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Metabolism
The sum of chemical reactions in cells
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Catabolism
- Energy (ATP) yielding.
- Conversion of fuels to end products.
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Anabolism
- Energy (ATP) requiring
- Biosynthetic processes
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Substrate-level phosphorylation
- forming ATP by direct phosphorylation of ADP.
- Transfer of phsphoryl group from "high energy" to ADP.
- Does not require O2
- important for ATP in tissues short of 02, for example, exercising muscle.
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Oxidative phosphorylation
- Requires O2
- For synthesis of ATP
- Oxidation of 2 nucleotides by electron transport chain
- 1. NADH
- 2. FADH2: flavin adenine dinucleotide
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Glycolysis
- "Emergency" energy-producing pathway when oxygen is the limiting factor
- important in RBC: they lack mitochondria, so they only use glycolysis.
- Exercising: When oxidative metabolism can't keep up with increased demand.
- The brain: Glucose is it's main fuel (120g/day)
- Pyruvate is the end product in mitochondria cells and from oxygen supply
- occurs in the cytosol
- Common step in BOTH Respiration and Fermentation
- uses 2ATP in energy investment phase & produces 4ATP in payoff phase.
- pyruvic is last step, if too much then turns acidic
- regulated by phosphofructokinase
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Aerobic glycolysis
- The oxidation of glucose to pyruvate
- oxygen is required to reoxidize NADH that formed during glyceraldehyde
- oxidative decarboxylation of pyruvate to acetyl CoA, a fuel of TCA(citric acid) cycle
- Glucose+2ADP+2NAD+ -> 2Pyruvate+2ATP+2NADH+2H
- 1nadh=2.5atp
- (energy generated: 4atp + 5atp by oxidation of 2nadh) - Energy Invested: 2atp = 7ATP
- Electrons from NADH are transferred to electron transport chain(ETC) via 2 shuttle systems & NAD is returned to cytosol
- Net gain of 2atp & 2nadh/glucose
- Glycerol phosphate shuttle: 2nadh to 4 atp
- Malate asparate shuttle: 2nadh to 6ATP
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Anaerobic Glycolysis
- oxidation of glucose to lactate
- Pyrvate reduced to lactate as NADH is oxidized to NAD+
- Occurs without oxygen
- Allow ATP production in tissue lacking mitochondria ex; in RBC's and cells deprived of O2
- Glucose+2ATP --> 2Lactate -> 2ATP
- or glucose+2atp->2pyruvate+4atp+2nadh
- requires initial input of ATP
- Occurs in Cytoplasm
- provides substrate with 1st step in respiration
- Energy Invested: 2ATP - energy generated: 4ATP = 2ATP total
- reduction of pyruvate to lactate by lactate dehydrogenase NAD
- Net gain of 2atp & no NADH/glucose
- Lactate converts back to pyruvate in liver & excreted in the urine.
- RBC has no mitochondria so only anaerobic resp.
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G Protein coupled receptor (GPCR)
Extracellular domain
Binding site for ligand (a hormone or neurotransmitter)
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G Protein coupled receptor (GPCR)
Intracellular domain
Interacts with G-proteins
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Slide 12: GTP-dependent regulatory proteins
- The G proteins (A,B,Y) sub-units bind to GTP and GDP to form a link between Receptor and Adenylyl Cyclase
- Inactive form: A is bound to to GDP
- Active form: A is bound to GTP and dissociates from B and Y sub-units.
