Cellular Respiration PDF

Cellular respiration Learning outcomes: 1- Understand the concept of cellular respiration 2- Determine the difference between aerobic and anaerobic glycolysis 3- Identify the source of ATP in the body Case study A fire exploded in a house, where there was a young woman, approximately age 35 years....

Cellular respiration Learning outcomes: 1- Understand the concept of cellular respiration 2- Determine the difference between aerobic and anaerobic glycolysis 3- Identify the source of ATP in the body Case study A fire exploded in a house, where there was a young woman, approximately age 35 years. The firefighters found her unconscious near the doorway; the entire house was smoke- filled. She was unconscious, flaccid and unresponsive to painful stimuli. Her vital signs included BP 70/50 mm Hg, pulse 120/min, respiration rate 30/min. She was being administered 100% oxygen via face mask. The woman is improved but is lethargic and disoriented.  Photosynthesis: Energy from sunlight is used to drive the synthesis of glucose from CO2 and H2O and oxygen is released. Respiration & cellular respiration ▪ is the 1ry fuel for cellular respiration ▪ If glucose breakdown occurs all at once…… energy is wasted as heat ▪ If glucose breakdown occurs in successive steps….. Energy is produced Cellular respiration: Definition: it is a metabolic pathway that breaks down glucose and produces ATP. Stages: 1- Glycolysis (Glucose is broken down to 2 pyruvate) 2- Oxidative decarboxylation (intermediate stage) 3- Krebs cycle 4- Oxidative phosphorylation (ETC) Aerobic glycolysis ▪ Definition: it is oxidation of glucose in presence of oxygen to release of energy. ▪ Cells transfer energy in organic compounds to ATP ▪ Carbon dioxide and water are released as byproducts (waste products of respiration). Water Glucose Aerobic glycolysis ATP CO2  Glucose is broken down to pyruvate (Glycolysis) ▪ It occurs in ▪ Breakdown of six carbon glucose molecule to 2 three-carbon pyruvate ▪ Energy released is stored in ATP (2 molecules) ▪ The compound nicotinamide adenine dinucleotide (NAD+) is converted to NADH during this step (2 molecules)  Oxidative decarboxylation 2 Pyruvate molecules produced from glycolysis then enter the mitochondria, where they are converted into 2 acetyl COA and 2 NADH are generated. Krebs cycle ▪ It is a series of chemical reactions to release stored energy through the oxidation of acetyl COA derived from CHO, lipids, proteins ▪ The acetyl group of acetyl-CoA is oxidized to form CO2 and energy is produced. ▪ Most of the energy obtained from the Krebs cycle is captured by the compounds 3 NAD+ and 1 FAD + and 1 ATP molecule for each 1 pyruvate. Reduced to 3NADH molecules Reduced to 1FADH2 molecule. Pyruvate  Oxidative phosphorylation (ETC): ▪ ▪ It is a group of that function in ▪ It is found in the ▪ They shuttle electrons from NADH and FADH2 made during krebs cycle to molecular oxygen→ which turn back into their 1- Transferring electrons via the ETC regenerates empty to be used again. 2- The transfer of protons across the membrane also establishes the proton gradients which provide energy for oxidative phosphorylation that synthesizes. At the end of the electron transport chain, oxygen accepts electrons and (Oxygen is the final acceptor of electrons at the end of the electron transport system) Total ATP production in aerobic glycolysis O2 Presence O2 Absence  Total ATP production in complete aerobic NADH= 3 ATP oxidation of one molecule of glucose FADH2= 2 ATP Anaerobic glycolysis Glucose oxidation in absence of oxygen. Source of energy for RBCs - Source of energy for contracting muscles In presence of oxygen In absence of oxygen (as in muscular exercise) Releases 38 ATP molecules Releases only 2 ATP molecules More efficient Less efficient  Glucose Pyruvate Aerobic Anerobic glycolysis glycolysis CO2, H2O, Lactate, 38 ATP 2 ATP Inhibition of cellular respiration 2- Inhibition of 1- Inhibition of oxidative glycolysis phosphorylation 1- Inhibition of glycolysis Pyruvate kinase deficiency: ▪ Autosomal recessive disease ▪ Inherited deficiency of pyruvate kinase enzyme (a key regulatory enzyme in glycolysis) ▪ It leads to hemolytic anemia because RBCs are dependent on glycolysis for ATP production ▪ Clinical findings: Anemia and jaundice  2- Inhibition of Oxidative Phosphorylation Oxidation: electron flow in ETC with production of energy Phosphorylation: energy released from ETC used in phosphorylation of ADP to ATP 1-Inhibitors of 2-Inhibitors of oxidation via ETC phosphorylation 3- Uncouplers 1-Inhibitors of oxidation Rotenone: inhibit Complex I Antimycin A: inhibit Complex III Cyanide (CN): inhibits Complex IV (cytochrome oxidase) Carbon monoxide (CO) 2-Inhibitors of phosphorylation Oligomycin antibiotic → inhibit ATP synthase (complex V) Uncouplers 3- Uncouplers: ▪ Ca injection ▪ High dose aspirin ▪ High level of thyroid hormones ▪ Progesterone  Case study ▪ A fire exploded in a house, where there was a young woman, approximately age 35 years. The firefighters found her unconscious near the doorway; the entire house was smoke- filled. She was unconscious, flaccid and unresponsive to painful stimuli. Her vital signs included BP 70/50 mm Hg, pulse 120/min, respiration rate 30/min. She was being administered 100% oxygen via face mask. The woman is improved but is lethargic and disoriented.  New Mansoura University MBBCh program Respiratory Module BMS 204 pH and Acid Base Balance By the end of this lecture, the students should be able to: 1. Differentiate between acids and bases 2. Define pH and its scale 3. List the sources of acids production in the body 4. Summarize the body defenses against blood pH changes 5. Describe buffer mechanism of action 6. List the important biological buffers 7. Outline acid base balance disturbances ✓Acids and bases ✓PH & its scale ✓What disturb the blood pH ✓Body regulation of blood pH a. Buffer system Buffers composition Important biological buffers b. Respiratory system c. Renal system ✓ Acid base disturbances  What are acids? ✓Definition: Acids is a substance that donate protons (H+ ions) ✓Example : HCl HCl contains 1 H atom and 1 Cl atom In solution, HCl splits into 2 ions - ( H+ & Cl ) (charged particles) HCl is a strong acid, and almost all dissociates into H+ and Cl-  What are bases? ✓Definition of Bases can accept protons (H+ ions) ✓Example : NaOH NaOH splits in solution to form Na+ and OH- (charged particles) NaOH → Na+ + OH- OH- ions can accept protons (H+) to form water. (OH- + H+ → H2O)  Strong Vs weak acids and bases ✓Strength of acids and bases depends on degree of dissociation (ionization) Acids Bases Strong HCL NaOH completely dissociate completely dissociate Weak CH3COOH NH4OH partially dissociates partially dissociates  Acids, Bases, or Neutral? OH- OH- H+ H+ OH- H+ H+ OH- H+ H+ H+ H+ OH- H+ OH- H+ OH- OH- OH- H+ OH- H+ OH- H+ OH- H+ H+ OH- OH- 1 2 3 In human ✓ The most acidic fluid: Gastric juice (pH 1-2) ✓ The most alkaline fluid: Pancreatic juice (pH: 7.5-8) ✓ Blood pH kept constant at narrow range (pH :7.35 - 7.45) pH: Potential Hydrogen ✓Definition Definition : pH is the negative logarithm of Hydrogen ion concentration (As it measures H+ conc, so it is a measurement of acidity) Remember: every 1unit pH change = 10-folds [H+] change (why) pH scale: ✓pH scale: 0-14 PH=0 in 1M HCl (the most acidic) pH values < 7:Acidic pH values > 7: Alkaline pH= 7: Neutral  Normally blood pH has a very narrow range: 7.35 - 7.45 Blood pH range compatibles with life (survival range) is : 6.8 - 8.0 Why is it important to maintain the body pH? Severe Changes Affects Changes in the shape proteins the pH of proteins functions  What disturbs the body’s pH? ✓ Continuous addition of acids disturb the body pH. ✓ Addition of acids is due to : Cellular respiration (oxidation of glucose) → CO2 (volatile acid) Metabolism (Metabolic acids): lactic acids, sulfuric acids, phosphoric acids etc. (fixed or nonvolatile acid)  How the body Regulate the blood PH ? Buffer system 1st line Chemical buffers → guard against sudden changes defence in acidity and alkalinity. Respiratory system 2nd line Breathing out CO2→↓ acid in the