Integrated Metabolism Flashcards
1
Q
Functions of Metabolism
A
- Supplies energy and biosynthetic precursors
- Provides mechanisms of excretion of waste products
- Provides protection
- Supplies molecules that operate control mechanisms
2
Q
Metabolic control and integration
A
- Hormonal controls
- CNS controls the release of the hormones
- Secondary messengers (intracellular and intercellular signalling)
- Availability of circulating substrates
3
Q
Co-operation between the different organs and tissues
A
- to continue to perform these key functions as conditions change, and to avoid substrate cycles
4
Q
Control and integration at whole body level
A
- Control of cellular activities and pathways via extracellular signals produced by other cells of the body, under control of the CNS
- circulating hormones, with specific mechanisms of action
5
Q
Regulation of enzyme activities
A
- allosterically (binding of a compound to another site on the enzyme);
- via covalent modification (mainly phosphorylation/ dephosphorylation)
- via changes in enzyme concentration, eg. new synthesis
6
Q
Regulation of pathways by regulatory enzymes
A
- to maintain balance between pathways
- to control synthesis and breakdown pathways in a reciprocal manner – activation of one and inhibition of the other – to avoid futile cycles
7
Q
Metabolic pathways involving carbohydrates
A
- Glycolysis
- Gluconeogenesis
- PDH reaction, Shuttles
- Pentose phosphates pathway
- Glycogen synthesis
- Glycogen breakdown
8
Q
Metabolic pathways involving lipids
A
- Fatty acid ß-oxidation
- Ketone bodies synthesis
- Fatty acid synthesis
- Complex lipid synthesis
- TAG synthesis
- TAG hydrolysis
- Cholesterol synthesis
9
Q
Metabolic pathways involving proteins
A
- Amino acids catabolism
- Transamination
- Amino acid synthesis
- Urea cycle
- Nucleotide synthesis
10
Q
Metabolic pathways involving energy
A
- Citric acid cycle (CAC)
- Electron transport chain (ETC)
- Oxidative phosphorylation (OxP)
11
Q
Metabolic features of brain
A
- Fuel: glucose (KB)
- Fuel store: none
- Fuel exported: none
- Pathways: glycolysis, PDH, AA cat, CAC, ETC, OxP
12
Q
Metabolic features of liver
A
- Fuel: glucose, fatty acids, AA
- Fuel store: Glycogen, TAG
- Fuel exported: glucose, KB, FA, VLDLs
- Pathways: glycolysis, PDH, FA Ox, AA cat, CAC, ETC, OxP;
Gluconeogenesis; Glycogen synthesis, glycogen breakdown, FA synthesis, TAG synthesis, KB synthesis; Urea synthesis
13
Q
Metabolic features of RBCs
A
- Fuel: glucose
- Fuel store: none
- Fuel exported: lactate
- Pathways: glycolysis
14
Q
Metabolic features of heart muscle
A
- Fuel: fatty acids; glucose
- Fuel store: none
- Fuel exported: none
- Pathways: glycolysis, PDH, FA Ox, AA cat, CAC, ETC, OxP;
15
Q
Metabolic features of adipose tissue
A
- Fuel: glucose, fatty acids, AA
- Fuel store: TAG
- Fuel exported: FA, glycerol
- Pathways: glycolysis, PDH, FA Ox, AA cat, CAC, ETC, OxP; TAG synthesis, TAG hydrolysis
16
Q
Metabolic features of skeletal tissue
A
- Fuel: fatty acids, glucose, AA
- Fuel store: glycogen
- Fuel exported: lactate, alanine
- Pathways: glycolysis, PDH, FA Ox, AA cat, CAC, ETC, OxP; glycogen breakdown; glycogen synthesis
17
Q
Metabolic control: aims, pathways and regulators
A
- Main aims: control blood glucose levels (glucose homeostasis), supply glucose to tissues which depend on it for their energy requirements (ATP synthesis)
- Main pathways: glycolysis and gluconeogenesis
- Main regulators: hormones - insulin and glucagon; epinephrine (adrenaline)
18
Q
Biochemical actions of insulin
A
- Activates/Increases: uptake of glucose in muscle cells and adipocytes, glycolysis, glycogen synthesis, TAG synthesis, protein, DNA and RNA synthesis
- Inhibits / Decreases: gluconeogenesis, lipolysis, protein hydrolysis
19
Q
Physiological actions of insulin
A
- Signals fed state
- Activates: fuel storage, cell growth and differentiation
- Decreases: blood glucose level
20
Q
Biochemical actions of glucagon
A
- Activates/Increases: cAMP level in liver and adipose tissue, glycogenolysis, TAG hydrolysis, gluconeogenesis
