Metabolism Flashcards
First Law of Thermodynamics
Total energy constant
Neither created/destroyed
Anabolism
Cellular work
ATP -> ADP + Pi
Catabolism
Energy from food
ADP + Pi -> ATP
Eintake =
Eexpended + Estored
basal metabolism + activities) + (weight gain
1J =
The energy to push 1N of force 1m
Atwater factors Fat Carbohydrates Protein Ethanol
38
17
17
29
Not all energy available eg
Cellulose - loss in faeces as fiber
Nitrogen - not oxidised and excreted in urine
Direct calorimetry
Whole body calorimeters
Measure heat output
Good at measuring BMR
Indirect calorimetry
O2 and CO2 using respirometer
1 mol O2 at STP = 22.4L
Respiration exchange rate
CO2/O2
Determine if fuel used
Basal metabolic rate
Energy expenditure at rest
Variation: gender, age, genetics, disease
Increase BMR
Training Late pregnancy Fever Drugs (caffeine) Hyperthyroidism
Decrease BMR
Malnutrition
Sleep
Drug (beta-blockers)
Hypothyroidism
Process of digestion
1) Hydrolysis of bonds (b/e connecting monomer units)
2) Absorption of products
Dietary carbonhydrates
40 - 50% energy intake
Starch from plants
Amylose
Amylopectin
Amylose
Linear polymer ⍺(1-4) linked glucose units
Amylopectin
Branched polymer ⍺(1-4) & ⍺(1-6) linked units
Cellobiose & lactose =
Stereoisomers
Cellobiose
Repeating disaccharide unit in cellulose
Mammals don’t have enzyme to hydrolysed β(1-4) bond
Maltase/isomaltase
Maltose/isomaltose ->
2 glucose
Sucarse
Surcose ->
Fructose + glucose
Lactase
Lactose ->
Galactose + glucose
Starch digestion 1
Amylase hydrolyse ⍺(1-4) glycosidic bonds = small oligosaccharides
Producing maltose/isomaltose disaccharides
Starch digestion 2
At brush border
Disaccharides -> monosaccharides
Digestion of protein
65g/day
Source of nitrogen an essential animo acid
Deficiency of dietary protein
Kwashiorkor
Osmotic imbalance in GI, retention of water
Protein digestion
Hydrolyses specific peptide bonds by several proteases
2 stages
All proteases
Secreted as inacitve forms
Activated by cleavage of peptides from their structure
Proteases inactive form
Zymogens/ proenzymes
Specificity proteases
Adjacent a.a side chain
2 stages of protein digestion
Endopeptidases
Exopeptidases
Endopeptidases
Attack peptide bond within protein polymer
Pepsin, trysin, chymotrysin
Exopeptidases
Attack peptide bonds at the ends of protein polymer
Aminopeptidases = N - terminal
Carboxypeptidase = C - terminal
Zyomgen activation
Pepsinogen (zymogen) -> pepsin
HCL = parts of pepsinogen unfolds and activates peptin protease
= hyrolysis of pepsinogen = stably activated pepsin
Sequential hydrolysis of proteases
Peptin (stomach) Trypsin (s.i) Chymotrypsin (s.i) Carboxypeptidase (s.i) Aminopeptidases (s.i)
Bile salt function
Solubilize fats
Forms micelles with TAGs (increase SA)
Bile salt structure
Hydrophoic and hydrophillic -ve surfaces
Bile salt produced and secreted regulation
Produced from cholesterol in liver and stored in gallbladder
Secreted in response to cholecystokinin
Digestion of lipids
Pancreatic lipase/colipase enzyme + lipid/aqueous interface of micelles
= hydrolysis triacylglycerol at 1 & 3 of glycerol backbone
Digestion of lipids products
Smaller micelles (bile salt, free fatty acids, 2-monoacylglycerol)
Fat malabsorption
Excess fat and fat soluble vits in feces
Caused by interference with bile or pancreatic lipase secretion
eg xenical
4 classes of lipoprotein
Chylomicrons
VLDL ( carriers TAGs)
LDL (bad - collects on arteries)
HDL (good - absorbs cholesterol and carries to the liver)
Lipoprotein function
Solublise lipid to transport in blood to tissue
Delivery system in/out cell
Apoprotein
ApoB
ApoE
ApoCII
ApoB
Structural for assembly
