Lectures 29/30: Integration of Metabolism Flashcards Preview

Biochemistry 2300 > Lectures 29/30: Integration of Metabolism > Flashcards

Flashcards in Lectures 29/30: Integration of Metabolism Deck (102):
1

Location of pyruvate transporter

Mitochondrial membrane

2

Location of cartinite/acyl carnitine transporter

Mitochondrial membrane

3

Location of citrate transporter

Mitochondrial membrane

4

Location of aspartate transporter

Mitochondrial membrane

5

Location of malate transporter

Mitochondrial membrane

6

Location of adenine nucleotide translocase

Mitochondrial membrane

7

Location of P-H symport proteins

Mitochondrial membrane

8

Location of citrulline transporter

Mitochondrial membrane

9

Location of ornithine transporter

Mitochondrial membrane

10

Location of citric acid cycle

Mitochondrial matrix

11

Location of oxidative phosphorylation

Mitochondrial matrix

12

Location of beta-oxidation

Mitochondrial matrix

13

Location of ketogenesis

Mitochondrial matrix

14

Location of amino acid synthesis and degradation

Mitochondrial matrix and cytosol

15

Location of urea cycle

Mitochondrial matrix and cytosol

16

Location of glycolysis

Cytosol

17

Location of gluconeogenesis

Cytosol

18

Location of pentose phosphate pathway

Cytosol

19

Location of fatty acid synthesis

Cytosol

20

Location of nucleotide synthesis

Cytosol

21

Metabolic control through compartmentation

Transport can control the activity of pathways
Transport is not always direct: converted
In general: synthetic pathways are cytosolic and oxidative pathways are in mitochondria (glycolysis and gluconeogenesis are exceptions as they share enzymes and are both mostly cytosolic)

22

Mitochondrial steps of gluconeogenesis

Pyruvate converted into oxaloacetate by pyruvate carboxylase: occurs in mitochondria
Oxaloacetate must leave mitochondria: indirectly transported into cytosol as malate using the malate transporter to enter glyconeogenesis

23

Malate transporter

Transports oxaloacetate in form of malate from mitochondrial matrix to cytosol, where it is oxidized to oxaloacetate

24

Malate dehydrogenase

Converts oxaloacetate to malate to be transported via malate transporter to cytosol to be used in gluconeogenesis

25

Alcohol intoxication and hypoglycemia

Ethanol is metabolized in cytosol to acetyl-CoA, generating NADH
Malate dehyrodgenase reaction is prevented from proceeding from matte and NAD+ to oxaloacetate and NADH: inhibition of gluconeogenesis in the liver
When this occurs in fasting period, blood glucose levels can drop leading to hypoglycaemia and unconsciousness

26

Maintenance of cellular homeostasis

1. Regulation of energy levels in the cell (ATP, AMP)
2. Regulation to avoid build-up or scarcity of metabolites: regulation through allosteric effectors and substrate availability

27

Maintenance of homeostasis in whole organism

Coordination of metabolism in different cell types/different tissues regarding energy and metabolite levels
Regulation through hormone signalling leading to changes in enzyme activity through covalent modification and changes in expression
1. Each tissue must recieve suffice energy in a form it can use
2. Build up of metabolites in body must be prevented
3. Xenobiotics must be degraded

28

Fatty acids

Highest caloric value per carbon
Most abundant stored energy in human body (triacylglycerol)
Last longest during fasting periods
No fatty acid oxidation in absence of oxygen or mitochondria
No fatty acid oxidation i brain
Cannot be converted to glucose

29

Glucose

Used by all tissues
Limited storage in form of glycogen
Can generate ATP even when oxygen is low
Precursor for all other metabolites
Also needed in pentose phosphate pathway

30

Amino acids

Glycogenic amino acids are nearly as versatile as glucose
Most amino acid storage is in muscle protein, not beneficial to break this down