- Inhibits/Decreases: glycolysis, glycogen synthesis
21
Q
Physiological actions of glucagon
A
- Activates/Increases: glucose release from liver, blood glucose level
22
Q
Biochemical actions of epinephrine (adrenaline)
A
- Activates/Increases: cAMP level in muscle, glycogenolysis, TAG hydrolysis
- Inhibits/Decreases: glycogen synthesis
23
Q
Physiological actions of epinephrine (adrenaline)
A
- Activates/Increases: glucose release from liver, blood glucose level
- Inhibits/Decreases: glucose use by muscle
24
Q
Digestion and Nutrient absorption in intestine in absorptive (fed) state (steps 1-3)
A
- Carbohydrate digestion - absorption of glucose –> blood
- Lipid (TAG) digestion - formation of chylomicrons –> lymph –> blood
- Protein digestion - absorption of AA –> blood
25
Q
What happens to blood glucose levels 2-4 hours after a meal? (step 4)
A
- increase
- Insulin is released from the β-cells in the pancreas
- Insulin levels are high
- Glucagon levels are low
26
Q
Metabolic integration in liver in absorptive (fed) state (steps 5-7)
A
- Glucose uptake by liver cells – Glycolysis (Insulin activated), PDH, CAC, ETC, OxP –> ATP, CO2 to meet the energy requirements of liver cells
- Glycogen synthesis in liver cells (Insulin activated) – excess glucose is stored
- Fatty acid and TAG synthesis in liver cells (Insulin activated) – excess glucose converted to fatty acids, esterified with glycerol and exported into blood as VLDLs
27
Q
Metabolic integration in the brain during fed state (step 8)
A
- Glucose uptake by CNS cells (dependent on glucose for energy; FA transport across the blood brain barrier too slow)
- Glycolysis, PDH, CAC, ETC, OxP –> ATP, CO2 to meet the energy requirements of brain cells
28
Q
Metabolic integration in RBCs during fed state (step 9)
A
- Glucose uptake by RBC (dependent on glucose for energy; no mitochondria)
- Glycolysis, Pyruvate reduced to lactate –> ATP, NAD+ to meet the energy requirements of RBC, lactate released in the blood
29
Q
Glucose uptake by the muscle cells and adipose tissue cells (step 10 of absorptive state)
A
- Insulin-stimulated transport - - Glycolysis (Insulin activated), PDH, CAC, ETC, OxP ATP, CO2 to meet the energy requirements
- also to convert glycolysis intermediates to glycerol-3-phosphate required for TAG synthesis in adipose tissue cells
30
Q
Glycogen synthesis in muscle cells (step 11 of absorptive state)
A
- Insulin activated
- excess glucose is stored to be used during muscle contraction
31
Q
Step 12 of absorptive state (TAG and VLDLs)
A
- TAG from chylomicrons and VLDLs are hydrolysed by lipoprotein lipases in capillaries –> FA and glycerol; FA taken up by adipose tissue cells
32
Q
Metabolic integration in adipose during absorptive state (step 13)
A
- TAG synthesis (from FA and glycerol-3-phosphate) and TAG storage in adipose tissue cells
33
Q
Metabolic integration in tissues during absorptive state (step 14)
A
- AA uptake into muscle, liver and other tissues is also activated by insulin –> protein synthesis; synthesis of other N-containing compounds; some are used for energy generation
34
Q
Glucose uptake by brain
A
- GLUT3 transporters – high affinity for glucose
- Independent of insulin
- Glucose is phosphorylated by hexokinase – low Km for glucose
35
Q
Glucose uptake by RBCs
A
- GLUT1 transporters – high affinity for glucose
- Independent of insulin
36
Q
Glucose uptake by liver
A
- Occurs only when blood glucose levels are high
- GLUT2 transporters – low affinity for glucose
- Independent of insulin
- Glucose: phosphorylated by glucokinase (higher Km for glucose than hexokinase and is not inhibited by glucose-6-phosphate)
- Glycogen synthesis is activated: glycogen synthase is dephosphorylated and activated (glycogen phosphorylase is phosphorylated and inhibited)
- Glucose-6-P is used mainly for glycogen synthesis
- PFK and pyruvate kinase are active; gluconeogenesis regulatory enzymes are inhibited
- Acetyl-CoA carboxylase is activated (catalyses rate limiting step in FA synthesis, the conversion of acetyl-CoA to malonyl-CoA)
