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PHASE 1 Revision
Akanksha Sinha
Regina Sarbaratnam
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Aims - Overview
• METABOLISM
(Carbohydrates, Protein, Lipid, Alcohol, Glycogen)
• ATP
(ATP-ADP cycle, Glycolysis, Kreb’s cycle, Oxidative Phosphorylation)
• FATTY ACID OXIDATION/KETONES
(Beta oxidation, Ketogenesis)
• ACID/BASE/BUFFER (Henderson-Hasselbach equation)
• OXYGEN TOXICITY (ROS, Haber-Weiss and Fenton reactions)
• HISTOLOGY (Stains, Epithelia)
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Metabolism
The chemical processes that occur
within a living organism in order to
maintain life
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Metabolism
4 main energy sources:
Carbohydrates: Starch, fructose, sucrose, glucose, 4kcal/g
lactose Mainly come from starchy foods and fruit.
Proteins: Largely come from meat ,dairy ,pulses , fish4kcal/g
Alcohol: typically ethanol
7kcal/g
Lipids: triacylglycerols
9kcal/g
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What happens to the excess energy intake?
1. Stored as triglycerides (approximately
15kg)
2. Stored as glycogen (approximately 200g
in liver, 150g in muscle)
3. Stored as protein (approximately 6kg)
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BMR
Energy needed to stay alive at rest
Increase BMR:
•Increased body weight
•Hyperthyroidism
•Low ambient temperature
•Fever/infection
•Caffeine/stimulant intake
•Pregnancy
Decrease BMR:
•Increased age
•Being female
•Dieting/Starvation
•Hypothyroidism
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ATP
ATP ‘Adenosine Triphosphate’
Structure components: Adenine, Ribose, 3 Phosphate
How does it provide Energy?
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ATP
-The ATP molecule has two
phosphoanhydride bonds.
ATP
- These are RELATIVELY WEAK
bonds, hence require relatively
less energy to break
Hydrolysis
- Overall more energy is released
in forming the products that used
to break bonds in the reactants
ADP
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ATP-ADP Cycle
CO2
ATP
Energy utilization:
Biosynthesis of
macromolecules
Muscle contraction
Active ion transport
Thermogenesis
Respiration:
Energy production
Carbohydrate
Lipid
Protein
O2
ADP + Pi
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ATP- ways to generate ATP?
-
Glycolysis
Kreb’s cycle
Oxidative phosphorylation
Substrate level phosphorylation
Via electron transport chain
Beta oxidation (Discussed in fatty acid oxidation)
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Glycolysis
• Glycolysis
Pathway of 10 steps
Takes place in cytoplasm
In short – Glucose 
2Pyruvate + 2ATP + 2NADH (AEROBIC)
2Lactate + 2ATP (ANAEROBIC)
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Glycolysis
Energy Investment Phase
- 2 ATP
Energy Generation Phase
+ 4 ATP
Glycolysis generates a NET
2 ATP plus 2 NADH
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Step 1
• Facilitated diffusion of Glucose into cell
mediated by Insulin
• Phosphorylation of Glucose by Hexokinase
• -ATP
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Step 2
• Isomerism
• G6PF6P
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Step 3**
• F6P F1,6BP
• Via phosphofructokinase (PFK is primary
regulated step of glycolysis; responds to both
cellular energy and hormonal regulation)
• -ATP
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Step 6-10
•
•
•
•
•
•
6: NADH (x2) produced
7: ATP (x2) produced
8:
9:
10: 2Pyruvate + ATP (x2) produced
Remember all the enzymes
Pyruvate enters
the TCA cycle
• “Good Gracious, Father Franklin Did Go By Picking
Pumpkins (to) Prepare Pies
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Acidosis affecting glycolysis
• PFK1 is pH dependent
– Inhibited in acidosis
Control of glycolysis via:
• Step 1
• Step 3* -key regulatory step in glycolysis
Positive regulators: AMP
Negative regulators: H+, ATP,
Citrate, hormonal
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Kreb’s/ TCA cycle
In Mitochondrial matrix
Acetyl CoA can come from
glycolysis/ fatty acid
breakdown/ amino acids’
carbon skeletons
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Kreb’s/TCA cycle
• Inhibited
by ATP,
NADH,
succinyl
CoA
• Activated
by ADP
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Electron Transport Chain
• The electron transport chain (ETC) is a process
in which the NADH and [FADH2] produced
during glycolysis, β-oxidation, and other
catabolic processes are oxidized
thus releasing energy in the form of ATP. The
mechanism by which ATP is formed in the ETC is
called chemiosmotic phosphorylation
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The chemiosmotic theory
Based on the following:
-inner mitochondrial membrane is impermeable
to protons, hence the mitochondrial matrix is a
closed environment
-the proton pumping of the ETC leads to the
proton motive force which in turn provides the
energy for ATP synthesis (Proton flow through
the ATP synthase protein drives ATP synthesis)
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The chemiosmotic theory
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Substrate level phosphorylation
• some ATP can be made in the cytoplasm
through a process called substrate-level
phosphorylation
• With this type of phosphorylation you have an
adenosine diphosphate (ADP), which is a unit
of adenosine attached to two (di) phosphate
groups
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oxidative phosphorylation
• Oxidative phosphorylation is the metabolic
pathway in which the mitochondria in cells
use their structure, enzymes, and energy
released by the oxidation of nutrients to
reform ATP
(involves ETC!!!)
