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Nutrition and Metabolism

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Foundations of Biomedical Science 1

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King's College London

Academic year: 2018/2019

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Nutrition and Metabolism

Lecture 1: Overview of Metabolism –

 Metabolism – seƌies of ƌeaĐtioŶs ǁithiŶ Đells foƌ ĐoŶǀeƌtiŶg ͚fuel ŵoleĐules͛ iŶto useful energy. Enzyme reactions of synthesis/breakdown/interconversion of essential biomolecules  Catabolism – breakdown of complex molecules in living organisms to form simpler ones. Generate ATP and NADH. Usually mitochondrial  Anabolism – synthesis of complex molecules in living organisms from simpler ones. Use ATP, GTP, UTP  usually occur in cytosol

Glycolysis and TCA cycle act together to convert glucose to CO2 (+30ATP, 2GTP produced through mitochondrial respiration)

Catabolism of sugars, fats and AA:

Fatty acids can diffuse through membrane but can use carrier proteins to cross membrane.

ATP:

 ATP is important as it is the energy currency of the cell.  Chemically stable at pH 6- 9  Hydrolysis gives ADP + Pi + H+ + ͚ENE‘GY͛  Hydrolysis is breakage of phosphoanhydride bonds and releases 30-  ATP hydrolysis shifts equilibria of coupled reactions by a factor of 10 8

Functions of ATP: 1. Used directly in cell motility and contraction 2. Used in Na+/K+ pumps, active transport systems 3. Used in metabolic control  phosphorylation of proteins can turn on or turn off a protein 4. Used in metabolism to add Pi to metabolic intermediates

Enzymatic Reactions:  Rate of biochemical reactions is dependent on enzymatic activity  Direction (equilibrium) of reaction is dependent on properties of chemical molecules

Regulation of enzymatic reactions: 1. Altering substrate availability (increasing transport system into cell) 2. Increasing amount of enzyme present in cell  by increasing rate of transcription from gene in DNA into mRNA a. Upregulation = induction & Down regulation = repression 3. Interconversion of active and inactive forms of key enzymes

Allosteric Control Mechanisms:

Metabolic reactions require cofactors  activating ions (Mg2+, Zn2+, Cl-) or prosthetic groups.

ATP acts as high energy cofactor for kinase enzymes

General Role of ATP:  Acts as high energy cofactor in the cell for driving mechanical events such as pumps, transporters, contractile events & movement.

Other high energy nucleotide cofactors:  UTP  synthesis of complex sugars  GTP  synthesis of proteins  CTP  lipid synthesis

Key definitions: 1. Nucleobase – when its just the base 2. Nucleoside – when its base + sugar 3. Nucleotide – when its base + sugar + phosphate group

Lecture 2: Anaerobic Metabolism –

Glycolysis pathway:

 Most important metabolic pathway

 Present in all tissues and all organisms

 Functions: synthesis of ATP, using glucose as fuel

Structure of Glucose:

Sources of Glucose for Glycolysis:  Sugars and starch from diet  Breakdown of stored glycogen from the liver  Recycled glucose (from lactic acid or amino acids or glycerol)

Key Points: Definition Glucose C 6  2 Pyruvate C 3 Location Cytosol (10 soluble enzymes) Tissues ALL tissues Functions ͚EŶeƌgLJ tƌappiŶg͛ ;ATP sLJŶthesisͿ

Glycolysis can be split into 4 stages: 1. Activation (using up ATP) 2. Splitting 6C sugar in half 3. Oxidation (removing 2H atoms) 4. Synthesis of ATP

Yields of ATP from Glycolysis:  Early stages use 2 ATP  Later stages make 4 ATP  Net yield = 2 ATP

Anaerobic Glycolysis:  When oxygen supplies to the tissue are limited, pyruvate is not metabolised to CO 2  Instead pyruvate is converted into lactate in order to convert cofactor NADH back to NAD+

Full Reaction:

Metabolic fates of Pyruvate: Glycolysis: Specialised functions in tissues –

Regulation of Glycolysis:

