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Glucose metabolism Flashcards

1
Q

Where are the main storage sites of glucose?

A

Liver and skeletal muscle

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2
Q

What is the primary fuel source at a fed state, how much is consumed daily?

A

Glucose, 160g consumed daily at rest

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3
Q

Describe the relative glucose use by brain, skeletal muscle, red blood cells and renal medulla.

A

Brain: 75% of total glucose, uses ketone bodies in starvation.

RBC: no mitochondria so use glycolysis to make ATP (convert glucose to lactate)

Renal medulla: high energy need - require glucose

Skeletal muscle: glycogen stores and glucose from liver via Cori cycle

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4
Q

When is glucagon secreted and what does it signal?

A

In fasting state

Signals substrate deficiency and signals to liberate glucose from LIVER ONLY

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5
Q

Describe when insulin is secreted and what it does to substrates

A

Stimulated by increase blood glucose, amino acids, fatty acids etc

Signals substrate excess, tells tissues to store fuel and breakdown glucose

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6
Q

What two ways can glucose be taken into cells?

A

GLUT (1-4) facilitated diffusion transport

SGLT mediated secondary active transport (intestine and renal tube)

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7
Q

What is the key important difference between GLUT 2, GLUT 3 and GLUT 4?

A

Km difference. GLUT 2 has highest Km then GLUT 4 and GLUT 3 is the lowest

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8
Q

Where are GLUT 4, GLUT 3 and GLUT 2 located and how are they adapted for function?

A

GLUT 2 is found in the liver, kidneys and pancreatic beta cells. High Km allows blood glucose to equalibrate across the membrane, glucose sensing tissue, glucose only taken up when very high.

GLUT 4 is found in skeletal muscle cells, glucose uptake controlled by insulin which controls transporter frequency, not Km.

GLUT 3 is found in the brain, low Km means that glucose is always up taken.

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9
Q

Which tissue are insulin insensitive in terms of glucose uptake?

A

WBC, RBC, liver (glucagon sensitive) and brain

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10
Q

What are functions of glucose phosphorylation?

A

Trap glucose in cell, activate glucose and maintain concentration for gradient

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11
Q

Which steps are regulated in glycolysis?

A

Glucose –> G6P (hexokinase/glucokinase)

F6P –> Fructose-1,6-bisphosphate (PFK)

Phosphenolpyruvate –> pyruvate (pyruvate kinase)

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12
Q

What does glycolysis produce?

A

2 pyruvate, 2 ATP, 2 NADH

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13
Q

What steps produce ATP in glycolysis?

A

1,3-bisphosglycerate –>
3-phosphoglycerate

Phospoenolpyruvate –> pyruvate

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14
Q

What is commited step of glycolysis?

A

F6P –> Fructose-1,6-bisphosphate

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15
Q

Which 2 steps use ATP in glycolysis?

A

Glucose –> G-6-P

F-6-P –> F-1,6-BisP

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16
Q

When is NADH produced in glycolysis?

A

G-3-P –>

1,3-bisphosphoglycerate

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17
Q

What activates PFK?

A

AMP, F-2,6-Bisp

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18
Q

What inhibits PFK?

A

ATP, citrate, H+

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19
Q

What inhibits pyruvate kinase?

A

ATP

Alanine

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20
Q

What stimulates pyruvate kinase in muscle?

A

F-1,6-BisP example of feedforward activation

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21
Q

What converts pyruvate to acetyl CoA, what reaction is this?

A

Pyruvate dehydrogenase

Oxidative decarboxylation

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22
Q

What happens to pyruvate and NADH from glycolysis in aerobic and anaerobic conditions?

A

Aerobic: NADH oxidised by ETC: 5 ATP. Pyruvate enters TCA: 25 ATP

Anaerobic: pyruvate converted to lactate by lactate dehydrogenase regenerating NAD+ so glycolysis continues.

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23
Q

What is max ATP production per glucose?

A

2 glycolysis
2 TCA
34 Oxidative phosphorylation

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24
Q

Why is PFK important step to regulate?