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TOTAL ATP
• Total ATP made from one molecule of glucose:
34 ATP
But this is very debatable
- Some sources will say 30 or 32 ATP
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Fatty acid oxidation/ Beta oxidation
Examples of fatty acids:
• Palmitoleic acid
• Linoleic acid
• Palmitic acid
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Fatty acid oxidation/ Beta oxidation
Fatty Acid
Acetyl CoA (used
in TCA/Krebs
cycle)
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Fatty acid oxidation/ Beta oxidation
ATP
Fatty Acid
PPi
Acyl adenylate
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Fatty acid oxidation/ Beta oxidation
CoA
Acyl
adenylate
AMP
Acyl CoA
Acyl CoA
synthetase
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Fatty acid oxidation/ Beta oxidation
The carnitine shuttle !!!
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The Carnitine Shuttle
Carnitine
CoA
Acyl CoA
Acyl Carnitine
Carnitine Acyl Transferase
I
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Inner mitochondrial membrane
CoA
Acyl
Carnitine
Carnitine
Acyl CoA
Carnitine Acyl Transferase
II
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Fatty acid oxidation/ Beta oxidation
Acetyl CoA
Acyl CoA
•
•



Acyl CoA – 2C
Sequential removal of 2- carbon units
Each round of β-oxidation produces:
1 mole of NADH
1 mole of FADH2
1 mole of acetyl-CoA
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Ketogenesis
The process by which ketone bodies
are produced as a result of fatty acid
breakdown.
Ketones are used for energy at low fat
states.
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Ketogenesis
2 AcetylCoA
CoA-SH
thiolase
AcetoacetylAcetyl-CoA + H20
HMG-CoA synthase
CoA
CoA-SH
HMG-CoA
HMG-CoA lyase
Acetyl-CoA
Acetoacetate
Acetone
β- hydroxybutyrate
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I know, no pathology …
Diabetic ketoacidosis
• Reduced supply of glucose due to a
significant decline in circulating insulin and
an associated increased in circulating
glucagon.
• The increased production of Acetyl-CoA
leads to ketone body production
• This lowers the pH of the blood
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Acid/Base/Buffer
• Acid = proton (H+) donor
HA ⇔ H+ + A-
• Base = proton (H+) acceptor
B + H+ ⇔ BH+
• Buffer = weak acids or bases that act to
maintain H+ concentration
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Acid/base/buffer
• Acidosis can either be respiratory or metabolic
• Alkalosis can either be respiratory or
metabolic
• pH range is 7.35-7.45. But ideal pH is 7.4
• Compensation: metabolic is slow, respiratory
is fast.
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Henderson-Hasselbalch equation
• Henderson’s formula:[H+ ] x [HCO3 - ] = K x pCO2
• Hasselbalch converted it to pH
pH = pK + log ([HCO3 - ] / [CO2])
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Acidosis
Carbonic anhydrase
• Respiratory
• Metabolic
• Insufficient ventilation retains CO2
so there is more carbonic acid in
the blood leading to acidosis
• Causes include COPD (chronic
bronchitis + emphysema), asthma
• Low bicarbonate levels leading to
acidosis
• Causes include bicarbonate losses
from the GI tract e.g. diarrhoea,
DKA, lactic acidosis (anaerobic
respiration), renal failure
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Alkalosis
• Respiratory
• Metabolic
• Blowing off too much CO2 leading
to alkalosis
• Causes hyperventilation, pink
puffers COPD (i.e. type 1
respiratory failure), anxiety, fever
• Loss of H+ or too much
bicarbonate leading to alkalosis
• gastric secretions contain large
quantities of hydrogen ions.
