Lecture 1

Question 1

what are the 5 major domains of biochemistry?

Answer 1

1. homeostasis
2. biochemical reactions
3. structure and function
4. evolution
5. information storage

this module will focus on the aspects of
-regulation
-atomic
-molecular
-cellular

Question 2

Define and describe glucose (carbohydrate) homeostasis, pathways of glucose metabolism, and control of glucose metabolism

Question 3

Discuss glucose (carbohydrate)metabolism in disease e.g. diabete

Question 4

Define and describe lipid catabolism and anabolism in relation to health & disease metabolism

Question 5

Describe the major plasma membrane components and explain their role in cellular signalling and function

Question 6

Describe the intracellular signalling pathways activated by major plasma membrane and nuclear receptors and explain their role in controlling gene transcription in health and disease

Question 7

Describe and explain the structure and function of the phospholipids and how they interact with each other and the aqueous compartments to form a bilayer membrane.

Question 8

Explain why the term “fluid mosaic model” is applied to this structure.

Question 9

Discuss the structure and functions of cholesterol.

Question 10

Describe and explain the role of diffusion within membranes with respect to lipids and membrane proteins

Question 11

Compare and contrast different membrane compartments, identifying how they differ in their constituents.

Question 12

Apply the properties of constituents within the membrane to explain their influence on the physical properties of the compartments

Question 13

what do you see in the video about the inner life of a cell- https://www.youtube.com/watch?v=wJyUtbn0O5Y

Answer 13

0:10 Blood vessel
0:18 Adhesion proteins/cadherins
0:44 Actin filaments
0:53 Polymerization of actin filaments
1:07 Microtubule polymerization
1:12 Microtubule depolymerization
1:15 Motor proteins (kinesin/dyneins)
1:28 Centrioles
1:36 Nuclear export of RNA through nuclear pores
1:48 Translation
1:57 Post-translational import into mitochondria
1:59 Co-translation import into ER
2:11 Motor proteins (kinesin/dyneins)
2:17 Golgi
2:22 Exocytosis
2:30 Collagen fibers & ECM + transmembrane proteins
2:47 White blood cell
lipid rafts
vesicle transport
recrutment of ribosomes to ER

Question 14

what are key and fundamentally important facts about the plasma membrane?

Answer 14

The plasma membrane is a critical component of cells, serving various functions essential to cellular life. Here are some key and fundamentally important facts about the plasma membrane:

1. Phospholipid Bilayer Structure
   The plasma membrane is primarily composed of a phospholipid bilayer. Each phospholipid molecule has a hydrophilic (water-attracting) head and two hydrophobic (water-repelling) tails. This arrangement forms a semi-permeable barrier that controls the movement of substances in and out of the cell.
2. Fluid Mosaic Model
   The plasma membrane is described by the fluid mosaic model, meaning it behaves like a fluid, where proteins and lipids can move laterally within the layer. Embedded within this bilayer are various proteins, cholesterol, and carbohydrates, giving the membrane a dynamic structure.
3. Selective Permeability
   The plasma membrane is selectively permeable, meaning it allows certain molecules to pass while restricting others. Small, nonpolar molecules (like oxygen and carbon dioxide) can diffuse freely, while larger or charged molecules require specific transport mechanisms (e.g., channels or carriers).
4. Embedded Proteins
   Integral proteins (spanning the membrane) and peripheral proteins (attached to the membrane’s surface) are essential for various functions:
   Transport proteins: Facilitate the movement of ions and molecules across the membrane.
   Receptor proteins: Allow the cell to respond to external signals (e.g., hormones, neurotransmitters).
   Enzymatic proteins: Catalyze chemical reactions at the membrane surface.
5. Cholesterol
   Cholesterol molecules are interspersed within the phospholipid bilayer. They regulate membrane fluidity, ensuring it remains flexible but stable at various temperatures.
6. Carbohydrate Chains (Glycocalyx)
   Carbohydrates attached to proteins (glycoproteins) and lipids (glycolipids) form the glycocalyx. This structure is involved in cell recognition, adhesion, and protection.
7. Signal Transduction
   The plasma membrane plays a crucial role in cell signaling. Receptors in the membrane detect external signals (like hormones), initiating intracellular responses. This is vital for processes like cell growth, immune responses, and neural communication.
8. Endocytosis and Exocytosis
   The plasma membrane can engulf material from the outside environment in processes like endocytosis (taking in large molecules) and can expel materials via exocytosis. These processes are essential for nutrient uptake, waste removal, and cell communication.
9. Electrical Properties
   The plasma membrane is responsible for maintaining an electrochemical gradient through ion channels and pumps (e.g., the sodium-potassium pump). This gradient is crucial for nerve impulse transmission and muscle contractions.
10. Barrier to Protect Internal Environment
    The plasma membrane acts as a protective barrier that helps maintain homeostasis by controlling the internal environment of the cell, allowing the cell to thrive in various external conditions.