body defence Renal system 3rd line Release of acid in urine→↓acids in the body defence  1. Buffer systems (1st line of defense) ✓ It is the immediate (1st) line of defense against pH change in the body. ✓ Definition of buffer: These are solutions that resist any change in their pH when a reasonable amount of an acid or alkali is added. ✓ Buffer is composed of 2 parts, called buffer pair; includes a taker and a giver. If H+ concentration increases in blood, the taker part removes H+ from the blood. If H+ concentration decreases in blood, the giver donates a H+ to the blood. ✓The buffer pair maintains normal blood pH. (It buffers [H+], but doesn’t remove it) ✓ Important Buffer Systems in the Body They Keep blood PH fixed ( 7.35-7.45) 1) Physiological buffers a. Bicarbonate b.Phosphate c. Protein systems. 2) Red blood cells buffers: a. hemoglobin buffer b. oxy-hemoglobin buffer ✓Composition of buffers: buffer is a mixture of Weak acid and its salts with a strong base: eg. Acetic acid (CH3COOH) & sodium acetate (CH3COO.Na) OR Weak base and its salts with strong acid : eg. Ammonium hydroxide (NH4.OH) & ammonium chloride (NH4.Cl) ❖Bicarbonate buffer system is the most important buffer 2.The respiratory system (2nd line of defense) ✓It is “fast” line of defense ,its action is maximum within hours. ✓ It regulates the removal of CO2 by the lungs. ▪ if pH is decreasing→ ↑↑ Hyperventilation (rapid respiration) → remove CO2→ ↓ acids → ↑ pH ▪ if pH is increasing→ ↑↑ Hypoventilation (slow respiration)→ keep CO2→ ↑ acids → ↓ pH 3. The kidneys (final line of defense) ✓ It is the final line of defense. ✓ It is the “slow” line of defense, taking hours to begin working. ✓ Helps to regulate pH by reabsorption or excretion of hydrogen as needed ✓ The kidneys also help regulate reabsorption or excretion of bicarbonate (a major buffer) in urine , when it is needed. Reference Range of Arterial Blood Gases (ABG)  Acid Base Imbalance ✓ When the body is unable to regulate pH, acid-base imbalances result ✓ The imbalance in the blood is called acidosis or alkalosis ✓ The imbalance can be life-threatening ✓ Types of Acid-base imbalance include: I. Acidosis Respiratory acidosis Metabolic acidosis II. Alkalosis Respiratory alkalosis Metabolic alkalosis  Disturbance of blood acid base balance ✓ Acidosis The blood pH tends to decrease < 7.35 Due to increased formation of excessive acids OR decreased the capacity of the body to neutralize and eliminate it. Types of acidosis a) Respiratory acidosis Due to lung or breathing disorders→ lung not able to release CO2 out (eg. In case of Asthma)→ accumulation of CO2→ ↓ pH. b) Metabolic acidosis Metabolic acidosis occurs when too much acid is produced by the body, Eg. lactic acidosis & diabetic ketoacidosis→↓ pH. ✓ Alkalosis It is a condition in which the blood pH tends to increase >7.45 It usually results from decreased level of acids in the blood or increased level of bases like bicarbonate above the capacity of the body to neutralize or eliminate it. Types of alkalosis a. Respiratory alkalosis ▪ due to lungs breathing out too much carbon dioxide→ ↑ pH Eg. Fever, infection, pain→ hyperventilation b. Metabolic alkalosis ▪ due to losing too much acid from the body or having too much bicarbonate→ ↑ pH Eg, severe prolonged vomiting→ loss of HCL The respiratory parameter of ABG Respiratory Metabolic Acidosis Alkalosis Acidosis Alkalosis PH ↓ ↑ ↓ ↑ PCO2 ↑ ↓ HCO3 ↓ ↑ the metabolic parameter of the ABG A client with diabetes mellitus has a blood glucose on admission of 596 mg/dL. The nurse anticipates that this client would be experiencing which of the following types of acid-base imbalance? a. Metabolic acidosis b. Metabolic alkalosis c. Respiratory acidosis d. Respiratory alkalosis A nurse is caring for a client who is nervous and is hyperventilating. The nurse would monitor the client for signs of which of the following acid-base imbalances? a. Respiratory acidosis b. Respiratory alkalosis c. Metabolic alkalosis d. Metabolic acidosis  New Mansoura University MBBCh program Respiratory Module BMS 203 Pulmonary surfactants