Week 8 - Metabolism Flashcards

(86 cards)

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
What are the properties of complex 3?
Cytochrome c reductase Heme prosthetic group Accepts CoQ electrons Transfers electrons to cytochrome c 2 protons pumped across
26
What are the properties of complex 4?
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
27
What are the properties of coenzyme Q?
Ubiquinone Small, lipid soluble compound Mobile carrier Accepts Fe-S protein electrons from complex 1 and 2 Electrons transferred to complex 3
28
What are the proeprties of cytochrome c?
Peripheral membrane protein bound to IMM loosely Bind to complex 3 and transfers electrons to complex 4 Highly conserved
29
What are the proeprties of ATP synthesis in oxidative phosphorylation?
ATP synthase is complex 5 In inner mitochondrial matrix Composed of 2 subunits: F1 ATPase – generates ATP, F0 coupling factor – proton channel spanning IMM
30
What agents affect oxidative phosphorylation?
ATPase inhibitors (oligomycin) SSI’s of electron transport chain Uncouplers (neutralise proton gradient and prevent ATP synthesis) à chemical = dinitrophenol, natural = uncoupling proteins
31
What is UCP1/ thermogenin?
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
32
What is the process of fatty acid mobilisation?
Glucagon or adrenaline activate hormone-sensitive lipase Triacyglycerol in adipose tiossue is hydrolysed Free fatty acids and glycerol is formed
33
Why can't the brain take up free fatty acids?
Cannot cross blod-brain barrier
34
What happens during 'beta'-oxidation of fatty acids?
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
35
What is used for LCFA import into mitochondria?
Carnitine shuttle CoA esters cannot cross mitochondrial inner membrane
36
What are the proeprties of carnitine?
From meat Liver and kidney synthesise it Kidneys supply to muscles via blood Deficiency leads to toxic LCFA build up causing neurological damage
37
What are the proeprties of ketone bodies?
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
What happens during ketone body synthesis?
Liver mitochondria Acetoacetate and ‘beta’-hydroxybutyrate form 2 ketone bodies Acetoacetate reduced to ‘beta’-hydroxybutyrate when high NADH (during starvation)
39
How are ketone bodies utilised?
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
What happens during ketoacidosis?
0.1mM = normal 7mM = tissue utilisation saturated so excreted in urine (ketonuria) - blood pH (ketoacidosis) Test using paper strips for ketonuria
41
When does gluconeogensis occur?
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
When is glucose required?
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
What are the properties of gluconeogenesis?
- Glucose synthesis from non-carbohydrate precursors - Occurs in liver, kidneys and small intestine - Occurs in cell cytosol - Is reversal of glycolysis
44
When is gluconeogenesis not the reversal of glycolysis?
_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
What effect does insulin have on gluconeogenesis? What effect does glucagon have on gluconeogenesis?
Promotes glycolytic enzyme synthesis Inhibits PEPCK synthesis Increases PEPCK and F1,6BPase expression
46
How do you form gluconeogenesis precursors from amino acids?
Remove amino group Use carbon skeleton to form glucose
47
What are the 4 types of metabolic pathways?
Fuel oxidative pathways Fuel storage and mobilisation Biosynthetic pathways Detoxification / waste disposal pathways
48
What is anabolism? What is catabolism? What are anabolic pathways? What are catabolic pathways?
Synthesis Breakdown Synthesis of large molecules Breakdown of large molecules
49
How is balance acheived in metabolism?
Blood nutrient concentration (fatty acids for example) Hormones (epinephrine for example (fight or flight)) CNS
50
What are the consequences of too low or high metabolism?
Low = hypoglycaemia, brain metabolism limited High = coma, non-enzymatic glycosylation of proteins
51
What is the role of insulin in metabolism?
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
What is the role of glucagon in metabolism?
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
Where is insulin and glucagon produced?
Pancreas: - 'alpha' cells secrete glucagon - 'beta' cells secrete insulin
54
What are the properties of glucagon in metabolism?
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
what are the intracellular events of glucagon and insulin in metabolism?
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
What are cellular responses to glucagon or insulin?
Reverses glucagon-stimulated phosphorylation Kicks off a phosphorylation cascade Induction/repression of enzyme Stimulate protein synthesis Stimulate glucose & amino acid intake
57
What are the 3 types of memory?
Sensory memory (registration) Working / short-term memory (limited capacity, acoustic coding, receny effect) Permanent / long-term memory (large capacity, primary effect, semantic coding)
58
How can you imporve patient recall?
Organisation (good structure) Less is more Stress importance Precise information Association with visual imagery Cues External aids
59
What is adherence? What are the forms on non-adherence?
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
What needs to be involved in a systematic review?
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
What is evidence based medicine?
Systematic review, appraisal and use of clinical research findings to aid optimum clinical care delivery to patients
62
How to formulate evidence based medicine?
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
What happens to dietary carbohydrates during the fed state?
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
What happens to glucose, proteins, free amino acids and fats during the fed state?
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
What do hormones effect on metabolic pathways?
Substrate availability Allosteric regulation of enzyme Covalent modification of enzymes Induction of enzyme synthesis
66
What is the role of liver in fed state metabolism?
Uses hepatic portal vein for venous drainage of gut and pancreas Takes up carbs, lipids and AA’s
67
What happens during carbohydrate metabolism in the fed state?
+ 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
What happens during fat metabolism in fed state?
Liver = primary fatty acid synthesis site --\> acetyl CoA carboxylase activated + acetyl CoA
69
What happens during the fasting state and starved state?
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
What are the 2 priorities during the starved state?
Maintain adequate blood glucose Mobilise fatty acids and synthesis ketone bodies
71
What is the role of body stores in the starved state?
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
What fuels does the brain use? What fuels does muscle use?
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
What fuels does the heart use? What fuels does adipose tissue use? What fuels does the liver use?
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
_Liver_ What happens during carbohydrate metabolism during the starved state?
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
_Liver_ What happens during fat metabolism during the starved state?
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
_Adipose tissue_ What happens during carbohydrate metabolism during the starved state?
Depressed glucose transport as insulin sensitive Reduced glycolysis Reduced triacylglycerol synthesis
77
_Adipose tissue_ What happens during fat metabolism during the starved state?
Lipolysis mobilises adipose triacylglycerols --\> fatty acids and glycerol released Increased fatty acid usage with increased fasting length
78
_Adipose tissue_ What happens during fatty acid metabolism during the starved state?
Increased release as hydrolysis of triacylglycerols Decreased uptake as adipose LDL activity is low
79
_Resting skeletal muscle_ What happens during the fasting state?
Resting muscle moves further from glucose to fatty acids and ketone bodies as become main energy source for contraction
80
_Resting skeletal muscle_ What happens during carbohydrate metabolism in the starved state?
Depressed glucose transport as insulin sensitive Reduced glycolysis
81
_Resting skeletal muscle_ What happnens during lipid metabolism during the starved state?
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
_Resting skeletal muscle_ What happens during protein metabolism during the starved state?
Early stages = + breakdown of muscle protein (+ liver gluconeogenesis) Fall in insulin initiates this
83
_Brain and kidney_ What happens during the starved state?
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
What are the properties of diabetes mellitus?
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
What are the properties of Type 1 diabetes mellitus?
'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
What are the properties of Type 2 diabetes mellitus?
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