A

Consumes ATP
Irreversible
Committed step

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25
What is important of pyruvate kinase regulation in type 2 B (glycotic) skeletal muscle fibre?
Feed forward activation by fructose-1,6-bisphosphate. Important as skeletal muscle has low capacity for oxidative phosphorylation and no triacylglycerol stores.
26
Describe hormonal regulation of PFK in liver?
Glucagon and adrenaline inhibit PFK2 (PKA phosphorylates PFK2 making it inactive) reducing production of F-2,6-BisPase which activates PFK-1
27
What happens as increase in fatty acid in long term exercise, what's inhibited?
Hexokinase inhibited (increased G6P, due to decreased glycolysis) PFK inhibited (increased mitochondrial acetylCoA, increased cytoplasmic citrate) PDH inhibited (increased mitochondrial Acetyl-CoA, so PDK (pyruvate dehydrogenase kinase) inactivates PDH. Pyruvate --> OAA (not acetyl CoA) so acetyl CoA from FA oxidation can be oxidised in TCA cycle.
28
How is galactose metabolised?
Galactose --> | Galactose-1-phosphate --> Glucose 1 phosphate --> Glucose 6 phosphate
29
How is fructose metabolised in liver?
Fructose --> | fructose-1-phosphate --> Glyceraldehyde + DHAP --> Both can --> G3P
30
Describe fructose metabolism in adipose tissue
Hexokinase converts fructose to | fructose-6-phosphate --> glycolysis
31
What does the branched structure of glycogen mean?
Rapid synthesis and degradation Increased solubility so can be stored closer to site of utilisation (but lipids in adipose tissue must be transported to site of utilisation)
32
Where are the largest glycogen stores found?
Liver: for blood glucose conc regulation | Skeletal/cardiac muscle: local store of energy for contraction
33
Why do we need glucose store rather than just fat store?
Need constant glucose supply for brain, RBC and renal medulla (can't turn fatty acids to glucose) Need to be able to produce ATP anaerobically
34
What does glycogen phosphorylase do?
Catalyse cleavage = of 1-4 alpha glycosidic bond liberating G-1-P
35
What happens to glycogen when branch length is 4 residues, (debranching)?
3 residues removed by transferase to adjacent chain for breakdown by phosphroylase and single residue remaining broken down by alpha-1,6-glucosidase
36
What constitutes debranching enzyme?
Transferase and alpha-1,6-glucosidase
37
What converts G-1-P to | G-6-P in most tissue?
Phosphoglucomutase
38
What converts G-6-P to glucose, where does this occur in the liver?
Glucose-6-phosphatase, in the SER
39
What happens in glycogenesis?
Addition of UDP-glucose by alpha-1,4-glycosidic bond to 4'OH end of existing glycogen chain using glycogen synthase
40
What is cost of storing glucose as glycogen?
1 ATP used to generate UDP-glucose 1 in 10 glucose residues released in glycogenolysis will be branch point and released as glucose --> G-6-P for glycolysis. So metabolic cost is 1.1 ATP per glucose
41
What is glycogenin?
Primer and catalyst for addition of first few glucose residues (once chain around 8 residues long then glycogen synthase takes over)
42
What does branching enzyme do?
When at least 11 residues added, branching enzyme breaks off a chain around 7 residues in length and joins it by alpha-1,6-glycosidic bond to free 6'OH group at least four residues away from nearest existing branch
43
How do you get from G6P to UDP glucose?
G-6-P --> G-1-P (phosphoglucomutase) G-1-P + UTP --> UDP-glucose + 2Pi UDP-glucose + glycogen --> glycogen (+1) + UDP
44
Protein phosphatase 1 deactivates glycogen phosphorylase (dephos), explain what activates PP1 and what inhibits it
Activates: Insulin Inhibit: Glucagon and Adr
45
What enzyme controls phosphorylase kinase?
PKA (activated by cAMP), cAMP increases due to glucagon in liver and Adr via Ca2+ in muscle
46
What inhibits phosphorylase kinase?
Insulin
47
What is the allosteric regulation of glycogen phosphorylase (T or R form)?
In muscle cell (mainly B): AMP activates whilst ATP and G-6-P inhibit. In liver (mainly A): glucose inactivates (only at high glucose conc as GLUT 2 has low Km) BUT insensitive to ATP and AMP
48
What is meant by a and b state?
A = active b= inactive (governed by phosphorylation or intrinsic control)
49
How is glycogen synthase inactivated by phosphorylation?
PKA Phosphorylase kinase Ca2+ Calmodulin CaM Kinase II
50
What does PP1 do?
Dephosphorylates glycogen phosphorylase (inactivates) and and activates glycogen synthase
51