Allosteric feedback inhibition of phosphofructokinase occurs via ATP and citrate

Lecture 3: Aerobic Metabolism –

TCA Cycle = Krebs cycle, citric acid cycle, tricarboxylic acid cycle

Lactate Dehydrogenase

 Skeletal Muscle: ATP production during intense exercise  RBC: only pathway for ATP production (no mitochondria)  Brain: major source of ATP (cannot use fats as fuels)

Increased rate of Glycolysis –  Intense muscle work and exercise  After high carbs meal (high insulin levels)

Decreased rate of glycolysis –  Fasting state (high levels of circulating glucagon)

Key Points: Definition Oxidation of acetyl CoA to CO2 and H Location Mitochondrial matrix Tissues All tissues with mitochondria (not RBC or white muscle fibres) Functions Energy trapping, biosynthesis of intermediates

Link Reaction:  Conversion of pyruvate to Acetyl CoA

Condensation Reaction: 2. Isomerisation
First loss of CO 2 : 4. Second loss of CO 2 :
1 enzyme reaction produces FADH
1 enzyme reaction produces GTP

Irreversible stages & TCA cycle regulation 1. Citrate synthetase: NADH inhibits & Succinyl CoA inhibits 2. Isocitrate dehydrogenase ADP activates & NADH inhibits 3. Ketoglutarate dehydrogenase NADH inhibits & Succinyl CoA inhibits

Biosynthetic role of TCA cycle:

Lecture 4: Fat as Fuel (B-oxidation pathway) –

Biological Functions of Lipids: 1. Components of cell membranes (phospholipids and cholesterol) 2. Precursors of hormones (cholesterol forms steroid hormones & arachidonic acid forms prostaglandins) 3. Long term fuels (triglycerides)

Triglycerides as Fuel:  Stored as large fat droplets in the fat cells of adipose tissue  A 70kg adult has: 11kg fat (as TG), 150g glycogen & 10g glucose  Efficiency on weight basis: o 1g fat yields 38kJ o 1g protein 21kJ o 1g carbohydrate 17kJ

Structure of triglyceride (triacyl glycerol) fat: glycerol backbone + 3 FA tails

Breakdown of stored triglyceride fat in adipose tissue:  Lipase activated by adrenaline & glucagon  Glycerol diffuses in blood stream to all tissues  Free fatty acids travel in plasma bound to albumin

Metabolism of Glycerol: Glycerol is water soluble and is taken up by all tissues

 In most tissues  enters glycolysis pathway for conversion to pyruvate, then TCA pathway for oxidation to CO 2  In liver/starvation  enters glycolysis pathway + converted to glucose by gluconeogenesis

Fatty Acid Metabolism by B-oxidation Pathway:  All reactions occur in the mitochondrial matrix  Intermediates present as CoA thioesters  Biological energy of fatty acid molecule conserved as transfer of 2H atoms to cofactors NAD+ and FAD to form NADH and FADH 2  Series of 4 enzyme reactions in removal of 2C unit as acetyl CoA

Activation of Long Chain Fatty Acid:  CoA forms thioester bonds with COOH

Transport of FA into Mitochondria:

CoA cleaved off and FA joined with carnitine and transported with CPT through outer mitochondrial membrane
CACT transports acylcarnitine through inner mitochondrial membrane
Re-esterified using CoA Reaction 1: Removal of 2H atoms: Reaction 2: Addition of Water –

Lecture 5: Glycogen Synthesis and Regulation –

Glycogen:  Branched polysaccharide (a1-4 for chain and a1-6 for branches)  400g in tissue stores  Low osmolarity  Medium term fuel store  Branched structure so can easily be hydrolysed

Role of glycogen in liver glucose homeostasis:  Liver is sensitive to blood glucose concentration  Acts to maintain blood glucose under the control of insulin and glucagon

Glycogen in muscle fuel for exercise:  Muscle is sensitive to energy needs of tissue  Sensitive to adrenaline, calcium, AMP, ATP

3 types of phosphate enzymes: 1. Kinase = enzyme that phosphorylates using ATP 2. Phosphorylase = enzyme that hydrolyses using phosphate 3. Phosphatase = enzyme that removes phosphate