ApoE & B
Ligands for cell surface receptors
ApoCII
Enzymes cofactors
Lipid transport pathways
Exogenous chylomicron (dietary fat) Endogenous VLDL/LDL (endogenously synthesised fats)
Chylomicron assembly
TAG & lipids + apoB (in ER) = chylomicrons
Secreted from intestinal epithelial cells to blood via lymphatic system
Milky after fat rich meal
Lipoprotein lipase
Enzyme on endothelial surface
ApoCII actives hydrolyse of TAG in lipoprotein = glycerol and fatty acids
Highest activity in heart & skeletal muscle
Defects in ApoCII or lipoprotein lipase
Increase chylomicrons and plasma triacylglycerol
Familial Hypercholesterolemia
Premature atherosclerosis (fat build up in arteries)]
Defect in LDL receptor gene
LDL x2-3 normal
Familial Hypercholesterolemia treatment
Statins (type of drug)
Decrease LDL and increase HDL
Glucose transporters
SGLT1
GLUT2
Na+/K+ ATPase
SGLT1
Active
Against conc gradient
ATP needed
Glucose - Na+ symport
GLUT2
Facilitative
Down conc gradient
Na+ outside cell
120-140 mmol/L
Na+ inside cell
20-30 mmol/L
Peptide absorption
Di- & tri- con-transported with H+
Membrane transporter PepT1
Further digested into a.a by cytoplasmic peptidase
A.a absorption
From lumen of s.i by transepitelial transport
A.a absorption
Semispecific Na+ - dependent transporter
Lactose intolerence
Lactose enzyme deficiency
Fermentation of lactose by intestinal bacteria
Pancreatitis
Inappropriate activation of zyogens
Self-digestion
Stomach ulcers
Breakdown mucosa
No protection against protease action
Cystic fibrosis
Thick mucous secretions, block pancreatic duct & secretion pancreatic enzymes
Malabsorption
Coeliac disease
S.i
Reacts against gluten protein
Antibodies react with transglutaminase = villi flatten and no absorption
Nucleic acid polymers
Partically hydrolysed by acidic conditions
Exonuclease enzymes release individual nucleotides
Vitamins characteristics
Essential Organic molecules No energy when broken down Low = symptoms of deficiency Small amounts required
Minerals characteristics
Essential
Non - organic elements
Low = symptoms of deficiency may appear
Small amounts
Bioavailability =
Amount absorbed/used
Accessing patients methods
Clinical Examination
Anthropometry
Biochemical tests
Dietary assessment
Dietary assessment
Measure what you eat
Compare with Nutrient Reference Valves
Vitamins co enzymes
Organic carriers
Make catalysis reaction smoother
Vitamins co factors
In catalysis - stablise adn help convert
Metabolism (energy)
Synthesis DNA/RNA
Minerals co factors
Transfer e- in redox
Structural role
Constituent of molecules
Nerve impulse, electrolyte balance
Niacin Deficient Diet
Vit B3
NAD & NADP
To carry redox = synthesis and breakdown carbs, lipids, a.a
Niacin Deficient Diet consequences
Low variety diet
4 D’s
Rough skin, rash on areas exposed to sun
4 D’s
Dermatitis (eczema)
Diarrhea
Dementia
Death
Mg2+ for muscle cramps
No solid evidence
ATP hydrolysis
-30kJ/mol
ATP synthesis
+30kJ/mol
Reaction coupling
G1 + G2 < 0
Energetically favourable
Release of energy
Phosphorylation of ADP -> ATP
Redox reaction
Oxidation
Energy release
Step - wise
Captures energy for ATP production
Without steps = energy released
Reduction
Coenzymes NAD & FAD
H -> H+ + e-
Enzyme > dehydrogenase
NAD
Carries 2e-, 1H+
Glycolysis, fatty acid oxidation, CAC
FAD
Carries 2e-, 2H+
Fatty acid oxidation, CAC
Tightly bound to proteins which they interact with
CoA
Not carrier of e-
RBC glucose
Essential fuel
Lack of mitochondria = no other pathway
Brain glucose
Favoured
Readily cross blood/brain barrier
120g per day
Eye glucose
Blood vessels & mitochondria refract light in optical path
White muscle cells glucose
