Lectures 29/30: Integration of Metabolism Flashcards
Location of pyruvate transporter
Mitochondrial membrane
Location of cartinite/acyl carnitine transporter
Mitochondrial membrane
Location of citrate transporter
Mitochondrial membrane
Location of aspartate transporter
Mitochondrial membrane
Location of malate transporter
Mitochondrial membrane
Location of adenine nucleotide translocase
Mitochondrial membrane
Location of P-H symport proteins
Mitochondrial membrane
Location of citrulline transporter
Mitochondrial membrane
Location of ornithine transporter
Mitochondrial membrane
Location of citric acid cycle
Mitochondrial matrix
Location of oxidative phosphorylation
Mitochondrial matrix
Location of beta-oxidation
Mitochondrial matrix
Location of ketogenesis
Mitochondrial matrix
Location of amino acid synthesis and degradation
Mitochondrial matrix and cytosol
Location of urea cycle
Mitochondrial matrix and cytosol
Location of glycolysis
Cytosol
Location of gluconeogenesis
Cytosol
Location of pentose phosphate pathway
Cytosol
Location of fatty acid synthesis
Cytosol
Location of nucleotide synthesis
Cytosol
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)
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
Malate transporter
Transports oxaloacetate in form of malate from mitochondrial matrix to cytosol, where it is oxidized to oxaloacetate
Malate dehydrogenase
Converts oxaloacetate to malate to be transported via malate transporter to cytosol to be used in gluconeogenesis
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
Maintenance of cellular homeostasis
- Regulation of energy levels in the cell (ATP, AMP)
- Regulation to avoid build-up or scarcity of metabolites: regulation through allosteric effectors and substrate availability
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
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
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
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
Metabolic goal of fed state
Remove glucose form blood
Store energy for later
Metabolic goal of post-absorptive state
Provide glucose to the tissues that need glucose
Provide energy to other issues, maintain glucose levels in blood
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
Metabolic goal of exercise
Provide energy to muscle
Increase oxygen supply to muscle
Metabolites secreted by adipose tissue
Fatty acids and glycerol
Metabolites secreted by muscle
Lactate and amino acids
Metabolites secreted by liver
Glucose, ketone bodies, lipoproteins
Metabolites secreted by brain
None
Brain
Virtually no energy storage No fatty acid oxidation Glucose is obligatory fuel No secretion of energy metabolites Ketone bodies used when present
Heart
Virtually no energy storage
Fatty acids or glucose used
No secretion of energy metabolites
Ketone bodies used when present
Ketone bodies as fuel
Ketone bodies only cover 70% of what brain needs, brain will still need glucose
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
Adipose tissue in fasted state
Lipolysis of TG
Secretion of fatty acids and glycerol
Provision of energy during fasting
Skeletal muscle in fed state
Glucose uptake, storage as glycogen
Amino acid uptake for protein synthesis
Skeletal muscle in fasting/starvation
Protein breakdown
Amino acids (as alanine) to liver
At rest: fatty acid oxidation
Ketone bodies used if present
Skeletal muscle in active sate
Glycogenolysis
Anaerobic glycolysis
Secretion of lactate
Fatty acid oxidation if sufficient oxygen
Kidney
Some gluconeogenesis
Glutamine breakdown and excretion of ammonium
Excretion (NOT production) of urea
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
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)
Liver failure
Can lead to hypoglycaemia during fasting due to insufficient gluconeogenesis and increased ammonium levels
Cori cycle
Transport of lactate from muscle to liver where it is converted to pyruvate and then glucose and released
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
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
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
Ionotropic receptors
Ion channels
Neurotransmitters
G-protein coupled receptors
Over 800
Catecholamines
Glucagon
Vision, taste, smell
Cytokine receptors
Cytokines: inflammatory molecules
Receptor tyrosine kinases
Insulin
Growth factors
Nuclear hormone receptors
Membrane-permeable ligands
