MPharm PHA115 Essential Biochemistry: Cellular Respiration W10 PDF

WEEK 11 MPharm PHA115 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Essential Biochemistry:...

WEEK 11 MPharm PHA115 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Essential Biochemistry: Cellular Respiration Dr Steve Darby PHARMA Forensic scientist [email protected] Dale 117 WEEK 11 Respiration Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology By the end of the lecture you should be able to: 1. Describe the process of respiration 2. Understand and explain the process and function of glycolysis and Krebs cycle 3. Understand the difference between aerobic and anaerobic respiration WEEK 11 Why Is Metabolism Clinically Important? Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Understanding Metabolism Allows Us To Study Fundamental biochemistry of humans Hormone imbalance – impact cellular diabetes etc metabolism S , MANY Diseases’ impact on metabolism Diabetes – abnormal glucose levels Malnutrition – impacts metabolism Many Therapeutic targets Age – impact on metabolism of cells Musculo-skeletal disorders – metabolism related Faults in enzymes – over or underactive Production of unwanted by-products Inherited diseases – altered from birth Can Impact blood pH Metabolic diseases – glycogen Abnormal Lactate generation – critical disorders clinically Cancer – impact on metabolism of cells WEEK 11 We Obtain “Nutrition” From Our Diet Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Gastrointestinal system will be covered in detail in stage 2 Food is digested into basic components Fats / lipids Carbohydrates Amino acids Vitamins and Minerals Basic components can then be converted into required biomolecules Proteins, lipids/fats, complex sugars, DNA Biomolecules can also undergo Metabolism Metabolism - chemical processes that occur to maintain living systems Digestive enzymes WEEK 11 Glucose is a MAJOR Fuel Source Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology In our diets, we consume a generous amount of starch and a smaller amount of glycogen. These complex carbohydrates are converted into simpler carbohydrates for absorption by the intestine and transport in the blood Glucose is the only fuel that the brain red blood cells use C6H12O6 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology WEEK 11 WEEK 11 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Glucose: The Provider Of Cellular Energy Glucose is the “sugar of life”-multiple purposes Storage: Glycogen and starch Structural: Cellulose in plants Glycogen Cellulose Starch Energy: Principle provider of cellular energy Catabolism of glucose to produce ATP Structural Storage Catabolism: Breakdown of compounds into simpler molecules to: (i) release energy Glucose (ii) provide smaller building blocks Energy Anabolism: Building a more complicated molecule from smaller units (eg, amino acid proteins) ATP (i) requires energy  Cellular Respiration: Oxidation Of Glucose WEEK 11 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Cellular Respiration: the breakdown of glucose in many small steps to make ATP - Breakdown a “large sugar” molecules into smaller ones - breaking bonds and moving electrons from one molecule to another - electrons “carry energy” - energy is used to make ATP – ATP = Adenosine Tri-Phosphate CoH1206 6OL GCOr to ATP Glucose + Oxygen Carbon + Water + Energy dioxide C6H1206 + 6O2 6CO2 + H2O + ATP Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology WEEK 11 Oxidation and Reduction Key processes in cellular respiration Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology WEEK 11 Redox Reaction Glucose is oxidised and oxygen is reduced Redox reaction WEEK 11 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Movement Of Electrons In Biology Electrons cannot move alone in the cells Electrons can move as part of a hydrogen atom Move hydrogen atom = move electron Consider: H H+ + e- Hydrogen Hydride 1H One proton One proton. One electron Two electron H H: or H:- WEEK 11 We Need Electron carriers Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology High energy electrons produced during the breakdown of glucose Certain molecules are particularly effective in accepting or donating these electrons, these are therefore called electron carriers ↳ facilitators NAD – Nicotinamide Adenine Dinucleotide FAD – Flavin Adenine Dinucleotide NAD+ coenzyme and FAD cofactor are very good at carrying electrons and donating them to target molecules Once the energy is harvested from electrons….. oxygen is very good at accepting electrons to forms water as end product of respiration O2 + 4H+ +4e- 2H2O WEEK 11 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Electron Carriers: NAD+ NAD+ is a coenzyme which regulates the activity of the enzyme it is bound to Co-enzymes can move around the body Derived from the vitamin nicotinic acid/niacin NAD+ is the oxidised form NAD+ can accept two electrons from two hydrogen atoms to be reduced to NADH NAD+ + 2H+ +2e- NADH + H+ One hydrogen is transferred as a hydride ion: H- and the second liberated in