These facts collectively highlight the plasma membrane’s complexity and vital role in cell survival, communication, and function.

Question 15

why are interactions between the components of the cell membranes important?

Answer 15

because the lipid bilayer is fragile and we must maintain the integrity of the cell

Question 16

what are the key components of the cell membranes

Answer 16

-Phospholipids
*Cholesterol
*Protein
*Glycoprotein
*Glycolipid
glyco suggests there is a sugar involved this is important to help determine your blood type

Question 17

what are the important properties of phospholipids?

Answer 17

*Contain:
*2 Fatty acid chains
*glycerol
*highly polar or charged group
*Amphipathic
and are a Major component of cell membranes

not all lipids contain choline

Question 18

what are the properties of sterols such as cholesterol?

Answer 18

*4 ring ridged structure at the centre
*Saturated hydrocarbon tail

they are called sterols because of the 4 ring sterol structure

the negative hydroxyl group at the top and fatty acid tail means some people believe it to be an amphipathic molecule

Question 19

how is cholesterol multifaceted?

Answer 19

▪Generated in the liver from Acetyl-CoA
▪Often converted here into physiologically relevant products.
▪Dietary intake can cause toxicity because you can have too much

if the amount of cholesterol is in a 1-1 ratio with phosphlipids it would mean that the membrane becomes very rigid

Question 20

what is the pathway to cholesterol generation?

Answer 20

The biosynthesis of cholesterol from Acetyl-CoA follows a multi-step pathway called the mevalonate pathway. Here’s the ordered process:

1. Condensation of Acetyl-CoA to form HMG-CoA
   two Acetyl-CoA molecules condense to form Acetoacetyl-CoA via the enzyme thiolase.
   A third Acetyl-CoA is added to Acetoacetyl-CoA to form 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA). This step is catalyzed by HMG-CoA synthase.
2. Conversion of HMG-CoA to Mevalonate
   HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, converts HMG-CoA to mevalonate. This step requires NADPH as a reducing agent.

to control the amount of cholesterol produced the HMG-CoA is inhibited or activated

3. Phosphorylation of Mevalonate to Isopentenyl Pyrophosphate (IPP)
   Mevalonate is phosphorylated by mevalonate kinase to form mevalonate 5-phosphate.
   A second phosphorylation by phosphomevalonate kinase forms mevalonate 5-diphosphate.
   Finally, mevalonate 5-diphosphate decarboxylase converts mevalonate 5-diphosphate into Isopentenyl Pyrophosphate (IPP) through decarboxylation.
4. Conversion of IPP to Geranyl and Farnesyl Pyrophosphate
   IPP isomerase converts IPP to Dimethylallyl pyrophosphate (DMAPP).
   IPP and DMAPP are condensed by geranyl pyrophosphate synthase to form Geranyl Pyrophosphate (GPP).
   A second IPP is added to GPP to form Farnesyl Pyrophosphate (FPP) by farnesyl pyrophosphate synthase.
5. Formation of Squalene
   Two molecules of Farnesyl Pyrophosphate (FPP) condense to form squalene via the enzyme squalene synthase. This step requires NADPH.
6. Formation of Lanosterol
   Squalene epoxidase converts squalene into squalene 2,3-epoxide.
   Squalene 2,3-epoxide undergoes cyclization via the enzyme lanosterol synthase to form lanosterol, the first sterol in the pathway.
   (1) Lanosterol to Desmosterol (via the Bloch Pathway)- The enzyme desmosterol reductase (DHCR24) catalyzes the reduction of the Δ24 double bond in desmosterol, converting it into cholesterol.
   (2) Lanosterol to 7-Dehydrocholesterol (via the Kandutsch-Russell Pathway)-The enzyme 7-dehydrocholesterol reductase (DHCR7) reduces the Δ7 double bond in 7-dehydrocholesterol, converting it into cholesterol.
7. Conversion of Lanosterol to Cholesterol
   A series of 19 steps then convert lanosterol to cholesterol. These steps involve the removal of three methyl groups, the reduction of double bonds, and other modifications to the sterol backbone to produce cholesterol.