- Malonyl-CoA inhibits carnitine transferase (FA aren’t transported into mitochondria for β-oxidation: no futile cycle)
37
Q
Glucose uptake by muscle cells
A
- Occurs only when blood glucose and insulin are high
- Insulin binds to its receptors: GLUT4 transporters are delivered to cell membrane (insulin-dependent uptake)
- Glucose is phosphorylated by hexokinase (low Km for glucose)
- Glycogen synthesis is activated: glycogen synthase dephosphorylated and activated (glycogen phosphorylase is phosphorylated and inhibited, as in the liver cells)
- Glucose-6-P is used mainly for glycogen synthesis, also used for glycolysis -> Acetyl-CoA -> PDH -> CAC -> ETC -> OxP -> ATP
38
Q
Glucose uptake by adipose cells
A
- Occurs only when blood glucose and insulin are high
- Insulin binds to its receptors: GLUT4 transporters are delivered to cell membrane (insulin-dependent uptake)
- Glucose phosphorylated by hexokinase and glucose-6-P is used for glycolysis to DHAP stage - DHAP is reduced to glycerol-3-P needed for TAG synthesis
- Insulin activates lipoprotein lipase in adipose tissue capillaries -> hydrolyses FA from dietary TAG (in chylomicrons) and VLDLs -> FA taken up by the adipose tissue cells (glycerol returns to the liver cells) and used for TAG synthesis
- Insulin inhibits the hormone-sensitive lipase – no futile cycles
39
Q
Blood glucose levels during basal fasting state
A
- Glucagon is released from the α-cells in the pancreas - Glucagon levels are high, Insulin levels are low
40
Q
Glycogen breakdown in liver cells during basal fasting state
A
- about 2-3 hours after a meal
- glucose is released in the blood, for brain and RBCs
41
Q
Glucose uptake by brain cells and RBCs (steps 3-4 of basal fasting state)
A
- Glucose uptake by brain cells - Glycolysis, PDH, CAC, ETC, OxP –> ATP, CO2 to meet the energy requirements of brain cells
- Glucose uptake by RBC - Glycolysis, Pyruvate reduced to Lactate –> ATP, NAD+ to meet energy requirements of RBC
42
Q
TAG hydrolysis in adipose tissue (step 5 of basal fading state)
A
- hormone-sensitive lipase –> FA and glycerol released in the blood for other tissues
43
Q
FA uptake by muscle and liver cells during basal fasting state (steps 6-7)
A
- FA uptake by muscle cells – FA Ox, CAC, ETC, OxP –> ATP, CO2 to meet energy requirements of muscle cells
- FA uptake by liver cells – FA Ox, CAC, ETC, OxP –> ATP, CO2 to meet energy requirements of liver cells; KB synthesis –> KB released in the blood
44
Q
KB uptake in muscle cells in basal fasting state (step 8)
A
- KB uptake by muscle cells –> Acetyl CoA - CAC, ETC, OxP –> ATP, CO2 to meet energy requirements of muscle cells
- Skeletal muscle cells also use their own glycogen stores –> ATP –> activity
45
Q
Protein degradation in muscle cells in basal fasting state (step 9)
A
- AA released in the blood (mainly alanine and glutamine)
- alanine is taken up by liver cells to be used as substrates for gluconeogenesis; glutamine is metabolised mainly by intestine and kidney cells
46
Q
Urea synthesis in liver cells in basal fasting state (step 10)
A
- urea released in the blood
- elimination of nitrogenous waste products in urine, via the kidney
47
Q
Substrates for gluconeogenesis (step 11-12 in basal fasting state)
A
- lactate released in blood by RBCs taken up by liver cells, to be used as substrate for gluconeogenesis
- glycerol released in blood from hydrolysis of TAG in the adipose tissue cells is taken up by liver cells, to be used as substrate for gluconeogenesis
48
Q
Changes during fasting - transition from basal to prolonged fasting
A
- Prolonged starvation: increase in circulating FAs and ketone bodies
- Mobilisation of fat reserves for energy generation
- Muscle proteolysis decreases: reduced requirement of glucose
- Glucose and ketone bodies released are used as energy source by the brain
- Utilisation of FAs by other tissues spares glucose for those tissues that rely on glucose as only energy source
- 3 days – 30% energy, 40 days – 70% energy from ketone bodies.