• Causes include excess vomiting
(because you’re losing H+),
pyloric stenosis, anorexia nervosa,
ingestion of bicarbonate
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Anion Gap
The anion gap is calculated by subtracting the serum concentrations
of ANIONS (Cl- and HCO3-) from the concentrations of CATIONS (Na+ and
K+)
BUT
potassium concentrations, being very low, usually have little effect on the
calculated gap. This leaves the following equation:
Anion gap = [Na+] − ([Cl−] + [HCO3−]) =16 meq/lit
The magnitude of this difference (i.e., "gap") in the serum is often calculated
when attempting to identify the cause of metabolic acidosis.
If the gap is greater than normal, then high anion gap metabolic acidosis is
diagnosed (due to increased cation: H+)
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Types of Buffer systems
• Proteins (51%)
– Weak acid/base groups
• Bicarbonate (43%)
 Most important
– CO2 removed via lungs, Bicarbonate regenerated
by kidneys
• Haemoglobin (6%)
Haemoglobin binds both CO2 and H+
and so is a powerful buffer
– Deoxy Hb binds H+  HHb + Bicarbonate
– Amine group on Deoxy Hb bind CO2
carbaminohaemoglobin
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Oxygen Toxicity
Toxic reactive oxygen derivatives with:
• Free radicals
• Unpaired electrons in outer shell
• High reactivity
OR
DEF: Chemically reactive molecules with
unpaired electrons in outer shell & free radicals
(unpaired electron) derived from oxygen
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Formation of ROS
e-, 2H+
eO2
O2
H2O2
Oxygen
Superoxide
Produced by ETC
e-, H+
H2O
Hydrogen peroxide Generates
radicals with
-,
+
e H
transition
metals (Fenton
or Haber Weiss
rx)
OH• +
H2O
Hydroxyl
radical
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ROS
OH• (hydroxyl radical)
•Most potent radical
•Lipid soluble
•Chain reaction forms lipid peroxides & organic radicals
H202 (hydrogen peroxide)
• Not actually a radical
• Oxidising agent in presence of Fe2+ or other transition metals
• Generates hydroxyl radical
• Lipid soluble
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Formation of hydroxyl radical
Fenton
reaction
Haber-Weiss
reaction
H2O2
O2
+
+
Fe2+
H 2 O2
H+
Fe3+
O2
+
OH•
+
H2O
+
+
OH-
OH•
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Production of ROS
• Endogenous
– natural by-product of O2 metabolism
– Produced mainly inside cell organelles ie.
(mitochondria)
• Exogenous
– UV radiation, smoking, inflammation
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+ve ROS
• Respiratory bursts
– ROS released during phagocytosis of bacteria
– Damages bacterial cell membrane
– Fenton’s reaction
• O2  O2-H2O2+Fe2+Fe3+ + OH- + OH•
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-ve ROS
• Cellular damage
• Damage to membranes of nucleus,
mitochondria, endoplasmic reticulum & cell
• Increased permeability leads to influx of
calcium, water & sodium
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Anti-oxidants
• Enzymes
– Catalase H2O2  2 H20 + 02
– Superoxide dismutase O2-  H2O2
– Glutathione peroxidase
• Antioxidant vitamins/Free radical scavengers
(vitC, vitE, carotenoids)
• Cellular Compartmentation
• Repair
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Histology of Epithelia
•
-
Roles of epithelia
Protection(skin)
Absorption(gut)
Secretion(pancreas)
Simple Epithelium
Stratified Epithelium
-Almost always squamous
Pseudo-stratified Epithelium
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Simple squamous epithelia
Found in:
-Alveoli
-Serosa
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Simple cuboidal epithelia
Found in:
-Kidney tubules
-Ducts of glands
 Sweat
 Salivary
 Pancreatic
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Simple columnar epithelia
Found in:
-Small intestine
-Gall bladder
-Bronchus
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Stratified epithelium
Protection
• Continually being worn down
• Cells replaced from below
• Found in areas where there is continuous abrasion
Squamous:
Keratinised – skin
Non keratinised – mouth, oesophagus, vagina
Cuboidal
found in some large ducts
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Stratified squamous non-keratinising
Found in:
- Mouth
- Oropharynx
- Oesophagus
- Vagina
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Stratified squamous keratinising
Found in:
-Skin (hairy or non-hairy skin)
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Pseudostratified columnar epithelia
Found in:
• Trachea and large airways (respiratory
epithelium)
• Urinary tract
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Cell Junctions
1) Adherent (tight) junctions
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Cell Junctions
2) Desmosome
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Cell Junctions
3) Gap junction
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Staining
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Alcian Blue
GAG-rich structures
Mucous goblet cells
Mast cell granules
Cartilage matrix
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Staining
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Eosin
Colloidal proteins (e.g.
plasma)
Keratin
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Staining
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Haematoxylin
Nuclei
RNA
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Staining
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PAS
Hexose sugars
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Questions?
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