Dr. Ghada Helal Assistant Professor of Medical Biochemistry  Students Learning outcomes At the end of this lecture students will be able to: 1.Define surfactants 2.Summarize the chemical structure of surfactants 3.Locate the site of surfactants synthesis 4.Outline the time course of surfactants synthesis  Contents 1.Introduction 2. Chemical structure of surfactants a.Lipids b.Proteins 3.Time course of surfactant synthesis 5.Testing of lung maturity  Introduction Surface tension: The molecules at the surface do not have other molecules on all sides → so pulled inwards. This creates some internal pressure → forces liquid surfaces to contract to the minimal area. Surfactants: Substances that absorb to the surfaces causing marked decrease in the surface tension.  Pulmonary surfactants Pulmonary surfactant is a surface-active lipoprotein complex formed by type II alveolar cell and secreted into the small airspaces around 22 weeks gestation. It covers the alveolar surface and terminal airways→ ↓ surface tension in the alveoli → decrease the pressure needed to re-inflate alveoli→ prevent lung collapse( atelectasis). Alveoli with surfactants Alveoli with lack of surfactants Uniform inflation Collapsed  Chemical Structure & Composition of different pulmonary surfactant It is lipoprotein complex: lipids (90% by weight) Proteins (10% by weight)  Both have: Hydrophilic region & Hydrophobic region.  1. Surfactant Lipids A) 90% Phospholipids 1 Phosphatidylcholine (lecithin) (DPPC) (90%) Major component → large ↓ in surface tensions → stabilize the lung at the end of expiration. 2 Phosphatidylglycerol (PG) (10%) Its unsaturated fatty acid chains → fluidize the lipid monolayer at the interface. 3 Phosphatidylinositol (PI) – Stabilize lecithin B) 10% cholesterol - surfactant fluidity & spreadability  2. Surfactant proteins (SP) Proteins make up 10% of surfactant. It consists of four specific proteins. They can be classified in two groups: 1) Hydrophilic surfactant proteins SP-A and SP-D 2) Hydrophobic surfactant proteins SP-B and SP-C.  1) Hydrophilic surfactant proteins SP-A: ↓ surface tension at the air-liquid interface in the lung alveoli. SP-D: Lung's defense against inhaled microorganisms. 2) Hydrophobic surfactant proteins SP B & SP-C – ↑ adsorption, spreading and stability of surfactant and lipids – Required for proper biophysical function of the lung surfactant. – Congenital absence of SP-B→ respiratory failure SP-C →chronic lung disease.  Time course of different phospholipids In early pregnancy: – Sphingomyelin is much greater than lecithin. Between 24 and 26 weeks of gestation: – Lecithin: begins to be secreted by the fetal lung Around 32 weeks gestation: – Lecithin and sphingomyelin : nearly equal.  After 35 weeks of gestation: – Lecithin:↑↑↑at 35 weeks→ continuous ↑till term. – PG: becomes detectable at 36 weeks Fetal lung maturity (37- 40 weeks): The L/S ratio > 2.0 PG: is detectable PI: ↓  Surfactant insufficiency Surfactant insufficiency is associated with Respiratory Distress syndrome ( RDS) in preterm infants → neonatal death. Management of RDS – Shortly before delivery: mother glucocorticoids → accelerate Lung maturation. – Post natal: Administration of natural or synthetic surfactant to neoborn → Prevent & treat infant RDS.  Testing lung maturity (Markers for lung maturity) Evaluation of fetal pulmonary maturation is important 1. To prevent Respiratory Distress Syndrome (RDS) caused by low surfactant. 2. To determine optimal time for obstetrical intervention in cases of possible fetal distress.  