31

Metabolic goal of fed state

Remove glucose form blood
Store energy for later

32

Metabolic goal of post-absorptive state

Provide glucose to the tissues that need glucose
Provide energy to other issues, maintain glucose levels in blood

33

Metabolic goal of fasting

Provide glucose to the tissues that need glucose
Provide energy to other issues, maintain glucose levels in blood
Reduce glucose requirements as much as possible

34

Metabolic goal of exercise

Provide energy to muscle
Increase oxygen supply to muscle

35

Metabolites secreted by adipose tissue

Fatty acids and glycerol

36

Metabolites secreted by muscle

Lactate and amino acids

37

Metabolites secreted by liver

Glucose, ketone bodies, lipoproteins

38

Metabolites secreted by brain

None

39

Brain

Virtually no energy storage
No fatty acid oxidation
Glucose is obligatory fuel
No secretion of energy metabolites
Ketone bodies used when present

40

Heart

Virtually no energy storage
Fatty acids or glucose used
No secretion of energy metabolites
Ketone bodies used when present

41

Ketone bodies as fuel

Ketone bodies only cover 70% of what brain needs, brain will still need glucose

42

Adipose tissue in fed state

Uptake of glucose and fatty acids
Synthesis of TG
Removal of blood glucose after a meal
Storage of energy for later

43

Adipose tissue in fasted state

Lipolysis of TG
Secretion of fatty acids and glycerol
Provision of energy during fasting

44

Skeletal muscle in fed state

Glucose uptake, storage as glycogen
Amino acid uptake for protein synthesis

45

Skeletal muscle in fasting/starvation

Protein breakdown
Amino acids (as alanine) to liver
At rest: fatty acid oxidation
Ketone bodies used if present

46

Skeletal muscle in active sate

Glycogenolysis
Anaerobic glycolysis
Secretion of lactate
Fatty acid oxidation if sufficient oxygen

47

Kidney

Some gluconeogenesis
Glutamine breakdown and excretion of ammonium
Excretion (NOT production) of urea

48

Liver in fed state

Glycogen synthesis and storage, but glucose uptake is not unregulated
Glycolysis
Fatty acid synthesis from excess acetyl-CoA
Triacylglycerol synthesis and secretion as VLDL

49

Liver in fasted state

Glycogenolysis
Secretion of glucose
Gluconeogenesis
Ketogenesis (when fasting is prolonged
VLDL secretion to provide triacylglycerols/fatty acids and cholesterol to heart and skeletal muscle
Urea cycle (also active when lost of amino acids are degraded)

50

Liver failure

Can lead to hypoglycaemia during fasting due to insufficient gluconeogenesis and increased ammonium levels

51

Cori cycle

Transport of lactate from muscle to liver where it is converted to pyruvate and then glucose and released

52

Glucose-alanine cycle

Pyruvate is produced by muscle glycolysis
Pyruvate is transaminate to make alanine
Alanine is transported from muscle to the liver where ammonium is released to urea cycle and pyruvate is used to make glucose

53

Hormones

Convey short and long-range signals
Can be polypeptides, amino acid derivatives, steroids
Signalling through specific receptors: maintenance of homeostasis, integration across organism
Response to external stimuli
Follow cyclic programs: sleep/wake, menstrual
Signalling: bind receptor, mediate response, terminate signal

54

Signal transduction

Ligand binds receptor
Intracellular signal propagation: activation of enzymes, formation of second messengers, secondary activation enzymes, protein translocation
Causes: cytoskeleton rearrangement, enzyme modification, gene expression changes

