Metabolism S5 - Protein and Amino Acid Metabolism Flashcards

1
Q

What is creatinine?

A
  • Breakdown product of creatine and creatine phosphate in muscle (v. Short term atp supply in muscle)
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2
Q

Why is creatinine a useful clinical marker?

A
  • Produced at a constant rate depending on muscle mass
  • Filtered via kidneys to urine
  • Creatinine urine excretion over 24 hours is proportional to muscle mass so provides an estimate of muscle mass
  • Commonly used as indicator of renal function
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3
Q

Nitrogen balance: what is N equilibrium?

A
  • Intake=output
  • No change in total body protein
  • Normal state in adult
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4
Q

Nitrogen balance: what is positive N balance?

A

Intake greater than output. Increase in total body protein. Normal in growth/pregnancy/adult recovering from malnutrition

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5
Q

What is negative nitrogen balance?

A

Intake less than output. Net loss of body protein. Never normal. Causes increased trauma/infection or malnutrition

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6
Q

Give an overview of protein turnover in the body

A

See image

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7
Q

Give an example of a glucogenic amino acid

A

Alanine

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8
Q

Give an example of a ketogenic amino acid

A

Lysine

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9
Q

When does mobilisation of protein reserves occur?

A

During extreme stress (starvation). Under hormonal control by insulin, growth hormone and glucagon

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10
Q

What is the effect of insulin and growth hormone on protein synthesis?

A

Increases it

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11
Q

What is the effect of insulin and growth hormone on protein degradation?

A

Decreases it

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12
Q

What is the effect of glucocorticoids (e.g. cortisol) on protein synthesis?

A

Decreases it

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13
Q

What is the effect of glucocorticoid on protein degradation?

A

Increases it

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14
Q

What are the 9 essential amino acids and what is the mnemonic for them?

A
  • Isoleucine, Lysine, Threonine, Histidine, Leucine, Methionine, Phenylalanine, Tryptophan, Valine
  • If Learned This Huge List May Prove Truly Valuable
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15
Q

Where do the carbon atoms from non-essential amino acid synthesis come from?

A
  • Intermediates of glycolysis (C3)
  • Pentose phosphate pathway (C4&C5)
  • Krebs cycle (C4&C5)
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16
Q

What is transamination/deamination?

A

Amino group is provided by other amino acids

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17
Q

Amino acids are required in the synthesis of other important compounds. What is tyrosine required for?

A

Catecholamines, melanin, thyroid hormones

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18
Q

Cysteine is required in the synthesis of….

A
Hydrogen sulphide (signalling molecule)
Glutathione
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19
Q

Tryptophan is required in the synthesis of…

A

Nictotinamide
Serotonin
Melatonin

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20
Q

Glutamate is required in the synthesis of…

A

GABA

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21
Q

Glycine is required in the synthesis of…

A

Purines, glutathione, haem, creatine

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22
Q

Arginine is required in the synthesis of…

A

Nitric oxide

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23
Q

What are the major nitrogen-containing compounds?

A
  • Amino acids
  • Proteins
  • Purines and pyrimidines (DNA/RNA)
  • Small amounts of others e.g. Creatine
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24
Q

What is transamination?

A

Transfer of amino group to keto acid

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25
Q

What are main aminotransferase enzymes?

A
Alanine aminotransferase (ALT): alanine -> glutamate
Aspartate aminotransferase (AST): glutamate -> aspartate

Used for liver function test

26
Q

What diseases does AST and ALT liver function test pick up on?

A

Viral hepatitis
Autoimmune liver diseases
Toxic injury

27
Q

What is deamination?

A

Liberates amino group as free ammonia, mainly occurs in liver and kidney

28
Q

What can keto acids be utilised for?

29
Q

Give some facts about urea

A

High nitrogen, non-toxic, extremely water soluble, chemically inert in humans, most urea excreted in urine via kidneys, performs useful osmotic role in kidney tubules

30
Q

What is the urea cycle?

A

Occurs in liver and involves 5 enzymes. High protein diet induces enzyme levels. Low protein diet represses levels.

31
Q

What is refeeding syndrome?

A

Malnourished patients
Ammonia toxicity significant factor (urea cycle down regulated)
Re-feed 5-10 kcal/kg/day to avoid

32
Q

What are the risk factors for refeeding syndrome?

A

BMI under 16

Unintentional weight loss of more than 15% in 3-6 monyhs

33
Q

What are defects in the urea cycle?

A

Autosomal recessive genetic disorders caused by deficiency of one of enzymes. Occur ~1 in 30,000 live births. Mutations cause partial loss of enzyme function. Leads to hyperammonaemia, accumulation/excretion of urea cycle intermediates

34
Q

What is clinical picture of NH3 toxicity?

A

Severity depends on nature of defect, amount of protein eaten. Severe urea cycle disorders show symptoms within 1 day after birth. Untreated -> child dies. Mild urea cycle enzyme deficiencies may not show symptoms until early childhood. Management: low protein diet, replace amino acids in diet with keto acids

35
Q

What are the potential toxic effects of ammonia?

