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Medicine 1 > Week 8 - Metabolism > Flashcards

Week 8 - Metabolism Flashcards

1
Q

What are metabolites?

What is the metabolic pathway?

A

Reactants, intermediates and products

Series of enzyme catalysed reactions

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2
Q

What are the differences between degradative pathways and biosynthetic pathways?

A
  • Converge on common intermediates
  • Metabolised further in central oxidative pathway
  • Few metabolites are starting point
  • Carry out opposite
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3
Q

What do membrane-bound compartments require?

A

Transport systems

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4
Q

How is metabolic flux controlled?

A
  • Allosteric control (enzymes regulated by effectors)
  • Determined by RDS
  • Covalent modification (hormonal control of ezymes)
  • Substrate cycles (vary rates of opposing reaction)
  • Genetic control (protein synthesis affects enzyme activity)
  • Supply and demand
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5
Q

What is the route of carbohydrate digestion?

A
  • Salivary amylase (to oligosaccharides)
  • Small intestine digestion with pancreatic enzymes
  • Mucosal cell enzymes (disaccharides to monosaccharides)
  • Active transport takes glucose into cells with Na+
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6
Q

What is the difference between D glucose and pyranose?

What is glucose stored as?

A

D = linear

Pyranose = Ring structure

Glycogen

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7
Q

What are the properties of glycolysis?

A

Provides ATP

+ O2 = Pyruvate as end product –> forms Acetly CoA when oxidative phosphorylated

  • O2 = Pyruvate reduced to lactate by lactate dehydrogenase
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8
Q

What are the 2 types of glucose transport?

A

Na+-independent facilitated diffusion –> Moves via concentration gradient

ATP-dependent Na+-monosaccharide transport –> Co-transport system against concentration gradient in intestinal epithelial cells

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9
Q

What are the proeprties of glucose phosphorylation and fructose 6-phosphate phosphorylation?

A

Catalysed by hexokinase

Irreversible

Rate limiting

Catalysed by phosphofructokinase-1

Inhibition of enzyme by + ATP/citrate concentration

Activation of enzyme by high AMP concentration

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10
Q

What are the properties of haemolytic anaemia?

A
  • Lack of mitochondria in red blood cells
  • Failure of ATP synthesis, altering cell shape
  • Caused by genetic defects of glycolytic enzymes
  • Regular transfusions required
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11
Q

When does gluconeogenesis occur?

What is glycogenolysis?

A

When there is insufficient glucose

Mobilisation of glucose from glycogen

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12
Q

What are the proeprties of glycogen?

A
  • Main stores in skeletal muscle and liver
  • Muscle fuel reserve for ATP synthesis
  • 1 reducing end
  • Non-reducing end on every branch
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13
Q

What are the 3 glycogen enzymes for degradation?

A

Glycogen phosphorylase:

  • A dimer
  • Breaks 1,4 linkages
  • Allosteric interactions and ocvalent modification
  • ATP, G6P, glucose = inhibitors
  • AMP = activator

Glycogen debranching enzyme:

  • Breaks 1,4 linkages then makes new ones on main branch, reducing branching

Phosphpoglucomutase:

  • Converts glcosyl units to G1P
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14
Q

What are the properties of glycogen synthesis?

A

Glycogen synthase = makes 1,4 linkages (active form = dephosphorylated)

Glycogenin attaches to glucose

Liver synthesis accelerates during well-fed and fasting periods

Skeletal muscle synthesis accelerates during rest and exercise periods

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15
Q

What are the properties of insulin, glucagon and adrenaline hormonal regulation?

A
  • Act through enzyme phosphorylated state changes
  • Adrenaline and glucagon act through second messenger
  • Adrenaline acts on muscle and liver
  • Glucagon acts on liver
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16
Q

When is gluconeogenesis inhibited?

When does glyconeogenesis increase?

What activates glycogenolysis in muscle?

A

When substrate and energy levels are high

When glucose and energy levels are low

By calcium as it binds and activates calmodulin

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17
Q

What are glycogen storage diseases?

A

Genetic diseases caused by defective enzymes needed for synthesis / degradation

Glycogen has abnormal structure or excess accumulation

Von Gierke’s disease

Type Vlll

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18
Q

What are the properties of the TCA cycle?

A

In mitochondrial matrix

NADH + H+ + FADH2 from NAD+ and FAD+ by removing electron pairs

Biosynthesis of metabolites

No ATP produced

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19
Q

What are the properties of the pyruvate dehydrogenase reaction?

