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104: Theme 2 > Metabolic Biochemistry > Flashcards

Metabolic Biochemistry Flashcards

Lectures 6,7,9,10

1
Q

What is the Fed state?

A
  • several hours after a meal

- high insulin to glucagon ration

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2
Q

What is a Fasting ratio

A
  • 6-12 hours after a meal

- low insulin to glucagon ratio

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3
Q

What is the absorptive and post-absorptive phase?

A
  • absorptive is after a meal, energy source for most cells is glucose, glucose is being converted into storage molecules
  • Post-absorptive phase is a while after the meal, the stored materials are converted to glucose, most source of energy is from triglycerides
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4
Q

Explain metabolism in the Fed state in the Liver

A
  • High insulin, glucagon ratio
  • glucose –> glycogen and TGs as VLDL
  • some glucose enters the TCA cycle
  • glycerol from peripheral tissues –> triacylglycerols
  • excess amino acids –> pyruvate and enter TCA or converted to triacylglycerols
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5
Q

Explain metabolism in the Fed state in Muscles

A
  • glucose enters muscles via insulin stimulated Glut 4 receptors
  • Glu is converted to glycogen or metabolised via glycolysis and TCA cycle
  • Fatty acids from the diet enter via chylomicrons and from the liver as VLDL
  • they are oxidised via Beta-oxidation to acetyl Co-a to produce ATP
  • the Liver Protein Lipase channel protein is increased in the high insulin to glucagon state
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6
Q

Explain metabolism in the Fed state in Adipose tissue

A
  • Glucose enters the adipose bu the insulin-dependent Glut 4 transport system
  • converted to Acetyl CoA and then fatty acids and triacylglycerol via glycolysis and PDH
  • Fatty acids enter from VLDL and chylomicrons and are converted to triacylglycerol
  • Glycerol released from TAGs is returned to Liver for re-use
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7
Q

Explain metabolism in the Fed state in the Brain

A
  • takes up glucose via Glut 1& 3 transporters and metabolises it oxidatively via glycolysis and the TCA cycle to produce ATP
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8
Q

Describe the overall impact of metabolism in early fasting state

A
  • the liver switches from a glucose-utilising to a glucose-producing organ
  • Decrease in glycogen synthesis and increase in glycogenolysis
  • this eventually switches to Gluconeogenesis
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9
Q

Describe the early fasting state of the Liver

A
  • drop is plasma glucose leads to decrease entry via the Glut 2 transporter as it has a low affinity
  • Liver changes to exporter of glucose
  • reduced insulin glucagon ratio activates glycogenolysis and gluconeogenesis ( from lactate and alanine) via cAMP production in response to glucagon
  • Protein in liver and other tissues are broken down to amino acids to fuel gluconeogenesis
  • Fatty acids fro lipolysis used to produce energy via Beta-oxidation
  • Citrate and acetly CoA produced from oxidation of fatty acids activate gluconeogenesis and inhibits glycolysis
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10
Q

Describe the early fasting state in Adipose tissue

A
  • reduced of glucose via Glut 4
  • metabolism via glycolysis is severely inhibited
  • Mobilisation of TG’s in response to reduced insulin;glucagon ratio and activation of the sympathetic NS by release of noradrenaline
  • some fatty acids used directly within the tissue to produce energy
  • remainder is released into the bloodstream to support glucose-independent energy production in muscle and other tissues
  • Glycerol cannot be metabolised and is recycled to the liver to support gluconeogenesis
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11
Q

Describe the early fasting state in Adipose tissue

A
  • reduced of glucose via Glut 4
  • metabolism via glycolysis is severely inhibited
  • Mobilisation of TG’s in response to reduced insulin;glucagon ratio and activation of the sympathetic NS by release of noradrenaline
  • some fatty acids used directly within the tissue to produce energy-
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12
Q

Describe the early fasting state of in the Brain

A
  • Continues to take up as Glut1 and Glut3 have high glucose affinity and they are independent of insulin levels
  • glucose continuous to be metabolised, brain cannot switch to fatty acid metabolism as free fatty acids cannot cross the blood brain barrier
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13
Q

Give an overview of what starved metabolism state is

A
  • Chronic low-insulin: glucagon state
  • decrease in concentration of thyroid hormones - decreasing the metabolic rate
  • free fatty acids become the major energy source
  • production of ketone bodies as alternative fuel source
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14
Q