55

Ionotropic receptors

Ion channels
Neurotransmitters

56

G-protein coupled receptors

Over 800
Catecholamines
Glucagon
Vision, taste, smell

57

Cytokine receptors

Cytokines: inflammatory molecules

58

Receptor tyrosine kinases

Insulin
Growth factors

59

Nuclear hormone receptors

Membrane-permeable ligands
Steroids
Thyroid hormones
Vitamins A, D

60

Insulin

Reduces blood glucose and builds energy stores (anabolic)
Polypeptide hormone made in pancreatic beta cells: secretion trigged by metabolism of glucose and ATP production because of glucose oxidation
Upregulation of glucose uptake in muscle and adipose
Increased glycolysis
Increased fatty acid uptake into adipose
Increased glycogen synthesis, fatty acid synthesis and protein synthesis

61

Glucagon

Increases blood glucose and mobilizes energy stores (catabolic)
Polypeptide made in pancreatic alpha cells
Increased gluconeogenesis in liver
Increased glycogenolysis, lipolysis, fatty acid oxidation, proteolysis
Does not act on muscle cells

62

Catecholamines

Mobilize energy for muscle activity "Fight or flight" response
Amino acid derivatives
Increased gluconeogenesis in liver
Increased glycogenolysis, lipolysis, fatty acid oxidation and proteolysis

63

Pancreatic islets

Produce insulin and glucagon
Pancreas in an endocrine organ and an exocrine organ

64

Regulation of insulin and glucagon secretion

Insulin levels rise quickly after a meal and glucagon levels decrease quickly after a meal
Glucose stimulates insulin secretion
Glucose and insulin inhibit glucagon secretion

65

Beta cells

Produce insulin
Pancreas
Contain glucokinase (also in liver): isoform of hexokinase

66

Glucokinase

In liver and beta cells of pancreas
Isoform of hexokinase
Acts as glucose sensor: activity is dependent on glucose concentration over a wide range
Does not react with other monosaccharides ie. fructose does not cause insulin secretion

67

Insulin action on muscle

Promote glucose transport into cells
Stimulates glycogen synthesis
Suppresses glycogen breakdown

68

Insulin action on adipose tissue

Activates extracellular lipoprotein lipase
Increases level of acetyl-CoA carboxylase
Stimulates triacylglycerol synthesis
Suppresses lipolysis

69

Insulin action on liver

Promotes glycogen synthesis
Promotes triacylglycerol synthesis
Suppressed gluconeogenesis

70

GLUT transporters

Takes up glucose

71

GLUT4

Only GLUT transporter unregulated by insulin
In muscle and adipose
Expression and localization regulated by insulin: causes translocation into membrane
Other isoforms are present in liver, pancreatic cells, brain, but are not regulated by insulin

72

Lipoprotein lipase

Activated by insulin causing increased uptake of fatty acids
Storage of dietary or liver-derived fat in adipocytes by hydrolysis of TG into lipoproteins and uptake of fatty acids for resynthesis to TG
Fatty acids are activated wth CoA to be esterified with glycerol-3-phoshate

73

Glycogen synthase

Glycogen synthesis pathway
Upregulated by insulin
Down regulated by glucagon

74

Acetyl-CoA carboxylase

Fatty acid synthesis pathway
Upregulated by insulin
Down regulated by glucagon
Inactive by phosphorylation

75

HMG-CoA reductaste

Glycogenolysis pathway
Down regulated by insulin
Upregulated by glucagon
Inactive by phosphorylation

76

Hormone sensitive lipase

Adipocyte lipolysis pathway
Down regulated by insulin
Upregulated by glucagon
Activated by phosphorylation

77

Phosphofructokinase 2

Glycolysis pathway
Upregulated by insulin and down regulated by glucagon
Inactive by phosphorylation

78

Insulin receptor

Receptor tyrosine kinase
Insulin signalling activates several phosphatases

79

Glucagon receptor

GPCR
1. Binding
2. Activation of receptor
3. Activation of G protein
4. Activation of adenylate cyclase
5. Production of cAMP
6. Activation of PKA
7. Downstream activation of other protein kinases

80

Glycogen phosphorylase

Activated by phosphorylation by phosphorylase kinase: promoted by glucagon and EN signalling
Deactivated by phosphoprotein kinase, which is promoted by insulin