49
Q
Metabolic changes during prolonged fasting
3-5 days of fasting
A
- Use of KB by muscle tissue decreases; FA become the main energy substrate for skeletal muscle cells, as well as for heart muscle cells
- Blood KB levels rise
- uptake of KB by brain cells increases; the use of glucose decreases, but glucose remains major fuel for brain
- RBCs keep using glucose
- Liver gluconeogenesis decreases
- Less muscle protein is degraded to provide AA for gluconeogenesis, less AA catabolism, less urea produced
- KB act on β-cells of pancreas to release a small amount of insulin, reduces the rate of proteolysis and lipolysis
- body uses its fat stores, to conserve functional proteins
- Gluconeogenesis also occurs in kidney cells
50
Q
Two ways to reversibly modulate the rate of an enzyme catalysed reaction in a cell
A
- Change the amount of enzyme present in the cell (change enzyme concentration)
- Change the rate of catalysis by a given amount of enzyme (change enzyme activity)
51
Q
Change the amount of enzyme present in the cell (change enzyme concentration)
A
- slow changes (hours, days) at the gene activation level
- Change the rate of enzyme synthesis
- Change the rate of enzyme degradation
52
Q
Change the rate of catalysis by a given amount of enzyme (change enzyme activity)
A
- rapid changes
- Allosteric control
- (instantaneous): activators or inhibitors (ligands) can bind to one or more allosteric sites (other than the active site for the substrates) – Km ↑ or ↓
- Covalent modification (rapid, but not instantaneous) usually triggered by chemical signals from other cells (hormones) - eg phosphorylation by kinases, or dephosphorylation by phosphoprotein phosphatases
53
Q
Mechanism of hormonal control
A
- Hormone (glucagon, adrenaline (epinephrine)
- Binds to receptor of target cell
- Increases cAMP level inside cell
- cAMP activates a protein kinase (PKA)
- PKA phosphorylates
specific proteins - Phosphorylation leads to
changes in enzyme activities and metabolic responses
54
Q
Glucokinase (GK)
A
- bound to a regulatory protein (GKRP) in nucleus – inactive
- Released when blood glucose levels increase
- When fructose-6-P increases, GK is rebound to GKRP and ‘switched-off’
55
Q
Phosphofructokinase (PFK1)
A
- Allosteric control
- controlled by activity of PFK2: bifunctional enzyme, with two catalytic sites: one synthesizes F-2,6-BP (kinase activity), other hydrolyses it back to F-6-P (bisphosphatase activity)
- kinase site is active when PFK2 is dephosphorylated -activated by insulin and inactivated by glucagon – levels of F-2,6-BP are high and Fructose 1,6-bisphosphatase is inactive
56
Q
Fructose 1,6-bisphosphatase
A
- Allosteric control
- Transcriptional control
- Also controlled by the activity of PFK2
- F-2,6-BP decreases when the bisphosphatase site is active (phosphorylated state) - activated by glucagon and inactivated by insulin
- PFK2 is phosphorylated, Fructose 1,6-bisphosphatase is active
57
Q
Regulation of PFK bi-functional protein
A
- Insulin aims to produce acetyl-CoA for FA synthesis – storage (fed - hyperglycemia)
- Glucagon aims to promote release of glucose (fasted - hypoglycemia)
- May be considered a modification mechanism - indirect
- Function is to control levels of fructose 2, 6-bisP – allosteric regulator
58
Q
Pyruvate kinase
A
- Allosteric control
- regulated via phosphorylation
- glucagon released when the blood glucose levels are low activates the adenylate cyclase, and cAMP is produced