Describe the starved state in the Liver

A
  • No glucose enters the liver and glycogen stores are depleted within 24 hours
  • Maintaining plasma glucose is dependent on gluconeogenesis from lactate, glycerol & alanine from fat and protein breakdown. The kidney is important in this
  • Urea synthesis stimulated to cope with increasing amino groups entering the liver
  • Glycogen synthesis and glycolysis inhibited
  • Fatty acids enter the liver and provide energy to support gluconeogenesis with excess acetyl CoA being converted to ketone bodies (acetoacetate and β-hydroxybutyrate). These are not used by the liver but released for oxidation by other tissues (muscle, brain)
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15
Q

Describe the starved state in Adipose tissue

A
  • Little glucose entry due to fall in insulin secretion
  • Switch to fatty acids from triacyglycerol to supply the energetic needs of major tissue
  • Lipolysis activated due to low insulin:glucagon ratio, blood levels of fatty acids rise 10x
  • Glycerol exported to the liver to be converted into glucose
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16
Q

Describe the starved state in Muscle

A
  • little glucose entry, switch to fatty acid metabolism
  • ketone bodies used as an energy source in the heart and muscle to conserve glucose
  • proteolysis stimulated by noradrenaline and cortisol –> for net glucose synthesis in the form of alanine
  • Ketone bodies reduce proteolysis and decrease muscle wasting
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17
Q

Describe the starved state in the Liver

A
  • uses ketone bodies as their plasma levels increase

- this conserves the glucose levels however glucose is still required by the brain

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18
Q

Explain the glucose-fatty acid cycle

A
  • Mobilisation of fatty acids in response to glucagon or adrenaline increases fatty acid oxidation in peripheral tissues to acetyl CoA
  • Excess acetyl CoA converted to citrate in TCA cycle which builds up in cytoplasm and inhibits PFK-1
  • Build up of G-6-P inhibits hexokinase and prevents glucose phosphorylation
  • Increase in glucose prevents further glucose entry and so conserves glucose
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19
Q

What is the source, trigger and effect of the hormone Glucagon on glycogenolysis and gluconeogenesis?

A

Source: Pancreatic alpha-cells

Trigger: Hypoglycaemia

Effect: rapid activation

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20
Q

What is the source, trigger and effect of the hormone Adrenaline on glycogenolysis and gluconeogenesis?

A

Source: Adrenal medulla

Trigger: Stress, hypoglycaemia

Effect: Rapid activation

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21
Q

What is the source, trigger and effect of the hormone Cortisol on glycogenolysis and gluconeogenesis?

A

Source: Adrenal Cortex

Trigger: Stress

Effect: Chronic activation

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22
Q

What is the source, trigger and effect of the hormone Insulin on glycogenolysis and gluconeogenesis?

A

Source: Pancreatic Beta-cells

Trigger: Hyperglycaemia

Effect: Inactivation

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23
Q

Explain in general reciprocal regulation of phosphorylase and glycogen synthase by phosphorylation

A
  • Glucagon (liver) and
    adrenaline (muscle) activate glycogen breakdown and inhibit synthesis by activating cAMP PK with ultimate phosphorylation of phosphorylase and glycogen synthase
  • Mimicked by increasing Ca2+ during contraction
  • Insulin activates protein phosphatase to reverse these effects
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24
Q

What are the irreversible steps in the glycolytic pathway? including enzymes

A
  • Glucose –(Hexokinase/Glucokinase)–> G-6-P
  • F-6-P –(PFK1)–> F-1,6-P2
  • PEP –(Pyruvate kinase)–> Pyruvate
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25
Q

What is gluconeogenesis?

A

production of glucose from non-carbohydrate precursors

  • lactate from glycolysis,
  • amino acids from protein breakdown,
  • glycerol (not fatty acids) from fat metabolism
  • these provide the carbon skeleton for the glucose
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26
Q

Where does gluconeogenesis get the energy to occur

A
  • from the metabolism of fatty acids
27
Q

What are the irreversible steps in the gluconeogenic pathway? (including enzymes)

A
  • Pyruvate –( pyruvate carboxylate–> Oxalaoacetate
  • Oxaloacetate –( Phosphoenolpyruvate Carboxykinase)–> PEP
  • F-1,6-P2–( Fructose-1,6-bisphosphate)–> F-6-P
  • G-6-P –( G-6-Pase)–> Glucose
28
Q

What is PFK-1 and how is it regulated?