1. Measurement of L/S ratio by thin layer chromatography (TLC) L/S= Lecithin/spingomylin ratio It is the gold standard method. But contamination from blood or meconium → give false mature results. L/S ratio: < 1.5 → high risk of RDS = 2.0 ( around 32 w) → uncommon RDS > 2 → lung maturity  2.Phosphatidyl glycerol (PG) assay – Sensitive test → detect PG antibodies in amniotic fluid. – Not affected by blood, meconium, or other contaminants – Useful at gestational age ≥35 weeks – Its presence→ 100% for lung maturity – Important in evaluating Fetal lung maturity of diabetic mothers (because the L/S is less reliable in these cases)  Premature Borderline Mature L/S 2 Disaturated 50 lecithin % PI 5-12 12-20 20-25 % PG 0 0 2-10 Diabetes delays development of the fetal lung. RDS may develop in spite of a mature L/S ratio. High % of lecithin, and high PI, to ensure lung  References Lippincott Illustrated Reviews: Biochemistry 7th Edition ISBN-10: 1-4963-6354-X USMLE step 1 lecture Notes 2017 Biochemistry and medical genetics. First AID Q& A for USMLE STEP 1 3rd Edition ISBN:978-0-07-174402-7 chapter 2 Biochemistry (page 17-page 52) https://medicombank.files.wordpress.com/2017/03/fi rst-aid-qa-for-the-usmle-step-1-third-edition.pdf Antioxidants Dr. Aya Ahmed El-Hanafy Lecturer of Medical Biochemistry and molecular biology By the end of this lecture, the students should be able to: 1. Define reactive oxygen species (free radicals) 2. List the types & sources of free radicals 3. Identify effects of free radicals 4. Define antioxidants 5. Outlines different types of antioxidants 6. Summarize the role of different types of antioxidants  Free radicals (Reactive Oxygen Species ) ✓Definition ✓Types ✓Sources ✓Effects Antioxidants ✓Definition ✓Mechanism of action ✓Types/roles Enzymatic Antioxidants Non- Enzymatic Antioxidants I. Free radicals  They are molecules with one or more unpaired electron The unpaired electrons in the outer most orbit making Mother them unstable and highly day has gone reactive  To become stable, they need to balance their electrons by losing or gaining an electron. A free radical tries to steal an electron from some other molecule to gain stability, which in turn becomes unstable and starts a chain of damaging reaction. So, Characteristics of Free radicals are: Highly reactive Unstable and try to become stable Very short life span as they tend to catch an electron from other molecules. Generate new radicals by chain reaction Cause damage to biomolecules, cells & tissues Reactive Oxygen Species (ROS) Reactive Nitrogen Species (RNS) Superoxide radical (O2 -) Nitric oxide (NO ) Hydrogen peroxide (H2O2) Nitrogen dioxide radical (NO2 ) Hydroxyl radical (OH ) Peroxy nitrite (ONOO -) Alkoxyl radical (RO ) ❑ NB: Out of these H2O2 and Singlet Peroxyl radical (ROO ) oxygen are not free radicals but due to extreme reactivity they are included in Singlet oxygen (1O2) ROS (Reactive oxygen Species).  Most of free radicals in the biological system are derived from oxygen Our bodies use oxygen we breath to convert foodstuffs such as fat and sugar into energy “Cellular respiration “ During Oxidation, electrons are transferred from one molecule to another.  Leakage of electrons during oxygen metabolism, creates highly reactive molecules called ROS “Reactive oxygen Species” causing damage to cell constituents.  Exogenous sources of free Endogenous sources of free radicals radicals ❑Environmental Pollution ❑Mitochondrial electron transport chain ❑Radiations (X-rays, UV light) is the main cellular source of ROS ❑Cigarette smoking ❑Peroxisomes ❑Alcohol consumption ❑Enzymatic sources in metabolism (Xanthine oxidase, NADPH oxidase, NO synthase). ❑Drugs & toxic chemicals ❑Human phagocytes (Respiratory burst) ❑Processed food, Food additives ❑Transition metals. ❑Fried/High fat diet ❑During metabolism of xenobiotics. ❑Infection / inflammation  Free radicals beget free radicals: i.e. generate free radicals from normal compounds which continues as a chain reaction Damaging almost all types of biomolecules (carbohydrates, lipids, proteins, nucleic acids). Lipid Peroxidation: Damage to cell membrane, LDL oxidation Protein Oxidation: Loss of protein function/enzyme inactivation DNA damage: Mutation and cancer CHO Glycation : Effect on receptors and signaling  Although free radicals are harmful, some of them have beneficial effect, as the body creates them to neutralize viruses and bacteria as a Mother defense mechanism (e.g. day has gone Respiratory burst) (when produced by adequate amounts). II. Free radical scavenger (Antioxidants)  Our bodies have some protective mechanisms against the harmful effects of free radicals. These are antioxidants.  