solution Ribose phosphate Ribose Nicotinamide Adenine dinucleotide (NAD+) WEEK 11 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Example of NADH Production Formation of oxaloacetate from malate in Krebs cycle ~ I 4 going around the cells electron - fueling movements Released as H+ NADH contains high energy electrons Added as H- Used to make ATP in the electron transport chain (ETC) WEEK 11 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Electron Carriers: FAD FAD is a cofactor which binds strongly to an enzyme FAD is synthesised from vitamin B2 or riboflavin FAD is the oxidised form FAD can accept two hydrogens and two electrons to be reduced to FADH2 FAD + 2H+ +2e- FADH2 Flavin Adenine dinucleotide (FAD) WEEK 11 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Example of FADH2 production Formation of fumarate from succinate in Krebs cycle I s NADH contains high energy electrons ↓ We will use this to make ATP in the electron transport chain (ETC) WEEK 11 ATP Is the Universal Currency of Free Energy in Biological Systems Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Energy required for muscle contraction, generating nerve impulses MANY MANY cells processes require energy – obtain this from ATP Hydrolysis of ATP provides energy h ATP WEEK 11 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Hydrolysis of ATP ATP is structurally unstable due to the repulsion between ionised oxygen atoms which are all in close proximity Hydrolysis of terminal phosphate group stabilises ATP and the process “releases energy” V Go is negative: (i) Reactant has more energy than the product (ii) Free energy is released (iii) Product is more stable (iv) Favourable reaction H2O ATP ADP + Pi Go = -30.5kJ mol-1 ATPase Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology WEEK 11 - - ATP ADP AMP - > Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology WEEK 11 WEEK 11 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Overview Of Respiration The complete oxidation of glucose proceeds in four key stages: 1. Glycolysis 2. Pyruvate processing (connects glycolysis to next stage) = oxidation 3. Citric Acid Cycle (aka Krebs Cycle, aka TCA cycle) 4. Electron transport chain => TO PRODUCE ATP ! Cytoplasm Mitochondria ↳ outside of the nucleus/ inside the cell  Glycolysis Is The First Stage Of Energy WEEK 11 Production Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology 26H1206 Glycolysis uses GLUCOSE from our diet as a starting material Glucose is converted to a chemical called PYRUVATE This has 10 chemical reactions all controlled by enzymes ran oxygen out of in cellular level The final product is then passed on to the next ↓ minimalise stage of respiration * lactic acidation - ? WEEK 11 Glycolysis Overview Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology 2 Major Stages: Stage 1 – Preparation stage, this stage needs energy to proceed and requires ATP Stage 2 – Cyclic rings are converted to smaller 3 carbon products – Providing products for the next step of metabolism - Pyruvate – ATP is harvested back during this stage WEEK 11 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Stage 1 of Glycolysis Preparatory/investment phase: uses ATP Breakwn ↓ Isomers WEEK 11 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Second Phase Of Glycolysis DHAP converted to G3P hence 2xG3P Payoff phase: ent to make ATP get rid of H and NADH Substrate level phosphorylation: Make ATP by transferring phosphate from a substrate WEEK 11 ATP Generation from Stage 2 of Glycolysis Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology * PEP converted to pyruvate Phosphate group returned back to ADP ATP WEEK 11 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Glycolysis Summary Glycolysis converts glucose to pyruvate 1. 10 step biochemical pathway 2. 2 NADH are produced by reduction of NAD+ 3. NET production of 2 ATP molecules by substrate level phosphorylation 4. 2 molecules of pyruvate are produced 1 2 3 5. Occurs in the cytoplasm 3 4 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology WEEK 11 Glycogen Starch Sugars Can Be Bound Together WEEK 11 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Feeder Pathway For Glycolysis Entry of glycogen, starch, disaccharide's into the preparatory stage of glycolysis You can now see how they all feed into ATP generation STAGE 2 – ATP producing WEEK 11 Metabolism and Lactose Intolerance Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Lactose is found in milk and can be converted to galactose and glucose If a person lacks or has a lower level of the enzyme “lactase” then this conversion does not occur and lactose remain undigested lactose m - intolerant ↓ So what happens next? BACTERIA in the gut ferment the undigested lactose – Gas – Bloating / pain – Diarrhoea WEEK 11 NAD+ Regeneration Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology For glycolysis to continue NADH must be recycled back to NAD+ Aerobic respiration - Occurs when oxygen is available as the final electron acceptor Anaerobic respiration (or fermentation) occurs when oxygen is not available; an