A

Pyruvate + NAD+ + CoA à Acetyl CoA + NADH + CO2

Controls glucose entry into TCA cycle

Rate limiting step

Irreversible

Regulated (allosterically, covalently, hormonally)

PDH = multienzyme complex, 3 enzyme complexes, 5 coenzymes

3 enzyme activities = Pyruvate decarboxylase, Dihydrolipoyl transacetylase, Dihydrolipoyl dehydrogenase (E1, E2, E3)

5 coenzymes = Thiamine pyrophosphate, Lipoamide, CoA, FAD+, NAD+

Mechanism = pyruvate decarboxylation –> acetyl CoA formation –> oxidised lipoamide regeneration

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20
Q

What are pyruvate dehydrogenase medical problems?

A

Beri-beri (thiamine deficiency) –> PNS damage and weakened muscle

PDH deficiency –> reduced ATP synthesis, + alenine

Mercury / arsenite poisoning

Vitamin deficiencies

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21
Q

What is produced for each Acetly CoA oxidised?

A

3 NADH

1 FADH2

2 CO2

1 GTP

4 pairs of electron

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22
Q

What are the properties of the elctron transport chain?

A

In inner mitochondrial matrix

4 protein complexes (3 proton pumps (complex 1,3,4), 1 link to TCA cycle (complex 2))

2 small components (CoQ, cytochrome c)

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23
Q

What are the properties of complex 1?

A

NADH dehydrogenase

NADH binds to it

Accepts NADH electrons

Transfers electrons to CoQ

4 H+ pumped out

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24
Q

What are the properties of complex 2?

A

Succinate dehydrogenase

Enzyme of TCA cycle

Accepts FADH2 electrons

Transfers electrons to CoQ via Fe-S proteins

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25
Q

What are the properties of complex 3?

A

Cytochrome c reductase

Heme prosthetic group

Accepts CoQ electrons

Transfers electrons to cytochrome c

2 protons pumped across

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26
Q

What are the properties of complex 4?

A

Cytochrome c oxidase

13 protein subunits with 2 heme groups and 3 copper ions

Cytochrome c electrons accepted

Electrons transferred to 1/2O2 –> reduced to H2O

8 protons pumped across

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27
Q

What are the properties of coenzyme Q?

A

Ubiquinone

Small, lipid soluble compound

Mobile carrier

Accepts Fe-S protein electrons from complex 1 and 2

Electrons transferred to complex 3

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28
Q

What are the proeprties of cytochrome c?

A

Peripheral membrane protein bound to IMM loosely

Bind to complex 3 and transfers electrons to complex 4

Highly conserved

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29
Q

What are the proeprties of ATP synthesis in oxidative phosphorylation?

A

ATP synthase is complex 5

In inner mitochondrial matrix

Composed of 2 subunits:

F1 ATPase – generates ATP, F0 coupling factor – proton channel spanning IMM

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30
Q

What agents affect oxidative phosphorylation?

A

ATPase inhibitors (oligomycin)

SSI’s of electron transport chain

Uncouplers (neutralise proton gradient and prevent ATP synthesis) à chemical = dinitrophenol, natural = uncoupling proteins

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31
Q

What is UCP1/ thermogenin?

A

In mitochondria of brown adipose tissue

Energy from electron transport chain = used to generate heat (non-shivering thermogenesis)

In new-borns and hibernating animals, is important

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32
Q

What is the process of fatty acid mobilisation?

A

Glucagon or adrenaline activate hormone-sensitive lipase

Triacyglycerol in adipose tiossue is hydrolysed

Free fatty acids and glycerol is formed

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33
Q

Why can’t the brain take up free fatty acids?

A

Cannot cross blod-brain barrier

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34
Q

What happens during ‘beta’-oxidation of fatty acids?

A

Activation in cytosol of long fatty acid chains forming fatty acyl CoA

Import of activated LCFAs into mitochondria

‘beta’-oxidation in mitochondrial matrix, generating NADH, FADH2, acetyl CoA

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35
Q

What is used for LCFA import into mitochondria?

A

Carnitine shuttle

CoA esters cannot cross mitochondrial inner membrane

36
Q

What are the proeprties of carnitine?

A

From meat

Liver and kidney synthesise it

Kidneys supply to muscles via blood

Deficiency leads to toxic LCFA build up causing neurological damage

37
Q

What are the proeprties of ketone bodies?