Summary of Major Steps:
Acetyl-CoA → HMG-CoA
HMG-CoA → Mevalonate (rate-limiting step)
Mevalonate → Isopentenyl Pyrophosphate (IPP)
IPP → Farnesyl Pyrophosphate (FPP)
FPP → Squalene
Squalene → Lanosterol
Lanosterol → Cholesterol

Each step is tightly regulated, with HMG-CoA reductase being the key regulatory point targeted by cholesterol-lowering drugs like statins.

Question 21

Where is cholesterol made?

Answer 21

Cholesterol is synthesized primarily in the liver, but it is also made in smaller amounts by nearly all cells in the body. Here’s a more detailed breakdown:

1. Liver (Primary Site)
   The liver is the main organ responsible for producing cholesterol, synthesizing around 70-80% of the body’s cholesterol. The liver not only makes cholesterol for its own needs but also supplies it to other tissues via the bloodstream, packaged into lipoproteins (like LDL and HDL).

cholesterol is formed at the smooth endoplasmic reticulum in the hepatocytes in the liver

2. Intestines
   The intestines play a secondary role in cholesterol synthesis, particularly in absorbing dietary cholesterol and synthesizing cholesterol needed for maintaining the intestinal cells and producing bile acids.
3. Other Tissues
   Cholesterol is also synthesized in smaller amounts in other tissues such as:
   Adrenal glands: Cholesterol is essential for the production of steroid hormones (e.g., cortisol, aldosterone).
   Gonads: Cholesterol is the precursor for sex hormones like estrogen, progesterone, and testosterone.
   Brain: Neurons and glial cells in the brain synthesize cholesterol, crucial for the formation and maintenance of myelin sheaths that insulate nerve fibers.
   Skin: Skin cells produce cholesterol, which plays a role in barrier function and, importantly, as a precursor to vitamin D when exposed to sunlight.
4. Cellular Level
   Cholesterol synthesis occurs in the cytoplasm and endoplasmic reticulum of cells. The process begins with acetyl-CoA, and the key regulatory enzyme involved is HMG-CoA reductase.
   Distribution of Cholesterol Production:
   Liver: Main producer, regulating systemic cholesterol levels and synthesizing bile acids for digestion.
   Peripheral Tissues: Produce cholesterol for local use, particularly for membranes, hormones, and nerve insulation.

In summary, while most cholesterol is synthesized in the liver, virtually all cells in the body have the capacity to produce cholesterol for their own needs.

cholesterol is released into the intestine and the products are reabsorbed

Question 22

why is cholesterol important?

Answer 22

1. Cholesterol Functions in the Body
   Structural component of cell membranes: Cholesterol is a key component of the phospholipid bilayer of cell membranes. It helps maintain membrane fluidity, stability, and permeability, allowing cells to function properly across a wide range of temperatures.
   Precursor to steroid hormones: Cholesterol is the precursor for the synthesis of steroid hormones, including:
   Glucocorticoids (e.g., cortisol): Involved in stress response and regulation of metabolism.
   Mineralocorticoids (e.g., aldosterone): Regulates salt and water balance.
   Sex hormones (e.g., estrogen, progesterone, testosterone): Critical for reproduction and secondary sex characteristics.
   Precursor to vitamin D: In the skin, 7-dehydrocholesterol, a cholesterol derivative, is converted to vitamin D3 upon exposure to ultraviolet (UV) light. Vitamin D is essential for calcium metabolism and bone health.
   Bile acid synthesis: Cholesterol is the primary precursor for bile acids, which are crucial for fat digestion and absorption.
2. Cholesterol’s Role in Bile Acid Synthesis
   Bile acids are derivatives of cholesterol synthesized in the liver. About 500 mg to 1 g of cholesterol is converted into bile acids each day. The two primary bile acids synthesized from cholesterol are:
   Cholic acid
   Chenodeoxycholic acid
   These bile acids are then conjugated with glycine or taurine to form bile salts, which are more effective at emulsifying fats. Bile acids are secreted into bile, stored in the gallbladder, and released into the small intestine during digestion.
3. Bile Acids and Their Role in Digestion
   Emulsification of fats: Bile acids act as detergents, breaking down large fat globules into smaller micelles in a process called emulsification. This increases the surface area of fats, making them more accessible to digestive enzymes, particularly pancreatic lipase.
   Fat absorption: The micelles formed by bile acids allow the products of fat digestion (e.g., fatty acids, monoglycerides) to be absorbed by the intestinal epithelial cells. This step is essential for the efficient absorption of fat-soluble vitamins (A, D, E, K) as well as cholesterol itself.
   Recycling of bile acids (Enterohepatic circulation): After aiding digestion, most bile acids (about 95%) are reabsorbed in the ileum of the small intestine and returned to the liver via the portal vein in a process called enterohepatic circulation. The liver then reuses these bile acids to continue the digestive process.
4. Cholesterol in Bile and Gallstones
   Cholesterol is also excreted in bile, but when the bile becomes oversaturated with cholesterol (due to factors like a high-cholesterol diet or decreased bile acid production), it can precipitate and form gallstones. These are solid deposits of cholesterol that can block the bile ducts and cause digestive issues.
   Summary of Cholesterol’s Importance in Bile Acid Formation and Digestion:
   Cholesterol is the precursor for bile acids, which are essential for the emulsification and digestion of dietary fats.
   Bile acids help form micelles, facilitating the absorption of fats and fat-soluble vitamins in the small intestine.
   The enterohepatic circulation allows for the efficient recycling of bile acids, reducing the need for constant bile acid synthesis.
   Cholesterol balance in bile is crucial for preventing gallstone formation.