A
  • an enzyme that converts F-6-P to F-1,6-P2, not found in the liver and kidney
  • allosterically regulated by ATP, AMP and H+
  • ATP, inhibits PFK-1 (there is enough ATP being produced so less glucose needs to be broken down)
  • AMP upregulated PFK-1 ( depleted source of ATP, more glucose needs to be broken down)
  • H+ inhibits glycolysis to prevent an even lower pH, can be overcome in the heart with a very high AMP
29
Q

What is PFK-1 and how is it regulated by nutrients?

A
  • an enzyme that converts F-6-P to F-1,6-P2, not found in the liver and kidney
  • allosterically regulated by Fru-6-P, Fru-6-P2 and citrate
  • Fru-6-P, inhibits PFK-1 and Fru-2,6-P2 activates PFK-1: both are a sign of high rates of glucose entry or glycogen breakdown. Fru-2,6-P2 is a most potent allosteric activator, both stimulate glycolysis to allow utilisation of energy or fat synthesis
  • Citrate inhibits: signals TCA cycle overload (more acetyl CoA than can be oxidised) or fatty acid oxidation (starvation) the need to conserve glucose bu inhibition of glycolysis
30
Q

What is fructose-2,6-bisphosphate (F-2,6-P2)?

A
  • most potent allosteric activator of PFK-1
  • potent Inhibitor of fructose-1,6-bisphosphate
  • F-6-P + ATP –(PFK-2)–> F-2,6-BP
  • not involved in the metabolic pathways: acts solely to re-enforce allosteric control on PFK-1
31
Q

How is F-2-6-BP regulated?

A

Fructose-2,6-bisphosphate is used to reinforce the allosteric control of PFK-1

  • Activated by F-6-P and AMP: when there is increased glucose cons. increased glycogen breakdown in the muscle an increased AMP concentration activating glycolysis
  • Inhibited by Citrate: when there is an increase in fatty acid oxidation leads to glycolysis being inhibited
32
Q

What are the energy status controls and nutrient controls of glycolysis at PFK-1?

A

Energy status: ATP (inhibit), AMP, H+ ions (activate)

Nutrient: F-6-P, F-2,6-P2, Citrate(inhibit)

33
Q

What is the impact of F-2,6–BP in the liver being affected by hormones?

A
  • Increased fatty acid oxidation -> increased Acetyl CoA -> activates pyruvate carboxylase ->produces more OAA -> PEP –> F-1,6-BP ( more gluconeogenesis rather than glycolysis)
  • increased glucagon inhibits PFK-2, and stimulates F-2-,6-BPase by phosphorylation
  • more F-2,6BPase action reduces F-2,6-BP conc.
  • decreased F-2,6-BP reduces activation of PFK-1 (inhibiting glycolysis) and relieves inhibition of F-1,6BPase (stimulates gluconeogenesis)
34
Q

What are the hormones that affect F-2,6-BP or (-P2)?

A
  • Glucagon
35
Q

What stimulates gluconeogenesis in the short term?

A
  • glucagon and adrenaline

- changes in protein phosphorylation or mobilisation fatty acids and production of acetyl CoA

36
Q

What stimulates gluconeogenesis in the long term?

A

enzyme induction by

  • glucagon
  • glucocorticoids
  • thyroid hormones
37
Q

What inhibits gluconeogenesis in the short term?

A
  • insulin

- via dephosphorylation and suppression of lipolysis

38
Q

What inhibits gluconeogenesis in the long term?

A
  • suppression of gluconeogenic enzymes
39
Q

Explain the urea cycle

A
  • increased gluconeogenesis = increased urea
  • amino acids need to be transaminated to lose their ammonia
  • NH3 +CO2 + 2H2O + 3ATP +asparate –> urea + fumerate + 2ADP+ AMP + 2Pi+ PPi
  • fumerate converted to OAA int the cytoplasm generating a substrate for gluconeogenesis
40
Q

What is the difference between Liver and muscle glycogen?

A
  • Liver: used to maintain plasma glucose

- Muscle: used for muscle contraction

41
Q

What product does the glycogenolysis produce?

A
  • converts glycogen to glucose-1-phosphate

- can then be converted to free glucose

42
Q

Describe the structure of glycogen?

A
  • found in granules in cells
  • glucose polysaccharide with alpha-1,4 linkages
  • there is a alpha-1,6 branch every 8-14 glucose molecules
43
Q

How is glycogen brokendown?

A
  • through phosphorolysis

- catalysed by glycogen phosphorylase: only breaks alpha-1,4 links up to 4 glucose units from the branch point

44
Q

What is the process for glycogen breakdown in muscles?

A
  • glycogen
  • Glucose-1-phosphate
  • Glucose-6-phosphate
  • Pyruvate
  • Lactate/ CO2
45
Q

What is the process for glycogen breakdown in th liver?