First stages of glycogen synthesis from glucose:  Hexokinase has low Km  will metabolise glucose at low concentrations  Glucokinase has high Km  will only metabolise glucose at high concentrations  Liver has low affinity glucose transporter GLUT2 so will only let glucose into liver at high BGC (so as to not compete with brain and RBC when BGC is low)

Formation of UDP Glucose: 1. Glucose-1-phosphate + UTP  UDP Glucose + PPi

Addition of glucose unit to protein primer (glycogenin):  Enzyme glycogen synthase used (GDP lost)  Glucose added to glycogenin  This continues in a straight chain  Branch points introduced into structure of glycogen (branch of straight chain broken off and put into chain)

Glycogen synthase (adds straight chain) and branching enzyme work together to produce branched structure of glycogen

Glycogen synthase is regulated by phosphorylation:  It is active when it is NOT phosphorylated

Glycogen breakdown:  Glycogen phosphorylase used with addition of inorganic phosphate  Breaks off one piece of glucose at a time  Forms glucose-1-phoshphate  This can work up to a stump on the branches  then you need debranching enzyme to destroy 1-6 glycosidic link  Straight chain 1-4 then degraded further by glycogen phosphorylase

Release of glucose:

Coordinated regulation of glycogen synthesis/breakdown:

Summary of degradation 

Liver control:  Responds to insulin/ glucagon  When glucose is high  binds to glycogen phosphorylase and inactivates it. Muscle:

 During contraction, Ca ions released into sarcoplasmic reticulum  Calcium binds calmodulin domain of glycogen phosphorylase kinase and activates it  This activates phosphorylase and glycogen is degraded providing energy for contracting muscle.

o growth of children o Recovering after serious illness o After immobilisation after accident o In pregnancy

Negative Nitrogen Balance: Nintake < Nexcretion  In starvation  During serious illness/ injury/ trauma  In late stages of some cancers  If not corrected & becomes prolonged  irreversible loss of body tissue  Ultimately lead to death

Pathways of Protein Degradation: 1. Most cellular proteins a. Recognised as old or damaged b. Removed through ubiquitin breakdown system c. Give a mixture of 20 AA 2. FoƌeigŶ ͚edžogeŶous͛ pƌoteiŶs a. Old or damaged subcellular organelles taken into vesicles via endocytosis or auto phagocytosis b. Vesicle fuses w/ lysosome & enzymes degrade proteins into AA c. Starvation and hormones e. cortisol increase rates of protein breakdown in muscle

Transamination & Deamination (both require VitB6): 1. Oxidative Deamination (remove hydrogen + amino group): a. Glutamate is only AA that can be deaminated directly

Transamination: a. Take NH2 group from amino acid and transfer to keto acid:

Metabolism of AA:  Use transamination to transfer amino group to 2- oxoglutarate  This becomes glutamate  This can now undergo oxidative deamination

Release of NH 2 group from glutamate using glutamate dehydrogenase turns it into 2-oxoglutarate and NH 4 + (toxic)

Fate of oxo-acids: 1. After losing amino groups, most of 20 AA become keto acids 2. These can enter TCA cycle to CO2 and H2O and provide source of ATP 3. During starvation, 13 of the AA can be converted back to glucose by liver  glucogenic AA

Ketogenic AA:  Leucine and lysine can only be degraded to acetyl CoA  ketogenic AA

Summary of AA metabolism:

Role of Liver in N metabolism: 1. Removal of AA, glucose + fats from portal blood supply 2. Absorbed AA used for protein synthesis 3. Synthesis of plasma proteins (albumin, clotting factors, lipid transport proteins) 4. Degradation of excess AA by transdeamination 5. Conversion of NH 3 to urea for excretion (urea/ ornithine cycle)

Transport of Amino Groups and Ammonia to liver:  Skeletal muscle continuously degrades proteins to AA  Liver is only organ that can convert amino groups of these AA to urea for excretion  Amino groups transported as glutamine in blood stream