Sprinting
Anaerobic
Fast twitch
Fatty acid preferred method
More reduced = more energy released
Lower space needed for some amount of energy
TAG ->
Lipase
FFA + glycerol
FFA transport into cell
In blood binds to albumin (albumin-FFA)
Passive into tissue and cell
In cell as FABP-FFA
FABP-FFA
FAtty acid binding protein
Glycerol transport into cell
Passive into liver
Beta-oxidation transportation
Outer
Fatty acyl-CoA carrier
Inner
Fatty acyl-carnitine
Beta-oxidation
Even no of carbons
Saturated
No ATP (energy transferred to NAD & FAD)
Cleavage b/w Calpha and Cbeta
Beta-oxidation products after 1 round
1 NADH
1 FADH
1 acetyl-CoA
eg C16 = 7 round (7 NADH, 7 FADH, 8 acetyl-CoA)
Isomerisation of citrate
Susceptible to decarboxylation
Aconitase catalyse both steps
Synthesis of GTP
Energy eq of ATP
Energy from cleavage
P from soln
Citric Acid Cycle inhibited by
Fluoroacetate
Problem with fluoroacetate
Cannot undergo dehydration reaction
Inhibit pyruvate & build-up acetyl-CoA
= no metabolism
Deamination
Carbon skeleton
Free amino group
Cleavage by enzymes into soln
Carbon skeleton
Catabolic reactions
Energy capture
Free amino group
Exerected
NH4+
Transamination
Aminotransferase enzymes cataylse
Transfer amino group to keto acid <=>
P.P
P.P1
Pyridonal phosphate (without amino) Co - enzyme
P.P2
Pyridoxamine phophate
Glucose - alanine cycle
Remove NH+ from muslce to liver and expelled as urea
Isolate mitochondria step 1
Tissue
Homogenisation in buffered surcose
Centrifuge at 1000xg
Stpe 1 products
Debris & nuclei
Supernatant
Isolate mitochondria step 2
Supernatant
Contrifuge at 7000xg
Spet 2 products
Pellet of mitchondria
Supernatant of membranes, ribosomes
and cytoplasm
Weak detergent on mitochondria
Only outer membrane removed
ETC works
No ATP synthesis
Strong detergent on mitochondria
Solubilises all membranes
ETC doesn’t work
ETC e- movement
Carrier accepts (reduced) or donates (oxidised) To carrier with higher reduction potential
ETC energy usage
More protons across inner membrane
Increase intermembrane space
Decrease matrix
NADH pathway
1 - UQ - 3 - cyt c - 4 - O2
FADH pathway
2 - UQ - 3 - cyct c - 4 - O2
Inhibitors of ETC
Rotenone
Cyanide
Carbon monoxide
Rotenone
Inhibits transfer from 1 to CO-Q
Cyanide
Bind to carrier in 4
Carbon monoxide
Binds where O2 binds
Inhibitor consequences
Stops e- flow
Build-up reduced co-enzymes
No H+ gradient
Reactive oxygen species = damage to cells
UQ/COQ
2e- from 1/2
Moves within inner membrane
2 redox reactions (only accepts/donate 1e- at a time)
Q - cycles
Cytochrome C
Move on outer surface of inner membrane
1e- via reversible Fe2+/Fe3+ redox reaction
Heme containing protein
NADH no of protons
10
FADH no of protons
6
Experiments used to support chemiosmotic theory - ATP synthesis
Artifical liposome
DNP
Artifical liposome
Bacteriorhodopsin - light inducible proton pump
In light = proton gradient
Yes ATP - light on
No ATP - light off
DNP
Uncoupler
Shuffle H+ from intermembrance space to matirx
Dissipate proton gradient
ETC continue, no ATP synthesis
Proton motive force
Chemical gradient/pH gradient due to H+ conc differences Electrical gradient (+ve in intermembrane, -ve in matrix))
F1F0
Rotor subunits - turn
Stator subunits - doesn’t turn
Proton flow drive rotor movement = conformational changes in stator
O =
T =
L =
Open - binding & releasing
Tight - ATP formation
Loose - hold ADP and P for catalysis
ATP from no of proton
4 protons = 1 ATP
Chemiosmotic coupling hypothesis knew
Inner membrane impermeable to protons and contains ETC
Chemiosmotic coupling hypothesis proposed
ETC pumps protons out of matrix
pmf and that it drives ATP synthesis
GABA is a….