A

Brain fuel source during starvation

Acetyl CoA in liver mitochondria makes it

Happens when high AcCoA levels

Small glycogen stores in babies = can quickly become ketotic

38
Q

What happens during ketone body synthesis?

A

Liver mitochondria

Acetoacetate and ‘beta’-hydroxybutyrate form 2 ketone bodies

Acetoacetate reduced to ‘beta’-hydroxybutyrate when high NADH (during starvation)

39
Q

How are ketone bodies utilised?

A

Not metabolised by liver

Adaptation of brain to use them during starvation

Used by heart muscle and kidney cortex under all conditions (spares glucose)

40
Q

What happens during ketoacidosis?

A

0.1mM = normal

7mM = tissue utilisation saturated so excreted in urine (ketonuria)

  • blood pH (ketoacidosis)

Test using paper strips for ketonuria

41
Q

When does gluconeogensis occur?

A

During exercise (lactate)

Short-term fasting (alanine)

Diabetes (insulin insensitivity)

Trauma (peripheral insulin resistance)

When glucose levels are low and ATP levels are high

42
Q

When is glucose required?

A

Brain + RBCs for fuel

Glycogen stores (enough for 1 day (190g))

Inhibited by alcohol (ethanol = + cytosolic NADH conc. In liver –> gluconeogenesis intermediates are therefore redirected to alternate reaction pathways so – glucose synthesis)

43
Q

What are the properties of gluconeogenesis?

A
  • Glucose synthesis from non-carbohydrate precursors
  • Occurs in liver, kidneys and small intestine
  • Occurs in cell cytosol
  • Is reversal of glycolysis
44
Q

When is gluconeogenesis not the reversal of glycolysis?

A

Pyruvate to PEP:

Pyruvate (in mitochondria) + CO2 + ATP –> oxaloacetate (in mitochondria) + ADP + Pi

F1,6BP to F6P:

ructose 1,6-biphosphate + H2O –> Fructose 6-phosphate + Pi

G6P to glucose:

G6P + H2O –> glucose + Pi

45
Q

What effect does insulin have on gluconeogenesis?

What effect does glucagon have on gluconeogenesis?

A

Promotes glycolytic enzyme synthesis

Inhibits PEPCK synthesis

Increases PEPCK and F1,6BPase expression

46
Q

How do you form gluconeogenesis precursors from amino acids?

A

Remove amino group

Use carbon skeleton to form glucose

47
Q

What are the 4 types of metabolic pathways?

A

Fuel oxidative pathways

Fuel storage and mobilisation

Biosynthetic pathways

Detoxification / waste disposal pathways

48
Q

What is anabolism?

What is catabolism?

What are anabolic pathways?

What are catabolic pathways?

A

Synthesis

Breakdown

Synthesis of large molecules

Breakdown of large molecules

49
Q

How is balance acheived in metabolism?

A

Blood nutrient concentration (fatty acids for example)

Hormones (epinephrine for example (fight or flight))

CNS

50
Q

What are the consequences of too low or high metabolism?

A

Low = hypoglycaemia, brain metabolism limited

High = coma, non-enzymatic glycosylation of proteins

51
Q

What is the role of insulin in metabolism?

A

Promotes fuel storage and use for growth

Glycogen formation in liver & muscle

Conversion of glucose to triacylglycerols (liver)

Protein synthesis (e.g. albumin) in liver

Storage of triacylglycerols (adipose)

Increases glucose uptake by muscle & adipose

Amino acid uptake & protein synthesis in skeletal muscle

52
Q

What is the role of glucagon in metabolism?

A

Promotes mobilisation and maintains fuel availability (not in muscle as lack of receptors)

Increased Glycogenolysis, reduced glycogen synthesis in liver

Stimulates gluconeogenesis & ketogenesis

Mobilizes fatty acids from adipose triacylglycerols

53
Q

Where is insulin and glucagon produced?

A

Pancreas:

  • ‘alpha’ cells secrete glucagon
  • ‘beta’ cells secrete insulin
54
Q

What are the properties of glucagon in metabolism?

A

Produced as preprohormone in Rough Endoplasmic Reticulum

Acts on liver & adipose tissue

Degraded by liver & kidneys (~5 min ½ life)

Secretion is regulated by [glucose] & [insulin]

55
Q

what are the intracellular events of glucagon and insulin in metabolism?