organic molecule is the final electron acceptor Fermentation Aerobic Respiration ↳ yeast , bacteria Anaerobic Respiration Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology WEEK 11 Increase Glycolysis Rate Exercise and Physical Demand Can WEEK 11 In The Absence Of Oxygen - Anaerobic Respiration Occurs Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology lactate In absence of O2 Pyruvate is reduced to form Lactic acid / Lactate BUT the transferred electrons oxidise NADH back to NAD+ This reaction is catalysed by the enzyme Lactate dehydrogenase (LDH) Lactic acid is converted back into glucose in the liver via the cori cycle HUGE implications - High lactate levels cause muscle cramps and pain VERY high lactate can be life threatening – many diseases implicated of cancer cells forms & lactic acidosis lactic acids !1 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology WEEK 11 > then close. phosphorylation open this channel , WEEK 11 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Cori Cycle (aka Lactic Acid Cycle) Lactate produced during ATP anaerobic glycolysis is transported to the liver and converted to glucose This process requires ATP The glucose is then supplied back to the muscle brown If glucose is not required store as glycogen  When The Body Lacks Fuel It Can Make Its WEEK 11 Own Glucose Supply Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology The Heart and Brain cannot be starved of fuel formation Pyruvate can be converted back This is a process called Gluconeogenesis (glucose-new-formation) Occurs in the liver To be discussed more in diabetes lectures Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology WEEK 11 one h active metabolically organs ! of the most WEEK 11 I Glycolysis Recap Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology 2 Major Stages: useI Stage 1 – Preparation stage, this stage needs energy to proceed and requires ATP Stage 2 – Cyclic rings are converted to smaller 3 carbon products – Providing products for the next step of metabolism - Pyruvate generates ATP – ATP is harvested back during this stage => end product WEEK 11 WHAT NEXT? Oxidation of Pyruvate Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology In the presence of oxygen, pyruvate is oxidised to acetyl CoA in the mitochondria Pyruvate moves easily through the porous outer mitochondrion membrane where it encounters the enzyme Pyruvate Dehydrogenase (PDH) (PDH) v Glycolysis - · xidation is done ! Starts ! Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology WEEK 11 From Pyruvate Now The Molecules Start to Get Larger WEEK 11 Acetyl CoA Then Enters - The Citric Acid Cycle Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Glycolysis produces Pyruvate Pyruvate is converted to Acetyl CoA Acetyl CoA now progresses to the next part mitochondrial of metabolism intermembrane space & The CITRIC ACID CYCLE – Also known as Tricarboxylic acid (TCA) cycle – Krebs Cycle Glucose will continuously be converted to pyruvate via glycolysis to feed this stage WEEK 11 The Citric Acid Cycle Harvests High-energy Electrons NADH and FADH2 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology From Pyruvate name Citric Acid Cycle O WEEK 11 Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology disorder/ lung cardiovascular diseases ↓ rid of CO2 can't get ↓ BodyP O2 ↓ life-threatening 3 C Citric Acid Cycle How to get rid of it ? - breath out Look at all the CO2 WEEK 11 Breakdown Of One Glucose: So Far.. Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Reaction Location Net yield of key molecules Glycolysis Cytoplasm 2 ATP 2 NADH Pyruvate Mitochondrial 2 NADH oxidation intermembrane space 2 ATP Krebs cycle Mitochondrial matrix 2 FADH2 6 NADH Only 4 ATP’s produced so far…. Where is the rest? All remaining ATPs are produced via the electron transport chain WEEK 11 So WHY Have We Been Collecting All This NADH And FADH2?? Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology The Electron Transfer Chain (ETC) utilises these “high energy electrons” There are FOUR major “proton pumps” that pump H+ out - Complex I, II, III, IV pump out WEEK The Enzyme ‘ATP Synthase’ Uses These Electrons 11 To Make LOTS More ATP Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology using high - energy + WEEK 11 Metabolism of Glucose Glycolysis Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Citric Acid Cycle Electron Transfer ALL work together to provide ATP (currency of energy) How Much ATP From 1 Molecule Of Glucose? Glycolysis = 2 Citric acid = 2 Electron Transfer = 26 Total = 30 ATP… Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology WEEK 11 WEEK 11 Metabolism is a VERY complex area Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology of biochemistry We will introduce more in later stages of the programme WEEK 11 Need Help or Want More Information? Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology Berg/Stryer – THE biochemistry textbook Brown – Much more basic textbook Fundamental Principles Of Anatomy, Physiology, Pharmacology And Microbiology WEEK 11 ANY Questions ?