- active state is short-lived because A has inherent GTPase activity, resulting in hydrolysis
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Figure 8.8:
Protein Kinases
- cAMP: 2nd messenger system
- CyclicAMP activates protein kinase A by binding to 2 regulatory subunits, causing release of active catalytic subunits
- Active subunits transfer phosphate from ATP to protein substrates
- Phphorylated proteins act directly on cell's ion channels, and in enzymes they become activated or inhibited
- Protein Kinase A can also phosporylate proteins that bind to DNA, causing changes in gene expression
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Dephosphorylation of proteins
phosphate added to proteins by protein kinases are removed by protein phosphatases
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Hydrolysis of cAMP
- cAMP -> 5AMP by cAMP phosphodiesterase
- 5amp is not intracellular signaling molecule
- Phosphodiesterase: Inhibited by methylxanthine derivatives such as theophylline in caffein
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2 transport mechanisms for glucose to go into cells
- 1. NA+ independent, facilitated diffusion
- 2. Na+ Monosaccharide COtransporter system
- glucose transports from extracellular fluid
- In tissues such as muscle and fat, the hormone Insulin is required to transport
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Ch.8 slide14, Control of Glucose: high glucose
Pancreas B cells are in effect, insulin takes glucose into target tissue.
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Ch.8 slide14, Control of Glucose:Low glucose
Pancreas A cells are in effect, Glucagon is used in the target tissue.
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SGLUT1
COtransports 1 glucose or galactose, and 2 sodium ions
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Glut-1
Transports glucose and galactose, not fructose.
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Glut-2
Transports glucose, glactose, and fructose.
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Glut-3
- transports glucose and galactose, not fructose.
- For Neurons
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Glut-4
Insulin transporter
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Glut-5
Transports fructose, but not glucose or galactose.
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NAD
- Nicotinamide Adenine Dinucleotide
- oxidizing agent
- accepts 2 H to reduce to NADH+H+
- AH2+NAD+=A+NADH+H+
- One H is in medium as proton H+.
- The other as hydride ion, H- attaches to the top of nico. ring.
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1st step of glycolysis
- Phosphorylation of Glucose to Glucose-6-phosphate
- Irreversible & traps glucose inside cell
- 2 enzymes involved: Hexokinase, Glucokinase.
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Hexokinase
- present In all tissues
- active in low (Km) glucose conc.; High affinity for glucose. high substrate affinity.
- low (Vmax); doesn't phosphorylate more sugars (large amount of glucose) than the cell can use
- active in low glucose concentrations
- Can't phosphorylate large amount of glucose
- Inhibited by G-6-P
- Not induced by insulin
- Substrate specificity: Glucose, fructose, galactose.
- Role: provides cells with Glu. 6 Phos. needed for energy
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Glucokinase
- In liver and pancreatic B cells
- (high Km): Active in high glucose concentrations. low substrate affinity.
- (High Vmax): Phosphorylates large amount of glucose
- Induced by insulin
- Not inhibited by Glucose-6-Phos. but promotes clearance of glucose by liver in FED (Feeding) state
- Substrate Specificity: Glucose only
- Role: allows for intracellular glucose to convert to glycogen or triacylglycerols.
- indirectly inhibited by fruct6phos
- indirectly stimulated by glucose
- functions as a glucose sensor in maintenance of blood glucose homeostasis.
- Diabetes type 2 (maturity onset) decrease the activity of glucokinase
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Isomerization of glucose 6 phosphate
- Isomerization of glu6phos to Fructose 6-phosphate
- catalyzed by phosphoglucose isomerase
- reversible reaction
- Not rate-limiting or regulated step
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Fructokinase-1 (PFK-1)
- important control point
- rate-limiting
- committed step of glycolysis.
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regulation of energy in PFK-1
- Inhibited allosterically by high levels of ATP, and high levels of citrate (indicates cell is making ATP).
- Activated allosterically by high conc. of of AMP, with which energy stores are depleted, and fruc. 2,6 Biphosphate formed by PFK2.
- 1 ATP is utilized
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Most potent activator of PFK-1
- Fructose 2,6-bisphosphate
- Activates enzyme even when ATP levels are high.
- Formed by phosphofructokinase-2 (PFK-1)
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PFK-2
- Bifunctional
- Kinase activity: produces fructose 2,6biphosphate
- Phosphatase activity: dephosphorylates fructose 2,6 bisphosphate to to fructose 6-phosphate.
- In liver-kinase domain is active if dephosphorylated, inactive if phosphorylated.