A
  • glycogen
  • glucose-1-phosphate
  • glucose-6-phosphate
  • free glucose
46
Q

What enzyme is important for mobilisation in the liver?

A
  • glucose-6-phosphatase
  • removes the phosphate from gluc-6-phosphate
  • muscles do not express theis enzyme
47
Q

What is the full degradation process of glycogen?

A
  • Phosphorylase: breaks alpha-1,4 up to 4 units of the branching point
  • Transferase: moves the last 3 units to another chain
  • Alpha-1,6-glucosidase: removes the single glucose left on the branch in a hydrolysis reaction
  • the chain can continued to be broken down as set out above
48
Q

How is glycogen synthesised?

A
  • Glucose
  • Glucose-6-phosphate
  • Glucose-1-phosphate
  • Uridine Diphosphate glucose (UDP-Glucose)
  • Glycogen(n) –> glycogne (n+1)
    This process needs energy input
49
Q

What enzymes are involved in glycogen synthesis?

A
  • to form G-6-P from glu: Hexokinase/Glucokinase (liver)
  • to form G-1-P from G-6-P: phosphoglucomutase
  • to form UDP-Glu: Uridine triphosphate (UTP)
  • Glycogen synthase adds glucose units onto glycogen using UDP-Glu
50
Q

How does a glycogen chain start?

A
  • glycogen synthase needs at least 4 glucosyl residues to add a glucose molecule to
  • Glycogenin protein acts as the primer
  • UDP donates the first glucosyl residue to the a.a tyrosine on the glycogenin
51
Q

How is a branch introduced to a glycogen chain?

A
  • a branching enzymes is used
  • transfers a block of 7 residues from a growing branch to create a new branch
  • uses an alpha-1,6 linkage
  • doesn’t form within 4 residues of the pre-existing chain.
52
Q

What are the pros and cons as glycogen as an energy store?

A

Pro: glycogen phosphorylase and synthase are sensitive to regulatory hormones, stress and muscle contraction
Pro: many branching points for fast mobilisation
Con: hydrophilic and associates with water -> increases the bulk and weight

53
Q

How is glycogen phosphorylase regulated?

A

Activated: allosterically regulated by AMP- present when ATP is depleted during muscle contraction

Inhibited: ATP and Glu-6-Phosphate competitive binder to AMP, these are signs of high energy levels
- In the liver the presence of glucose and G-6-P acts as the allosteric control

54
Q

How is glycogen synthase regulated?

A

Activated: allosterically by Glucose-6-phosphate and ATP

55
Q

How is glycogen regulated by covalent modification

A

> covalent modification refers to the addition or removal of phosphate groups: protein kinase (+), protein phosphatases (-)

  • phosphorylation of glycogen phosphorylase makes it MORE active (catabolic reaction)
  • phosphorylation of glycogen synthase makes it LESS active (anabolic reaction)
56
Q

What is the normative range for blood glucose?

A

2.5-8mM

57
Q

Name the hormones that increase the blood glucose levels?

A
  • Glucagon
  • Cortisol (adrenal glands)
  • Growth hormone
  • Catecholamines (adrenal glands, stress)
58
Q

Where are GLUT 1 transporters found?

A

many different cells

- erythrocytes, brain, muscle, kidney colon, placenta, foetal tissue

59
Q

Where are GLUT 2 transporters found?

A
  • in the liver
  • pancreatic Beta cells
  • low affinity only at high blood glucose conc.
60
Q

Where are GLUT 3 transporters found?

A
  • in the brain

- allows glucose uptake no matter the blood glucose level

61
Q

Where are GLUT 5 transporters found?

A
  • small intestine

- fructose transporter

62
Q

Where are GLUT 4 transporters found?

A
  • skeletal muscle

- adipose tissue (insulin sensitive)

63
Q

Which glucose transporter is insulin regulated and how does it work?

A
  • GLUT 4
  • insulin receptor, bind to insulin
  • triggers downstream signalling cascade
  • PI-3 kinase causes rapid translocation of GLUT4 transporters from inside the membrane to the surface membrane
64
Q

What is the Pentose Phosphate Pathway?

A
  • cytosolic pathway present in all cells
  • branches from G-6-P in glycolysis

Produces: Ribose phosphate- used to synthesize RNA and DNA
Produces: NADPH- used for reductive biosynthesis and to maintain redox balance

  • PP intermediates can be recycled back into glycolysis in cells with less biosynthetic active cells

104: Theme 2 (7 decks)

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