Steroids
Thyroid hormones
Vitamins A, D
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
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
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
Pancreatic islets
Produce insulin and glucagon
Pancreas in an endocrine organ and an exocrine organ
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
Beta cells
Produce insulin
Pancreas
Contain glucokinase (also in liver): isoform of hexokinase
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
Insulin action on muscle
Promote glucose transport into cells
Stimulates glycogen synthesis
Suppresses glycogen breakdown
Insulin action on adipose tissue
Activates extracellular lipoprotein lipase
Increases level of acetyl-CoA carboxylase
Stimulates triacylglycerol synthesis
Suppresses lipolysis
Insulin action on liver
Promotes glycogen synthesis
Promotes triacylglycerol synthesis
Suppressed gluconeogenesis
GLUT transporters
Takes up glucose
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
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
Glycogen synthase
Glycogen synthesis pathway
Upregulated by insulin
Down regulated by glucagon
Acetyl-CoA carboxylase
Fatty acid synthesis pathway
Upregulated by insulin
Down regulated by glucagon
Inactive by phosphorylation
HMG-CoA reductaste
Glycogenolysis pathway
Down regulated by insulin
Upregulated by glucagon
Inactive by phosphorylation
Hormone sensitive lipase
Adipocyte lipolysis pathway
Down regulated by insulin
Upregulated by glucagon
Activated by phosphorylation
Phosphofructokinase 2
Glycolysis pathway
Upregulated by insulin and down regulated by glucagon
Inactive by phosphorylation
Insulin receptor
Receptor tyrosine kinase
Insulin signalling activates several phosphatases
Glucagon receptor
GPCR
- Binding
- Activation of receptor
- Activation of G protein
- Activation of adenylate cyclase
- Production of cAMP
- Activation of PKA
- Downstream activation of other protein kinases
Glycogen phosphorylase
Activated by phosphorylation by phosphorylase kinase: promoted by glucagon and EN signalling
Deactivated by phosphoprotein kinase, which is promoted by insulin
Kinases
Inhibited by insulin
Phosphatases
Activated by insulin
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
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
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
Lipid metabolism with diabetes
Increased circulating triacylglycerol levels: lipoprotein lipase is not activated
Increased fatty acid levels linked to cardiovascular disease
Obesity
Caused by long-term positive energy balance
Caused by inheritance and lifestyle
Genetics, environment, epigenetics/microbiome
Genetics and obesity
Leptin Leptin receptor Melanocortin receptor Neuropeptide Y receptor Uncoupling protein Susceptibility genes
Environment and obesity
Availability of food
High-calorie food
Larger portion size
Lack of physical activity
Epigenetics and obesity
Micro biome and perinatal influences
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
Adiponectin
Hormone secreted from adipose tissue to regulate long-term energy storage
Activated AMPK to promote fuel catabolism
Characteristics of cancer cells
- Uncontrolled growth: high proliferation, high need for synthesis of DNA, lipids, proteins
- Growth without attachment: metastasis, growth of solid tutors instead of monolayers, inside of tumour can become hypoxic
- Growth without external growth factors: changes in signal transduction, mutations, escaping normal regulation mechanisms
- Dedifferentiation: support of unlimited growth
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
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
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
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
Glutamine
Major fuel after glucose for cancer cells
Anapldrotic reaction to glutamate and alpha-ketoglutarate
Can be fully oxidized when malic enzyme is active
Glucose uptake or hexokinae inhibitors
Affect cancer cells more than normal cells
PKM2 activators
Decreased use of glycolytic intermediates in synthesis
Some cancer cells become dependent on extracellular serine when PKM2 is activated
Dichloroacetate
Inhibits pyruvate dehydrogenase kinase
Activated pyruvate dehydrogenase: pyruvate is oxidized an not used in synthetic reactions
Glutaminase inhibitors
Targeting glutamine addiction of cancer cells