81

Kinases

Inhibited by insulin

82

Phosphatases

Activated by insulin

83

Type 1 Diabetes

Destruction of beta cells: total loss of insulin production
Beta cell destruction is often autoimmune response
Treatment by giving insulin
Untreated Type 1: ketoacidosis can develop

84

Type 2 Diabetes

Insulin signalling is less sensitive than normal, causing insulin resistance
Insulin levels are normal or even increased
Strongly linked to obesity
Can be treated with some oral drugs that increase insulin sensitivity and lifestyle changes
AMPK activators promote insulin sensitivity

85

Longterm effects of hyperglycaemia

Nerve and kidney damage
Risk of cataract formation
Possible mechanisms: glucose can react with proteins, protein modification impairs function
Glucose converted to sorbitol when glucose concentrations are very high: increases osmotic pressure

86

Lipid metabolism with diabetes

Increased circulating triacylglycerol levels: lipoprotein lipase is not activated
Increased fatty acid levels linked to cardiovascular disease

87

Obesity

Caused by long-term positive energy balance
Caused by inheritance and lifestyle
Genetics, environment, epigenetics/microbiome

88

Genetics and obesity

Leptin
Leptin receptor
Melanocortin receptor
Neuropeptide Y receptor
Uncoupling protein
Susceptibility genes

89

Environment and obesity

Availability of food
High-calorie food
Larger portion size
Lack of physical activity

90

Epigenetics and obesity

Micro biome and perinatal influences

91

Leptin

Hormone secreted from adipose tissue to regulate long-term energy storage
Signals satiety
Deficiency or impaired signalling can cause obesity: human obesity is often associated with leptin resistance

92

Adiponectin

Hormone secreted from adipose tissue to regulate long-term energy storage
Activated AMPK to promote fuel catabolism

93

Characteristics of cancer cells

1. Uncontrolled growth: high proliferation, high need for synthesis of DNA, lipids, proteins
2. Growth without attachment: metastasis, growth of solid tutors instead of monolayers, inside of tumour can become hypoxic
3. Growth without external growth factors: changes in signal transduction, mutations, escaping normal regulation mechanisms
4. Dedifferentiation: support of unlimited growth

94

Positron Emission Tomography Imaging

PET visualized the body metabolic activity following injection of 2-deoxy-2-fluoroglucose (fluorodeoxyglucose)
Deoxyglucose is phosphorylated by hexokinase but not further protein down, and accumulates in cell
Dark areas indicate tissues that take up a lot of glucose

95

Warburg Effect

1920s
Cancer cells generate high levels of ATP through glycolysis and lactate production even when sufficient oxygen is present
Mitochondria in cancer cells are dysfunctional: not generally confirmed
Later research confirmed that most cancer cells have very high rates of glycolysis even in presence of oxygen: various reasons

96

Metabolic needs of highly proliferating cells

More ATP production, synthesis of lipids, nucleotides and proteins
High requirement of NADPH and antioxidants
Metabolic adaptations in different cancers are highly diverse and depend on original cell type

97

Glycolysis in cancer cels

Less efficient way to generate ATP, but occurs even in presence of oxygen
Glycolytic intermediates and pyruvate are diverted into biosynthesis reactions

98

Glutamine

Major fuel after glucose for cancer cells
Anapldrotic reaction to glutamate and alpha-ketoglutarate
Can be fully oxidized when malic enzyme is active

99

Glucose uptake or hexokinae inhibitors

Affect cancer cells more than normal cells

100

PKM2 activators

Decreased use of glycolytic intermediates in synthesis
Some cancer cells become dependent on extracellular serine when PKM2 is activated

101

Dichloroacetate

Inhibits pyruvate dehydrogenase kinase
Activated pyruvate dehydrogenase: pyruvate is oxidized an not used in synthetic reactions

102

Glutaminase inhibitors

Targeting glutamine addiction of cancer cells