What is PP1 activated by?
Insulin
52
How do insulin and glucagon reciprocally regulate glycogen metabolism?
Insulin: Activate PP1 and inhibit glycogen synthase kinase Glucagon and Adr: Stimulate phosphorylase kinase and inhibit PP1
53
Why Is gluconeogenesis important?
Synthesis glucose to export to glucose dependent tissue e.g. RBC and brain
54
How long are glycogen stores sufficient for, what happens when they run out?
12 hours, if fasting exceeds 12 hours, then gluconeogenesis occurs
55
What organs contribute to gluconeogenesis?
Liver and renal cortex
56
Where does gluconeogenesis happen in a cell?
Mitochondria and cytosol
57
What is the substrate for gluconeogenesis?
Lactate, glycerol, amino acids (alanine and glutamine)
58
Where are alanine and glutamine from?
Alanine: transamination of pyruvate Glutamine: from muscles
59
How does glycerol feed into gluconeogenesis?
Via glycerol-3-phosphate via glyceraldehyde-3-phosphate to fructose-1,6-bisphoshate
60
What does acute and chronic control of gluconeogenesis entail?
Acute: allosteric by metabolites, covalently by hormones. Chronic: transcription of gluconeogenic enzymes
61
What controls pyruvate carboxylase?
Activated by acetyl CoA
62
What controls fructose-1,6-bisphosphatase allosterically?
Activated by 3-phosphoglycerate, citrate Inhibited by AMP and F-2,6-Bisphosphate
63
How is gluconeogenesis controlled externally by hormones?
Acute: glucagon stimulates gluconeogenesis by reducing F-2,6-BisP, so less inhibition of F-1,6-biphosphatase (insulin has opposite effects) Long term: Glucagon and insulin induce/press enzymes in glycolysis and gluconeogenesis
64
What enzymes does insulin upregulate?
Hexokinase PFK Pyruvate kinase Glycogen synthase
65
What enzymes does glucagon upregulate?
F-1,6-BisPase Pyruvate carboxylase Glucose-6-phosphatase
66
Describe why gluconeogenesis involves the cytosol and mitochondria?
Phosphoenolpyruvate --> pyruvate Irreversible (so not possible to revers in gluconeogenesis) So pyruvate enters mitochondria and converted to oxaloacetate which converted to malate (transporter for malate) which converted to OAA in cytosol which can then become Phosphoenolpyruvate.
67
Why can't mammals make glucose from FA?
No enzyme to catalyse acetyl CoA to OAA. Except in TCA can be combined, however, 2C input 2C output to TCA cycle so effectively FA are not contributing to the TCA cycle.
68
What is unique about Glucose 6 phosphatase?
Found in SER, transporters needed to get G-6-P into SER and glucose out.
69
What part of gluconeogenesis occurs in mitochondria?
Pyruvate to OAA to malate
70
What sort of bond joins glucose at branch points in glycogen?
Alpha 1,6 glycosidic
71
What enzyme can calcium activate?
Phosphorylase kinase (activates glycogen phosphorylase)
72
What is the substrate for glycogen synthesis?
UDP-glucose
73
What hormones activates glycogen phosphorylase in liver and in muscle?
Ca2+ ( due to Adr) and glucagon in liver Adr in muscle
74
What inactivates glycogen synthase?
Adrenaline and glucagon activate protein kinase so decrease glycogen production
75
The proportion of body energy stores in form of glycogen is
<5%
76
Does gluconeogenesis consume or produce Acetyl CoA ?
No
77
In addition to the cytosolic reactions, how many organelles are involved in gluconeogenesis?
2 (Mitochondria and SER)
78
Phosphorylase kinase is activated by calcium ions?
True
79
Glycogen synthetase is activated by dephosphorylation?
True
80
Muscle glycogen breakdown contributes directly to the maintenance of the blood glucose level?
False
81
Lactate is produces in anaerobic glycolysis to allow re-oxidation of NADH produced in the reaction catalysed by glyceraldehyde-3-phosphate dehydrogenase.
True
82
Lactate dehydrogenase exists in five different isoenzyme forms which differ in their catalytic properties.
True
83
Can glucose be synthesised from acetyl CoA?
No
84
Does gluconeogenesis consume Acetyl CoA?
No
85
What inhibits pyruvate dehydrogenase?
Acetyl CoA
86
In anaerobic glycolysis, pyruvate does not accumulate because...
It is reduced to lactate in the re-oxidation of NADH produced by glyceraldehyde-3-phosphate dehydrogenase
87
What inhibits PFK?
ATP
88
Example of a ketose sugar
Fructose
89
Compared with complete oxidation of glucose during aerobic metabolism, how much ATP is generated by partial oxidation of glucose to lactate?
5%

Metabolism (13 decks)

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