Importance of Glutamine:  Safe carrier of ammonia in blood (ammonia is toxic to brain)  Can carry 2 ammonia equivalents to liver for urea formation  Can deliver ammonium ions to kidney for pH regulation (buffering pH)

Urea Cycle:  Stars are where the 2 NH 2 groups come from

End products of nitrogen metabolism:

Urea – from protein breakdown
Creatinine – creatinine phosphate breakdown
Uric acid – from DNA/RNA breakdown
NH 4 + - from control of body pH

Roles of Glucose in the Liver: Main Pathway Function Glycolysis/TCA Acetyl CoA production Pentose Phosphate NADPH, pentoses production Glycogen synthesis/ glycogenolysis Glucose storage for other tissues Gluconeogenesis Glucose for other tissues

Glucose, Insulin and Glucagon over 24 hours:

Sources of Blood Glucose – 1. diet, 2. liver glycogen 3. liver gluconeogenesis

Gluconeogenesis:  When carbs deprived, glucose is synthesised from non-carbohydrate sources in the liver o Lactate o Glycerol o Glucogenic AA (ALL except Leu, Lys) o NOT FATTY ACIDS

Gluconeogenesis is not reversal of glycolysis  3 irreversible reactions in glycolysis: o Glucose  Glucose-6-phosphate (hexokinase/glucokinase) o Fructose-6-phosphate  Fructose-1,6-bisphosphate (Phosphofructokinase) o Phosphoenolpyruvate  Pyruvate (Pyruvate kinase)  ^^ all in cytosol

How to overcome irreversible reactions: 1. Go in a 2 step backward reaction to phosphoenolpyruvate 2. Use fructose-1,6-bisphosphatase to convert fructose-1,6-bisphosphate back into fructose-6-phospahte

Use glucose-6-phosphatase to convert glucose-6-phosphate back into glucose

Regulation of Gluconeogenesis:  Mobilisation of substrate: o Glycerol from fat breakdown o AA from muscle protein breakdown  Activation of enzymes: o Glucose-6-phosphatase, Fructose-1,6-bisphosphatase, PEP carboxykinase o Activation of pyruvate carboxylase by acetyl CoA

Blood Glucose Maintenance:  Insulin, glucagon & adrenaline co-ordinate activities of liver, adipose + muscle tissue  Maintain physiological bgc needed to preserve brain function

Islets of Langerhans (in exocrine pancreas): 1. Beta cells secrete insulin 2. Alpha cells secrete glucagon

Insulin & Glucagon:  In sulin is an anabolic hormone (promotes synthesis and storage)  Glucagon is a catabolic hormone (promotes degradation of stored fuel)

Sites of Insulin action on metabolism: Metabolic effects of insulin – Liver: 1. Inhibition of gluconeogenesis 2. Activation of glycogen synthesis (activation of glycogen synthase) 3. Increased fatty acid synthesis and lipid assembly 4. Increased AA uptake and protein synthesis

In the fed state, glucose will form glycogen + fat from pyruvate.

Dietary Reference Values (DRVs):  Estimated Average Requirements (EAR): notional mean requirement of nutrient (for a group of healthy individuals of population)  Reference Nutrient Intake (RNI): 2 S above EAR – sufficient of a nutrient to meet needs of majority of population  Lower Reference Nutrient Intake (LRNI): 2 S below EAR – intakes of nutrient below this level are almost certainly inadequate for most

E. Vitamin C (Ascorbic Acid):  EAR = 25mg (sufficient for 50% population)  RNI = 40mg (sufficient for 95%)  LRNI = 10mg (only sufficient for 5% population)

For energy requirements we do not use this method  instead use food tables:  Many samples of a particular food are analysed so mean content of energy, water, protein, fat etc. can be calculated  Data obtained may not be the most accurate but can still be used

Undernutrition:  Major problem in many developing countries e. south Asia, sub Saharan Africa#  In developed countries it is usually specific deficiencies i. proteins, vitamins + minerals o EldeƌlLJ at hoŵe oƌ iŶ old people͛s hoŵes o Young people on junk food o Cancer & AIDS patients o UP TO 40% of hospitalised patients

Overnutrition:  Main nutritional problem in developed world (and increasing in developing) o Too much fat, sugar, salt + generally food

BMI (body mass index): weight (in kg) / height (in m) 2

Consequences of high BMI:  Cardiovascular disease  Stroke  Some cancers  Others such as hypertension, type 2 diabetes, gallstones etc.