A

Hormones change substrate flux through pathway

Hormones bind to receptors on cell surface (second messengers activated, signal transduction)

3 types of transduction à receptor coupled to adenylate cyclase – receptor / kinase activity – receptor coupled to hydrolysis of PIP2

Insulin autophosphorylates cell receptor

Glucagon binding = causes formation of secondary messenger

56
Q

What are cellular responses to glucagon or insulin?

A

Reverses glucagon-stimulated phosphorylation

Kicks off a phosphorylation cascade

Induction/repression of enzyme

Stimulate protein synthesis

Stimulate glucose & amino acid intake

57
Q

What are the 3 types of memory?

A

Sensory memory (registration)

Working / short-term memory (limited capacity, acoustic coding, receny effect)

Permanent / long-term memory (large capacity, primary effect, semantic coding)

58
Q

How can you imporve patient recall?

A

Organisation (good structure)

Less is more

Stress importance

Precise information

Association with visual imagery

Cues

External aids

59
Q

What is adherence?

What are the forms on non-adherence?

A

Following advice from health professional

All aspects of self-management

Failure to make lifestyle changes necessary for health

Failure to monitor health

Failure to take up available health screening

Failure to keep appointments

60
Q

What needs to be involved in a systematic review?

A

a clearly stated set of objectives with pre-defined eligibility criteria for studies;

an explicit, reproducible methodology;

a systematic search that attempts to identify all studies that would meet the eligibility criteria;

an assessment of the validity of the findings of the included studies, for example through the assessment of risk of bias; and

a systematic presentation, and synthesis, of the characteristics and findings of the included studies.

61
Q

What is evidence based medicine?

A

Systematic review, appraisal and use of clinical research findings to aid optimum clinical care delivery to patients

62
Q

How to formulate evidence based medicine?

A

Formulate a clear clinical question from a patient’s problem

Search the literature for relevant clinical articles

Evaluate (critically appraise) the evidence for its validity and usefulness

Implement useful findings in clinical practice

63
Q

What happens to dietary carbohydrates during the fed state?

A

Turned into monosaccharides

Starch digested by ‘alpha’-amylase

Di/tri/oligosaccharides digested by enzymes

Monosaccharides absorbed by intestinal epithelial cells –> transported to hepatic portal vein

64
Q

What happens to glucose, proteins, free amino acids and fats during the fed state?

A

Glucose = oxidised for energy –> enters biosynthetic pathways –> forms carbon skeleton of most compounds

Proteins = cleaved by pepsin in stomach and proteolytic enzymes in pancreas (absorbed into intestinal epithelial cells –> released into hepatic portal vein)

Free amino acids = absorbed from blood and used for protein synthesis and biosynthesis

Fats = insoluble –> triacylglycerols = emulsified by bile sales and pancreatic lipase converts TAGs to fatty acids and 2-monoacylglycerols –> form micelles when in contact with bile salts

65
Q

What do hormones effect on metabolic pathways?

A

Substrate availability

Allosteric regulation of enzyme

Covalent modification of enzymes

Induction of enzyme synthesis

66
Q

What is the role of liver in fed state metabolism?

A

Uses hepatic portal vein for venous drainage of gut and pancreas

Takes up carbs, lipids and AA’s

67
Q

What happens during carbohydrate metabolism in the fed state?

A

+ glucose intake by hepatocytes (GLUT-2 = high Km)

+ glucose phosphorylation (glucokinase = forms glucose-6-phosphate)

Excess glucose converted into TAG (packaged into LDLs)

+ glucogenesis –> activation of glycogen synthase by allosteric effector and dephosphorylation –> glucose-6-phosphate converted into glycogen

+ pentose phosphate pathway/hexose monophosphate shunt activity

+ glycolytic enzymes as + insulin-to-glucagon conversion

  • glucose production
68
Q

What happens during fat metabolism in fed state?

A

Liver = primary fatty acid synthesis site –> acetyl CoA carboxylase activated

+ acetyl CoA

69
Q

What happens during the fasting state and starved state?

A

2-4 hours after meal:

blood glucose falls, insulin decline, glucagon rise, fuel release

3+ days:

survival depends on protein levels and adipose tissue amounts

Protein depletion = organ malfunction and infection –> death at around 40% body protein

70
Q

What are the 2 priorities during the starved state?