γ - aminobutyrate neurotransmitter transmitter
GABAa receptor
Membrane bound ligand - gated chloride channel
Increased NADH/NAD+ and ATP consequences
Slows: CAC ETC Pyravate dehydrogenase Glycolysis Fatty acid oxidation
Fatty acid oxidation consequences
Fatty acid -> TAGs
Fatty liver & hypertriglyceridemia (increase fatty acid in blood)
Increased NADH/NAD+ consequences
Pyruavate -> lactate (drives reaction)
= decrease pH
Inhibits gluconeogenesis (decrease blood glucose)
Alternative wat metabolisming alcohol
As toxin
Microsomes ethanol oxidising system
Microsomes ethanol oxidising system disadvantages
Oxidase = extra e- on O2 = O2-
Super oxidise = damges to tissue
Toxic effects from chronic alcohol consumption
Toxic acetaldehyde and reactive oxygen species Fatty liver inflammation Alcoholic hepatitis Necrosis Cirrhosis (death in liver cells) Coma & death
Need for storing fuels
Body cannot store ATP (made when needed at rate needed by oxidising fuels)
Maintain glucose supply b/w meals
Immediate fuel from increase activity
Long periods without food intake
Fat storage
In adipose tissue
Triacylglycerols (TAGs)
Excess converted to TAGs
Fat synthesis
Fatty acids (from chylomicrons) Glycerol backbone (from glucose) Stimulated by insulin
Fat mobilisation
Hydrolysis of TAG
Catalysed by hormone sensitive lipase
Release of FFA and glycerol
Fat mobilisation hormones involved
Adrenaline and glucagon
Glycogen
Brushed polysaccharides
⍺ 1-4 & ⍺ 1-6 glycosidic bonds
Stored in liver and muscle
Granules in cytoplasm (stored until needed)
Glycogen synthesis
Occurs in liver and muscle after meal
ATP & UTP - energy inputs
Activated high - energy precursor, UDP - glucose
Insulin stimulated
Glycogen mobilisation
Degraded by glycogenolysis
Liver > released as glucose
Muscle > release fuel for glycolysis
Adrenaline binds to β adrenergic receptors on muslce cells
Excess glucose ->
Converted into fatty acid
Exported as TAGs in VLDLto adipose tissue
Fuel for liver, heart
FFA
Fuel for muscle
Resting - FFA
Marathon - FFA and glucose
Starvation survival
Supply brain with glucose (120g)
Supply other tissues with fatty acids
Conserve protein (maintain structure & function)
Hormone - glucagon
Lipolysis
Enough fuel for 40 days
Use TAGs in adipose tissue
Glycerol movement after lipolysis
Into blood to liver
FFA movement after lipolysis
+ albumin in blood
To all aerobic tissue except brain
Glycogenolysis
90 - 120g glycogen -> glucose
Enough for brain for 1 day
Gluconeogenesis
In liver
Energy provided by fatty acid oxidation
Gluconeogenesis synthesis of glucose
Lactate from muscle glycogen
Alanine from muslce protein
Glycerol from adipose tissue
Storage proteins
None
Too much functional protein degraded into a.a = structural and functional damage = severe -ve N+ imbalance = death
Ketogenesis
Synthesised in liver from fatty acids
Can cross blood brain barrier
Reduce proteolysis by 1/2
Limited - make blood acidic so 7mmol = limit
Proteolysis
Breakdon of proteins & prevent -ve N+ imbalance
Ketone bodies levels
0mmol/L at start of fasting
ATP amount for how long
5micromol/g
For 1 second
Phosphocreatine
20micronmol/g in muscle
High-energy phosphate compound
Anaerobic glycoysis
ATP generate by substrate - level - phosphorylation
Rapid, short time only
Lactate = decrease pH in muscle = fatigue
Regulation in exercising muscle
Glycogen mobilisation - Ca2+ and adrenaline
Phosphofructokinase - increase by allosteric regulators
+ AMP & Pi
Use of ADP
ADP + ADP = ATP + AMP
Adenylate kinase
Aerobic generation of ATP
Oxidation of glucose and fatty acids
ETC, CAC, oxidative phosphorylation