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Phosphorylation of glucose to glucose-6-phosphate
- 1st regulated step in glycolysis
- Irreversible: traps glucose inside the cell
- 1. ATP utilized
- 2. enzymes involved (hexokinase & glucokinase)
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FED state
- induction of insulin (increased) and lack of inhibition of G6P promote clearance of glucose by liver.
- Decreased levels of glucagon and elevated levels of of insulin following a carb-rich meal.
- Increase fructose 2,6-bisphosphate
- intracellular signal, glucose is abundant.
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Starvation (fasting state)
- elevated levels of glucagon, low levels of insulin occur during fasting.
- decrease in intracellular conc. of fruc 2,6 bisphos.
- decrease in glycolysis
- inrease in gluconeogenesis
- Glycerol 3-P is converted to DHAP(used in gluconeogenesis)
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pg.100 High Insulin/glucagon ratio causes *
- decreased cAMP
- reduced active protein kinase A
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decreased protein kinase A favors *
Dephosphorylation of pfk-2/FBP-2
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Dephosphorylated pfk2 is active when *
FBP-2 is inactive; favors fructose 2,6-bisphosphate.
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Elevated fructose 2,6-bisphosphate activates *
PFK-1; which leads to increased glycolysis.
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Reversible reaction ?
conversion of G6P to Fructose-6-phosphate
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Irreversible reaction ?
conversion of F-6-P to 1,6 bisphosphate by PFK1
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Rate limiting step of glycolysis
Phosphofructokinase
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Fructose 2,6 biophosphate controlled by
Insulin
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Reversible conversion of F-1,6 bisphosphate to ?
3 Carbon by aldolase A. triophosphate isomerase
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slide 31: triophosphate isomerase reversibly converts ?
glyceraldehyde 3 phosphate to dihydroacetone phosphate (DHAP)
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DHAP reversibly converts ?
glycerol 3 phosphate by glycerol 3 phatsphate dehydrogenase (needs NADH as cofactor)
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Slide 33: Reversible glyceraldehyde 3P to 1,3BPG by glyc. 3P dehydrogenase using
NAD(must be replenished for glycolysis to continue)
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Regulation & irreversible rxn involves
conversion of PEP to pyruvate by kinase
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Anaerobic Respiration/metabolic acidosis/anaerobic glycolysis
- reversible conversion of pyruvate to lactate by lactate dehydrogenase using NADH cofactor
- in shock, extreme exercise cyanide poison, CO poisoning
- In alcoholics do to inc. NADH
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Lactic acidosis
over production or under utilization of lactic acid leads to lactic acidosis
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Genetic defects/toxins that inhibit glycolysis
- Recessive inherited pyruvate kinase defeciency: have up to 25% normal PK
- Fluoride ions inhibit enolase
- arsenate works as an uncoupling agent to substrate by binding to P-glycerate kinase & glyc-hyde3P Dehydrnase.
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uncoupling
pathway proceeding without ATP synthesis. Resulting in 0 ATP yield.
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8.1 glycolysis
regulated rxns are also irreversible rxns
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8.2 rxn catalyzed by PFK1
is the rate limiting rxn of glycolytic pathway
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8.3 contracting skeletal muscle shows
incr. conversion pyruvate to lactate.
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8.4. pt has weakness, fatigue, sob, vertigo. hemoglobin <7(normal 13.5), isolated RBC's, low lactate production. what anemia is this?
Pyruvate kinase
(this is defect in glycolysis)
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ethanol synthesis ?
- in yeast and bacteria (inestinal flora)
- thiamine pyrophosphate dependent pathway
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Pyruvate dehydrogenase complex ?
- inhibited by acetyl CoA
- source of Acetyl coA for TCA and faty acid synthesis
- irreversible
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Pyruvate carboxylase ?
- activated by Acetyl CoA
- replenishes intermediates of TCA
- provide substrate for gluconeogen.
- irreversible
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nutrients like Carbs, fats, proteins through catabolism gives you
energy poor productus CO2, H20, NH3
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Precursor molecules like AA's sugars, fatty acids, nitrogenous bases through Anabolism give you
complex molecules like proteins, polysaccarieds, lipids, nucleic acids.
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