They are molecules that are able to neutralize reactive free radicals They can neutralize free radicals by donating one of their own electrons to the free radical ending the electron stealing reaction reducing oxidative damage 1. Preventive mechanism: prevent the production of ROS and free radicals blocking the initial chain reaction of free radicals e.g. Catalase, Glutathione peroxidase. 2. Chain breaking mechanism: inhibit the propagation of electron stealing chain by donating electron to the free radical present in the system e.g. SOD, vitamin E, uric acid. 3. Repair mechanism: eliminate & repair the molecular damage caused by free radicals.  Enzymatic antioxidants Non-enzymatic antioxidants ❑Superoxide dismutase (SOD) (a) Nutrient antioxidants e.g. ❑Catalase Antioxidant Vitamins Antioxidant Minerals ❑Glutathione peroxidase Ascorbic acid (vit C), * Selenium α tocopherol (vitamin E ), ❑Glutathione reductase. β-carotene (pro-vitamin A). Copper, Iron Zinc, Manganese They neutralize superoxide Flavenoids: Eg: Green tea, Olives radicals & H2O2 - (b) Metabolic antioxidants e.g. glutathione, uric acid, ferritin, ceruloplasmin, transferrin, Alpha lipoic acid, bilirubin, hormones as melatonin A. Superoxide dismutase (SOD): Act as the 1st line defense system against ROS to protect cells from the injurious effects of superoxide Converts highly reactive superoxide free radicals to less toxic hydrogen peroxide B. Catalase : Hydrogen peroxide, produced by superoxide dismutase, is metabolized by catalase It removes hydrogen peroxide from our bodies by converting it to water and oxygen C. Glutathione Peroxidase/ Glutathione reductase: 1. It also detoxifies H2O2 into water (while reduced glutathione (GSH) is converted to oxidized glutathione (GSSG). The reduced glutathione can be regenerated by the enzyme glutathione reductase utilizing NADPH) 2. It catalyze the reduction of lipid hydroperoxides to their corresponding alcohols thus protect against lipid peroxidation  A number of intracellular reducing agents, such as ascorbic acid (vitamin C), α-tocopherol (vit E ), and β-carotene (pro-vitamin A). Prevent the oxidation of cell components by free radicals 1. α-tocopherol (vitamin E ): Fat-soluble antioxidant. It is an antioxidant present in all cellular membranes, (The major membrane-bound antioxidant). Its main antioxidant function is protection against lipid peroxidation It can directly act on oxyradicals (e.g. O2 – , OH–, singlet oxygen), and thus serves as an important Chain breaking antioxidant 2. Vitamin C (ascorbic acid) It is a water soluble antioxidant It is a reducing agent, capable of reducing ROS such as H2O2 Ascorbic acid is a strong antioxidant. It spares vit A & vit E from oxidation 3. β-carotene: Fat-soluble antioxidant Destroy a damaging form of singlet oxygen  a) Selenium b) Copper c) Zinc d) Manganese e) Iron ❑ Selenium is part of glutathione peroxidase. ❑ Copper, zinc, manganese are part of SOD. ❑ Iron is a cofactor for catalase enzyme.  Consumption of foods rich in fruits & vegetables is a natural source of antioxidant compounds that has been correlated with a reduced risk for certain types of cancers, as well as decreased frequency of certain other chronic health problems.  Oxidative Stress It is a condition produced by the imbalance between oxidants (Free radicals) and antioxidants in a biological system as a result of: 1) an increase in oxidant generation 2) a decrease in antioxidant protection  Disturbances in the normal redox state of tissues can cause toxic Damage to all components of the cell, including proteins, lipids, and DNA. Commonly associated with diseases like: Cancer Cardiovascular diseases Inflammatory/Autoimmune diseases Neurodegenerative disease Accelerated aging Thank you ❑ Harper’s illustrated Biochemistry, 30th edition ❑ Chatterjea’s Textbook of Medical Biochemistry, 8th edition. ❑ Vasudevan's Textbook of Biochemistry For Medical Students, 7th Edition. ❑ Lippincott’s Illustrated Reviews: Biochemistry, 8th edition