- cAMP activates protein kinase A
- Protein kinase A phosphorylates pyruvate kinase and inhibits its activity
- Phosphoenolpyruvate is used for gluconeogenesis
59
Q
Glucose-6-phosphatase
A
- Activated by transcriptional changes, controlled by insulin and glucagon
60
Q
PEP carboxykinase
A
- Allosteric control
- Activated by transcriptional changes, controlled by insulin and glucagon
61
Q
Pyruvate carboxylase
A
- Allosteric control
- Activated by high acetyl-CoA (which inhibits PDH)
- Gluconeogenesis is promoted
62
Q
Control of glycolysis in muscle cells
A
- Muscle glycolysis influenced by ATP requirements
- primary regulatory control is the energy charge of the cell
ATP:AMP ratio - ATP (allosteric inhibitor)
- AMP (allosteric activator)
- ADP not involved in allosteric control due to action of adenylate kinase, which salvages ATP from ADP in myocytes
63
Q
Muscle hexokinase
A
- regulated by levels of glucose-6-P
- High [glucose-6-P] = maximal glycogen synthesis – Hexokinase is inhibited
- Not a major site of regulation as the product is precursor of other pathways
- PPP minimal in muscle: main exit routes for glucose-6-P are glycolysis and glycogen synthesis
64
Q
Muscle phosphofructokinase PFK-1
A
- most important regulatory enzyme
- Tetrameric enzyme: L and M subunits e.g. M4, M3L, M2L2, L4, Myocytes M4, liver L4
- enzyme is inhibited by a decrease in pH (anaerobic production of lactate) to protect against acid damage
- Inhibited allosterically by high [ATP]: More active at low [ATP], reduced affinity for fructose-6-P
- Activated allosterically by AMP
- Activated allosterically by F-2,6-B, F-2,6-B levels depend on activity of PFK-2
65
Q
PFK-2 in muscle tissue
A
- M isoform of PFK-2 in heart and skeletal muscle, L isoform in liver
- Differences in regulation – phosphorylation of M isoform activates kinase site (M isoform not controlled by glucagon) – activates glycolysis in muscle cells
- Hormonal regulation - by epinephrine
66
Q
Pyruvate kinase (glycolysis control in liver cells)
A
- controls pyruvate production
- Inhibited allosterically by increased alanine levels
- Inhibited allosterically by ATP
- Tetrameric protein: each subunit is allosterically regulated by ATP
- High [ATP] inhibits the enzyme
- Activated allosterically by high [fructose 1,6-bisP]
67
Q
Leptin
A
- Expressed by adipocytes
- Decreases appetite – hypothalamus
- Increases FA oxidation via activation of AMP-activated protein kinase (activated when the AMP/ATP ratio increases – low energy levels)
- Prevents accumulation of FA in non-adipose tissue
- Obesity – correlated with leptin resistance
68
Q
Adiponectin
A
- Released by adipocytes – regulator of AMP-activated protein kinase activity (↑ phosphorylation, ↑ activity)
- Receptors on both liver and muscle cells (similar effect as insulin)
- In liver: increases FA oxidation and decreases gluconeogenesis
- In muscle: increases glucose uptake and glucose/FA oxidation
69
Q
Ghrelin / Peptide YY (PYY3-36)
A
- Involved in short term regulation of appetite
- Ghrelin: peptide released by stomach, increases during fasting, stimulates appetite.
- PYY3-36: peptide released by intestine, inhibits food intake.
70
Q
Roles of hypothalamus
A
- Several neuronal cell activities in the arcuate nucleus region of the hypothalamus
- NPY/AgRP neurons increase appetite (NPY = neuropeptide Y; AgRP = Agouti related protein)
- POMC/CART neurons suppress appetite (POMC = proopiomelanocortin; CART = cocaine- and amphetamine- regulated transcript)