A

Maintain adequate blood glucose

Mobilise fatty acids and synthesis ketone bodies

71
Q

What is the role of body stores in the starved state?

A

Fuels are readily oxidizable

Carbs stored as glycogen (fluctuates, binds water as polar molecule)

Triacylglycerols have more calories than carbs or protein

Body protein can be used

72
Q

What fuels does the brain use?

What fuels does muscle use?

A

Glucose = primary fuel

Ketones = during starvation

Glucose

Fatty acids

Ketone bodies

(glycogen to glucose by glucose-6-phosphate for contraction, fatty acids used by resting muscle)

73
Q

What fuels does the heart use?

What fuels does adipose tissue use?

What fuels does the liver use?

A

Fatty acids

Ketone bodies

Lactate

Glycerol-3-phosphate for triacylglycerol synthesis, requires glucose

provides brain, muscle and peripheral organ fuel, forms glycogen from carbs, forms ketone bodies from fatty acids

74
Q

Liver

What happens during carbohydrate metabolism during the starved state?

A

produce glucose from gluconeogenesis or glycogenolysis and produce ketone bodies for non-glucose dependent tissues

Glycogen degradation then gluconeogenesis:

+ Glucagon to insulin ratio

PKA-mediated phosphorylation of glycogen phosphorylase kinase

+ glycogen phosphorylase phosphorylation

Gluconeogenesis skeletons = derived from glucogenic amino acids, muscle lactate and adipose tissue glycerol

75
Q

Liver

What happens during fat metabolism during the starved state?

A

Fatty acid oxidation = liver main energy source, from triacylglycerols in adipose tissue –> TCA cycle inhibited by NADH

+ ketone body synthesis = not used by liver (as lacks thioporase)

76
Q

Adipose tissue

What happens during carbohydrate metabolism during the starved state?

A

Depressed glucose transport as insulin sensitive

Reduced glycolysis

Reduced triacylglycerol synthesis

77
Q

Adipose tissue

What happens during fat metabolism during the starved state?

A

Lipolysis mobilises adipose triacylglycerols –> fatty acids and glycerol released

Increased fatty acid usage with increased fasting length

78
Q

Adipose tissue

What happens during fatty acid metabolism during the starved state?

A

Increased release as hydrolysis of triacylglycerols

Decreased uptake as adipose LDL activity is low

79
Q

Resting skeletal muscle

What happens during the fasting state?

A

Resting muscle moves further from glucose to fatty acids and ketone bodies as become main energy source for contraction

80
Q

Resting skeletal muscle

What happens during carbohydrate metabolism in the starved state?

A

Depressed glucose transport as insulin sensitive

Reduced glycolysis

81
Q

Resting skeletal muscle

What happnens during lipid metabolism during the starved state?

A

First 2 weeks = fatty acids from adipose tissue and ketone bodies from liver are used

3 weeks = reduced use of ketone bodies so more for the brain

82
Q

Resting skeletal muscle

What happens during protein metabolism during the starved state?

A

Early stages = + breakdown of muscle protein (+ liver gluconeogenesis)

Fall in insulin initiates this

83
Q

Brain and kidney

What happens during the starved state?

A

Early = brain uses glucose

Later stages = glucose replaced by plasma ketone à some glucose needed for neurotransmitters

Reduction in protein degradation as less protein catabolism for gluconeogenesis

Kidneys = express gluconeogenesis enzymes (compensates for acidosis by ketone bodies)

84
Q

What are the properties of diabetes mellitus?

A

Heterogeneous metabolic disease –> multifactorial, polygenic, characterised by hyperglycaemia, insulin deficiency

0.1 : 0.9 type 1 (insulin-dependent) and type 2 (non-insulin-dependent)

85
Q

What are the properties of Type 1 diabetes mellitus?

A

‘beta’-cell autoimmune attack causes insulin deficiency

Hyperglycaemia and ketoacidosis –> + blood sugar and ketone levels, + gluconeogenesis, + fatty acid mobilisation and liver oxidation

Hypertriacylglycerolemia –> excess fatty acids converted to triacylglycerols, decreased enzyme production

86
Q

What are the properties of Type 2 diabetes mellitus?

A

Dysfunctional ‘beta’-cells and insulin

Hyperglycaemia –> + hepatic production and reduced use, minimal ketosis

Dyslipidaemia –> Fatty acids converted to triacylglycerols and secreted as VLDLs in liver, low lipoprotein lipase

Medicine 1 (28 decks)

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