A

pH effects (alkaline)
Interfere with metabolism of excitatory amino acid neurotransmitters
Alteration of blood-brain barrier
Interfere with TCA cycle

36
Q

What are two mechanisms for safe transport of ammonia from tissues for disposal?

A

Glutamine

Alanine

37
Q

What are the clinical problems of amino acid metabolism?

A

Over 50 inherited diseases involving defects in amino acid metabolism
Loss of enzyme activity
Rare
Can lead to intellectual impairment

38
Q

What does heel prick test test for?

A

Sickle cell disease
Cystic fibrosis
Congenital hypothyroidism
Inborn errors of metabolism (PKU)

39
Q

What is PKU?

A

Phenylketonuria: deficiency in phenylalanine hydroxylase

Autosomal recessive

40
Q

What is homocystinuria?

A
Problem breaking down methionine
Excess homocystine (oxidised form of homocysteine)
Defect in cystathionine Beta-synthase most common
41
Q

How is homocystinuria treated?

A

Low methionine diet

Avoid milk, meat, fish, cheese, eggs

42
Q

What are typical plasma lipid concentrations?

A

Total lipids: 4000-8500 mg/L

Cholesterol: less than 5.0 mmol/L

43
Q

What is cholesterol?

A

Some obtained from diet, most synthesised in liver
Essential component of membranes
Precursor of steroid hormones and bile acids
Transported around body as cholesterol ester

44
Q

What are the five distinct classes of lipoproteins?

A
Chylomicrons
VLDL
IDL
LDL
HDL
Each consists of apolipoprotein, triglyceride, cholesterol and cholesterol ester
45
Q

How does particle diameter relate to its density?

A

Inversely proportional

46
Q

Describe chylomicron metabolism

A

Loaded into small intestine and apoB-48 added before entering lymphatic system - travel to thoracic duct which empties into left subclavian vein - acquire 2 new apoproteins - apoC and apoE - apoC binds LPL on adipocytes and muscle - released fatty acids enter cells depleting chylomicron of its fat content - apoC dissociates and chylomicron = chylomicron remnant - chylomicron remnants return to liver - LDL receptor on hepatocytes binds apoE - chylomicron remnant taken up by receptor mediated endocytosis

47
Q

Describe VLDL metabolism

A

VLDL made in liver for purpose of transporting TAG to other tissues - apoB100 added in formation - apoC and apoE added from HDL particles in blood - VLDL binds to LPL on endothelial cells in muscle and adipose - depleted of triacylglycerol

48
Q

In muscle what are fatty acids taken up used for?

A

Energy production

49
Q

In adipose what are fatty acids used for?

A

Re-synthesis of triacylglycerol and stored as fat

50
Q

How are IDL and LDL formed?

A

VLDL to IDL to LDL
As triacylglycerol content of VLDL particles drops, VLDL particles dissociate from LPL enzyme complex and return to liver - VLDL content depletes and particle becomes short-lived IDL particle - taken up by liver or rebind to LPL enzyme to further deplete TAG content - upon depletion, IDL loses apoC and apoE and becomes an LDL particle (high cholesterol content)

51
Q

What is the function of LDL?

A

To provide cholesterol from liver to peripheral tissues
Peripheral cells express LDL receptor and take up LDL via process of receptor mediated endocytosis
LDL do not have apoC or apoE so not efficiently cleared by liver

52
Q

What is the clinical relevance of IDL and LDL metabolism?

A

Half life of LDL in blood is much longer than VLDL or LDL making LDL more susceptible to oxidative damage

53
Q

How do LDL enter cells?

A

By receptor mediated endocytosis. apoB-100 on LDL acts as ligand for these receptors. Receptor/LDL complex taken into cell by endocytosis by endosomes. Fuse with lysosomes for digestion to release cholesterol and fatty acids.

54
Q

How is HDL synthesised?

A

By liver and intestine (low TAG levels)
HDL particles can “bud off” from chylomicrons and VLDL
Free apoA-I can acquire cholesterol and phospholipid from other lipoproteins and cell membranes to form nascent-like HDL

55
Q

How does HDL mature?

A

Nascent HDL accumulate phospholipids and cholesterol from cells lining blood vessels
Hollow core progressively fills and particle takes on more globular shape
Transfer of lipids to HDL does not require enzyme activity

56
Q

What are hyperlipoproteinaemias?

A

Raised plasma level of one or more lipoprotein classes (6 main classes). Caused by either: 1. Over-Production 2. Under-removal

57
Q

What are the clinical signs of hypercholesterolaemia?

A

Xanthelasma: yellow patches on eyelids
Tendon Xanthoma: Nodules on tendon
Corneal arcus: white circle around eye

58
Q

What is raised serum LDL associated with?

A

Atherosclerosis

59
Q

How are hyperlipoproteinaemias treated?

A

First approach: reduce cholesterol and saturated lipids in diet. Increase fibre intake. Lifestyle- increase exercise, stop smoking

No response: drugs. Statins. Bile salt sequestrants.

60
Q

What is the mechanism of action of statins?

A

Reduce cholesterol synthesis by inhibiting HMG-CoA reductase. Rate limiting step in cholesterol synthesis in liver. Increases expression of LDL receptors in hepatocytes.