change in structure, so either a gain or loss of function - degradation).

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17
Q

What is the importance of disulphides bonds in which types of proteins and how can inappropriate folding affect them?

A

Disulphides bonds are important in the folding and stability of some proteins e.g. Insulin (usually for proteins to be secreted or extra cellular domains) formed between thinly groups of cysteine residues.
Inappropriate formation can lead to misfolding, cross linking and disruption of function.

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18
Q

How do ROS cause damage to lipids?

A

Free radicals extract a H atom from a polyunsaturated fatty acid in a membrane lipid, so a lipid radical forms and reacts with oxygen to make a lipid peroxyl radical, which extracts a H from a nearby fatty acid, starting a chain reaction - hydrophobic bilayer disrupted, membrane integrity fails.

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19
Q

Sources of biological oxidants can be endogenous or exogenous, give some examples.

A

Exogenous: radiation, pollutants, drugs and toxins.
Endogenous: electron transport chain, nitric oxide synthesis and NADPH oxidises.

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20
Q

Which free radical may be made by the electron transport chain and how?

A

In the chain, FADH2 and NADH supply electrons from metabolic substrates, which pass through it and reduce oxygen to water at complex IV, but if an electron escapes the chain and reacts with dissolved oxygen, it could form a superoxide radical.

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21
Q

What’s the difference between iNOS, eNOS and nNOS and which reaction do they all catalyse?

A

Inducible NO synthase produces a high NO concentration, for direct toxic effects in phagocytes.
Endothelial NOS is for signalling.
Neuronal NOS is for signalling.
All: arginine —> citrulline + NO - for vasodilation, neurotransmission etc (NADPH +O2 —> NADP + H2O)

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22
Q

What’s the respiratory burst?

A

A rapid release of superoxide and hydrogen peroxide from phagocytes cells - ROS and peroxynitrite destroy invading bacteria as part of the antimicrobial defence system.

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23
Q

What is Chronic granulomatous disease?

A

A genetic defect in the NADPH oxidase complex (used to make superoxide), causing an enhanced susceptibility to bacterial infections.

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24
Q

Explain the cellular defence of SOD (superoxide dimutase).

A

Superoxide –> hydrogen peroxide + oxygen, 3 isoenzymes, primary defence as superoxide is a strong initiator of chain reactions. Hydrogen peroxide can then be converted by catalase.

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25
Q

Explain the cellular defence of Catalase.

A

Hydrogen peroxide from superoxide simultaneously reaction –> oxygen and water, is a widespread enzyme, important in immune cells to protect them against the oxidative burst.

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26
Q

Explain the cellular defence of Glutathione.

A

A tripeptide synthesised in the body to protect against oxidative damage - think group of cysteine on GSH (reduced form), donates an electron to ROS then joins another to form disulphides (GSSG) catalysed glutathione eroxidase, which requires selenium. GSSG is reduced back to GSH by glutathione reductase - needs NADPH (from pentose phosphate pathway).

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27
Q

Vitamin E is a free radical scavenger, what does it do? What about vitamin C (ascorbic acid)?

A

Vitamin E is a lipid soluble antioxidant important for protection against lipid peroxidation.
Vitamin C is a water soluble antioxidant with a role in regenerating vitamin E.

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28
Q

Aside from Vit. C and Vit. E, give some examples of free radical scavengers.

A

Uric acid and melatonin, they all reduce free radical damage by donating a H atom to them in a nonenzymatic reaction.

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29
Q

If there are antioxidants and free radical scavengers, why do they damage proteins/lipids/DNA?

A

Oxidative stress occurs when oxidants outweigh defences.

30
Q

What is galactosaemia?

A

A deficiency in any 1 of 3 enzymes (uridyl transferase, galactokinase and UDP- pgalactose epimerase) metabolising galactose for glycogenesis or glycolysis favours the conversion of galactose to galactitol - activity of Aldose reductase consumes excess NADPH, so compromised defences against ROS damage - crystalline protein in lens of eye denatured (and osmotic pressure causes lens to swell).

31
Q

What are the symptoms of galctosaemia?

A

Cataracts, hypoglycaemia, renal failure and vomiting.

32
Q

What’s the problem with Glucose-6-phosphate dehydrogenase deficiency?

A

It is used in the pentose phosphate pathway to produce NADPH, which itself is used to reduces oxidised glutathione (GSSG). There is therefore less protection against damage from oxidative stress. When there’s hydrogen peroxide (from infection, drugs, broad beans etc), protein damage and lipid peroxidation can’t be stopped. Aggregates of cross linked haemoglobin lead to haemolytic and there are Heinz bodies.

33
Q

What are Heinz bodies and what happens to them?

A

Dark staining within RBCs from precipitated haemoglobin, which bind to the cell membrane, altering its rigidity - increased mechanical stress when they’re squeezed through capillaries - the spleen removes bound Heinz bodies, resulting in ‘blister cells’. They are a clinical sign of G6PDH deficiency.