Training consquences
Rely less on glycogen “top up”
Muscles different with type of training
Marathon runner muscles
Type 1 fibres => red, slow - twitch
High jumpers muscles
Type 2 fibres => white, fast - twitch
Endurance type 1
Increase:
Capillaries, myoglobin content, no and size of mitochondria, capacity of mitochondria, oxidise lipid and carbohydrate capacity
Anaerobic
High intensity
Rapid generation of force
Short periods
Aerobic
Low intensity
Prolonged, sustained force
% of anaerobic and aerobic depends on
Different durations involving maximal work
Increase aerobic, increase exercise duration
Diabetes clinical symptoms
Fatigue
Increas thirst and urination
Diabetes biochemical symptoms
Hyperglycaemia => constant high glucose
Glyucosuria => Overwhelm kidney’s ability to filter glucose
Ketones
Insulin - dependent
Juvenile - onset Type 1 Auto - immune destruction β cells 0.5% whole pop Genetic and environment factors Treatment - insulin injections
Non - insulin - dependent
Maturity - onset Type 2 Resistance of insulin 2% whole pop Genetic and environment factors Treatment - diet, exercise, drugs
Long - term complication
Retinopathy Neuropathy Nephropathy Cardiovascular disease Peripheral vascular disease
Blood glucose high complications
Target structural proteins
eg crystalline protein of eye, lens = opaque
Blood glucose low complications
<1mmolL-1
Sweating
Heartbeat increases
SNS = vomiting
No glucose for brain = convulsions, coma
Fluctuations glucose tolerence test
Increased plasma glucose vs normal and takes longer to decrease/ return to normal levels for diabetic
Fluctuations injected insulin
Mimic normal rise
Abnormal decrease and takes longer to respond
Type 2 treatment
Hypoglycaemic drugs
Impairs TAG usage - forcing glucose usage
Body Mass Index
= W/h^2
Obese
Overweight
Healthy weight
Underweight
> 30
25 - 30
20 - 25
<20
Energy expenditure =
Basal metabolic rate
Basal metabolic rate depends on
Obligatory energy expenditure
Physical activity
Adaptive thermogenesis
Obligatory energy expenditure
Cellular and organ function
Adaptive thermogenesis
Variable, regulated by brain
Responds to temp and diet
In brown apipocyte mitochondria, skeletal muscle…
Increases risk of obesity =
Culture
Monogenic syndromes
Susceptibility genes
Brown fat
Special thermogenic tissue
Many mitochondria and fat droplets
Contains UCP
Uncoupling protein (UCP)
Inner mitochondria membrane
Regulate proton channels -> “couple” ATP synthesis by dissipating H+ gradient
Releases heat , increase metabolic rate, uses more fuels
White adipose tissue
UCP2, UCP3
Increase metabolic rate and burn off excess energy
Lipin
Coded by obese gene
Hormoe from “fat” fat cells
Signals the brain to decrease food intake, increase energy expenditure
Lipin + ?
Lepun receptor in hypothalamus and other tissues
Strategies for treatment
BAT - oriented
Leptin/leptin - receptor
Anti obesity drugs
BAT - oriented
Stimulate existing BAT
Switch on brown fat differentiation and growth
Transplantation
Leptin
Mutant obese mouse doesn’t produce leptin
Injected leptin = lipostat
Decrease appetite, increase energy use
Leptin - receptor
Obes diabetic mouse and fatty rat
Leptin receptor absent
2 - 6% severe obesity due to defect in MC4R in signalling pathway
Anti obesity drugs food breakdowwn
Xenical
Pancreatic lipase blocked - less fat absorbed
Anti obesity drugs satiety signals
Trials underway
Increase leptin levels
Anti obesity drugs mitochondria and brown fat
Future?
Uncouple oxidative phosphorylation from ETC
Increase functional BAT
White adipose tissue
Numberous hormones secreted for many pathways
Multifunctional