Obesity in UK:  2/3 adults overweight or obese  22% men & 23% women obese  Obesity has tripled in past 20 years  Globally, percentage of obese/overweight grew from 23% to 34%  Obesity in 6 year olds doubled to 9%  Trebled in 15 year olds to 15%

Risks for Cardiovascular Disease: 1. High blood cholesterol 2. Hypertension 3. Smoking 4. Inactivity 5. Obesity

 High bp often related to high salt intake (9g) when max recommended is 6g actually need 1g  British of South Asian origin have higher incidence of strokes (and diabetes & hypertension)

Recommendations of Department of Health: to change percentage contribution towards total energy to: Total fat - Saturated

30 -33%

10%

Protein 10 -15% Sucrose No more than 10% Alcohol No more than 5%

Solutions: 1. Education 2. Clear labelling of food products 3. Support and provision of facilities for deprived groups of population 4. Control of advertising 5. Pressure on food industry

Lecture 9: Energy Balance and Control of Body Weight –

How body composition is measured:  Body density  Body water  Total body potassium (found in non fat)  lean body mass  Methyl histidine or creatinine excretion (total creatinine excretion is proportional to lean body mass)  Skinfold measurements: o Biceps, triceps, supra iliac, sub scapular  Mid-arm circumference

Bioelectrical Impedance: electrical signal sent through body  travels quickly through lean tissue (high water % so good conductor) but more slowly through fat – calculates body fat percentage

Energy Derived from Food: Energy from Food: Total – ǁhat LJou͛d get if LJou Đoŵďusted it Digestible – ǁhat͛s aďsoƌďed Metabolizable – digestible minus that lost in urine & sweat  50% lost as heat, less than 50% used for work

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Nutrition and Metabolism

Module: Foundations of Biomedical Science 1

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University: King's College London

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P a g e | 1

Nutrition and Metabolism

Lecture 1: Overview of Metabolism –

 Metabolism – series of reactions within cells for converting ‘fuel molecules’ into useful

energy. Enzyme reactions of synthesis/breakdown/interconversion of essential

biomolecules

 Catabolism – breakdown of complex molecules in living organisms to form simpler ones.

Generate ATP and NADH. Usually mitochondrial

 Anabolism – synthesis of complex molecules in living organisms from simpler ones. Use ATP,

GTP, UTP  usually occur in cytosol

Glycolysis and TCA cycle act together to convert glucose to CO2 (+30ATP, 2GTP produced through

mitochondrial respiration)

Catabolism of sugars, fats and AA:

Fatty acids can diffuse through

membrane but can use carrier proteins to

cross membrane.

ATP:

 ATP is important as it is the energy currency of the cell.

 Chemically stable at pH 6-9

 Hydrolysis gives ADP + Pi + H+ + ‘ENERGY’

 Hydrolysis is breakage of phosphoanhydride bonds and releases 30.5kJmol-1

 ATP hydrolysis shifts equilibria of coupled reactions by a factor of 108

Functions of ATP:

1. Used directly in cell motility and contraction

2. Used in Na+/K+ pumps, active transport systems

3. Used in metabolic control  phosphorylation of proteins can turn on or turn off a protein

4. Used in metabolism to add Pi to metabolic intermediates

Enzymatic Reactions:

 Rate of biochemical reactions is dependent on enzymatic activity

 Direction (equilibrium) of reaction is dependent on properties of chemical molecules

Regulation of enzymatic reactions:

1. Altering substrate availability (increasing transport system into cell)

2. Increasing amount of enzyme present in cell  by increasing rate of transcription from gene

in DNA into mRNA

a. Upregulation = induction & Down regulation = repression

3. Interconversion of active and inactive forms of key enzymes