34
Q

What’s the normal metabolism of paracetamol and how does this change above the recommended dosage?

A

Normally metabolised by conjugation wit sulphate or glucoronide, but above a toxic dosage metabolite NAPQI accumulates with direct toxic effects (oxidative damage to hepatocytes - lipid peroxidation and damage to proteins and DNA.

35
Q

What is the antidote for paracetamol (acetaminophen) and how does it work?

A

Acetylcysteine works by replenishing glutathione levels (depletion would lead to oxidative damage that’s irreversible, so you need to act fast).

36
Q

How does creatinine act as a useful clinical marker?

A

It’s the breakdown product of creatine and phosphocreatine (PCr) in muscles, usually produced at a constant rate and filtered via the kidneys into the urine, so excretion over 24 hours is proportional to muscle mass and a marker of renal function (raised in nephron damage). In urine each day is 14-26mg/kg for men and 11-20mg/kg for women.

37
Q

What are nitrogen equilibrium, positive N balance and negative N balance?

A

N equilibrium where intake = output.
+ve N balance where input > output - increased total body protein, normal growth, pregnancy or recovery from malnutrition.
-ve N balance where input < output - net loss of body protein is never physiological with causes including trauma, infection and malnutrition.

38
Q

What is protein turnover?

A

The balance between synthesis and degradation.

39
Q

What combines to make free amino acids, used in the synthesis of cellular proteins and regenerated in proteolysis?

A

Dietary protein and de novo amino acid synthesis.

40
Q

How are free amino acids split in the liver?

A

In amino groups, then urea into the urine.
The carbon skeleton with glucogenic amino acids feed into gluconeogenesis and ketogenic amino acids making ketone bodies (can be both, depending on the side chain, but not all amino acids go down the same metabolic pathway to produce energy).

41
Q

Give an example of a glucogenic, a ketonic and a both amino acid?

A

Glucogenic - Methionine
Ketogenic - Lysine
Both - Phenylalanine

42
Q

How is mobilisation of protein reserves controlled, e.g. in times of extreme stress (starvation)?

A

It is under hormonal control, with insulin and growth hormone increasing protein synthesis and decreasing degradation, while Glucocorticoids (e.g. Cortisol) have the opposite effect.

43
Q

Why is Cushing’s syndrome?

A

Excess cortisol, meaning an excessive breakdown of proteins, weakening skin structure causing striae.

44
Q

Amino acid structure: amino group-CH-________ group and carbonyl group, all joined by _________ bonds. __ types of amino acid mean __ different side chains, __ of these are essential.

A

Variable
Peptide
20 (x2)
9

45
Q

The body can synthesise non essential amino acids, where do the carbon atoms come from (3 sources) and how are they amino groups added?

A

C3 intermediates of glycolysis, C4&5 pentose phosphate pathway and C4&5 TCA cycle.
Amino groups come from other amino acids by transamination or from ammonia.

46
Q

As well as in protein synthesis, amino acids are used to make other important compounds, give some examples.

A

Tyrosine for catecholamines, arginine for nitric oxide and cysteine for glutathione.

47
Q

For the carbon skeleton of a peptide to be used, the ____ ______ must first be removed. Once that’s done, the nitrogen goes into other compounds or is excreted as ____.

A

Amino group

Urea

48
Q

What are the two pathways for amino group removal and why do they entail?

A

Transamination, with swapping the amino acid on one amino group with O on a ketoacid to make a different amino acid. Deamination, which liberates the amino acid as free ammonia.

49
Q

Mostly alpha-ketoglutarate is used by ________ enzymes to funnel the amino group to _________. The exception is _______ _____________ (AST), which uses oxaloacetate to make ________. All aminotransferases need ________ pyridoxal phosphate - a derivative of vitamin ___.

A 
Aminotransferase
Glutamate
Aspartate aminotransferase 
Aspartate 
Coenzyme
B6
50
Q

What are the 2 key aminotransferases?

A 
Alanine aminotransferase (ALT) - alanine --> glutamate.
Aspartate aminotransferase (AST) - glutamate --> aspartate.
51
Q

What are plasma ALT and AST a measure of?

A

Liver function - high in conditions with extensive cellular necrosis (e.g. Viral hepatitis or toxic injury).

52
Q

Where does deamination occur mostly?

A

In the liver and kidneys.

53
Q

Keto acids can be utilised for ______ and are important in the ________ of dietary D-amino acids (from plants and _____ _______). Ammonia/NH4+ (at physiological pH) are very toxic and ultimately converted into ___, to be excreted directly in the _____.

A 
Energy
Deamination
Micro organisms
Urea
Urine
54
Q

Several enzymes can be used for deamination, name 3 types.

A

Amino acid oxidases
Glutaminase
Glutamate dehydrogenase

55
Q

Urea has a high __ content, is extremely ____ soluble and is chemically ______ in humans, most is excreted in the urine via the ______. It also has an osmotic role in the _______ _________.

A 
N
Water
Inert
Kidneys
Kidney tubules
56
Q

What is the purpose of the urea cycle and where does it take place?

A

Allows amine groups of amino acids to be safely disposed of in the body via nontoxic urea - aspartate and glutamate can feed in. It occurs in the liver.

57
Q

How many enzymes are involved in the urea cycle? The cycle is induced, but not regulated, explain.

A

5 enzymes - the amount of which is normally related to the need to dispose of ammonia. High protein diets induce enzyme levels whereas low protein diets or starvation represses.

58
Q

When may Refeeding syndrome occur?

A

When nutritional support is given to severely malnourished people, ammonia toxicity is a significant factor.

59
Q

Defects in the Urea cycle include autosomal recessive genetic disorders, occurring in 1 in every 30,000 live births, which causes a deficiency in an enzyme. What may the partial loss of function lead to in the body.

A

Hyperammonaemia and the accumulation/excretion of urea cycle intermediates.

60
Q

What are the symptoms of NH3 toxicity (caused by autosomal recessive genetic disorders affecting Urea cycle enzymes) and when do they appear?

A

Vomiting, lethargy, irritability, mental retardation, seizures, and a coma depending on the nature of the defect and how much protein is eaten.
Symptoms appearing within 1 day of birth need immediate treatment or the patient will die, but a mild enzyme deficiency may not show until early childhood.

61
Q

How is NH3 toxicity (caused by autosomal recessive genetic disorders affecting Urea cycle enzymes) managed?

A

With a low protein diet and replacement in the diet of amino acids with keto acids.

62
Q

NH3 toxicity is particularly bad because it is readily diffusible and toxic to the brain, at what levels should ammonia be kept at in the blood and what are some of the toxic effects?

A

25-40micromoles/L.
Potential toxic effects: interference with amino acid transport and protein synthesis, disruption of cerebral blood flow, effect on pH (increases), interference with metabolism of exciter your amino acid neurotransmitters (glutamate and aspartate), alteration with blood brain barrier and interference with the TCA cycle.

63
Q

What are the 2 mechanisms for safe disposal of ammonia by peripheral tissues?

A

Ammonia combining with glutamate to make glutamine, by glutamate synthase.
Ammonia combing with pyruvate to form alanine.

64
Q

What happens to the glutamine and alanine once they’ve been formed to dispose of ammonia?

A

They travel in the blood to the liver and the kidneys where glutamine is cleaved by glutaminase, the reformed NH3 enters the urea cycle in the liver or excreted directly at the kidneys. Alanine is converted back to pyruvate by transamination - NH2 is fed into the urea cycle by glutamate into the urea cycle for disposal (and the pyruvate is converted into glucose, which is fed back into the tissues.

65
Q

Clinical problems of amino acid metabolism involve over __ inherited defects, most commonly involving partial _____ of enzyme ________. They are individually rare, but collectively as a group, significant. If untreated, they may lead to ___________ ____________. They’re treated by ___________ specific amino acids in the _____.

A 
50
Loss
Function
Intellectual impairment
Restricting
Diet
66
Q

What does the Heel prick test look for?

A

Sickle cell, cystic fibrosis, congenital hyperthyroidism and informs error of metabolism including phenylketonuria and homocystinuria.

67
Q

Phenylketonuria (PKU) is the most common inborn error of metabolism, what is it and how is it treated?

A

A deficiency in phenylalanine hydroxylase - accumulation of phenylalanine in tissues, plasma and urine - phenylketones in urines mean a musty smell.
It is treated with a strict, low phenylalanine diet (avoid artificial sweeteners and high protein foods).

68
Q

What is the inheritance pattern of PKU and what does it stand for?

A

Phenylketonuria is autosomal recessive (chromosome 12).

69
Q

Because phenylalanine is not converted into tyrosine in phenylketonuria, many pathways are affected, name some. What are some symptoms of the condition?

A

Pathways of noradrenaline and adrenaline, dopamine and melanin, amongst others are affected.
Symptoms of PKU: severe intellectual disability, developmental delay, microcephaly, seizures and hypopigementation.

70
Q

What are homocystinurias?

A

Problems breaking down methionine, a set of autosomal recessive disorders - a defect in cystathionine beta-synthase is the most common. Excess homocystine (oxidised homocysteine), is excreted in the urine.
Methionine is reversible converted into cysteine before cystathionine beta-synthase is used.

71
Q

What in the body does homocystinuria affect and how is it treated?

A

Connective tissue, muscles, the central nervous system and cardiovascular system are affected.
Homocystinuria is treated with a low methionine diet, avoiding certain high protein foods and taking some supplements.

Metabolism, Endocrinology and Haemotology (12 decks)

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