Question 23

why is cholesterol important for fat-soluble vitamins?

Answer 23

1. Bile Acid Production from Cholesterol
   Cholesterol is the precursor to bile acids, which are synthesized in the liver. Bile acids are critical for breaking down and absorbing dietary fats, as well as fat-soluble vitamins. Without adequate bile acids, the body cannot properly digest or absorb these vitamins.
   When bile acids are released into the small intestine, they help emulsify dietary fats and fat-soluble vitamins, forming micelles, which are small, water-soluble particles that can be absorbed by the intestinal cells.
2. Emulsification of Dietary Fats and Vitamins
   Fat-soluble vitamins (A, D, E, K) are transported along with dietary fats. These vitamins are hydrophobic (not soluble in water), so they require the action of bile acids to be absorbed.
   Bile acids, derived from cholesterol, act like detergents, breaking down large fat globules into smaller droplets in a process called emulsification. This increases the surface area available for pancreatic lipase and other enzymes to act on, allowing the fats and the fat-soluble vitamins to be incorporated into micelles.
3. Micelle Formation
   Bile acids form micelles by surrounding fat molecules and fat-soluble vitamins. These micelles are soluble in the watery environment of the small intestine, allowing the fats and vitamins to be transported to the surface of the intestinal cells (enterocytes) for absorption.
   Inside the enterocytes, fat-soluble vitamins are absorbed and packaged into chylomicrons, which enter the lymphatic system and eventually reach the bloodstream.
4. Absorption of Fat-Soluble Vitamins
   Once incorporated into micelles, fat-soluble vitamins are absorbed by the intestinal lining (specifically in the small intestine). From there, these vitamins are transported to various tissues where they perform essential functions:
   Vitamin A: Important for vision, immune function, and skin health.
   Vitamin D: Vital for calcium absorption and bone health.
   Vitamin E: Acts as an antioxidant, protecting cells from damage.
   Vitamin K: Essential for blood clotting and bone metabolism.
5. Cholesterol as a Precursor for Vitamin D
   In addition to aiding the absorption of fat-soluble vitamins, cholesterol itself is a precursor for vitamin D synthesis. In the skin, 7-dehydrocholesterol, a derivative of cholesterol, is converted into vitamin D3 upon exposure to sunlight (UV radiation). Vitamin D3 is then activated in the liver and kidneys to its biologically active form, calcitriol, which plays a key role in calcium and phosphorus metabolism.
6. Fat Malabsorption and Cholesterol
   In cases where cholesterol-derived bile acids are deficient or not adequately released (due to liver disease, gallbladder removal, or bile duct obstruction), the absorption of fat-soluble vitamins can be impaired. This can lead to deficiencies in these vitamins, causing problems like:
   Vitamin A deficiency: Night blindness and immune dysfunction.
   Vitamin D deficiency: Osteomalacia or rickets (bone softening).
   Vitamin E deficiency: Nerve and muscle damage.
   Vitamin K deficiency: Increased risk of bleeding due to impaired blood clotting.

Question 24

Can you think of any lipid-soluble hormones?

Answer 24

1. Steroid Hormones such as cortisol
   -teststerone
2. thyroid hormones such as thyroxine; thyroxine is not generally ia not generated from cholesterol

Question 25

what are the importance of hormones in cell functions

Answer 25

1. Ligand able to cross the plasma membrane because of its lipophilicity.
2. Bind to ligand dependent transcription factors, which can only bind to specific DNA sequences when bound to a ligand.
3. DNA binding induces transcription of specific genes and therefore changes in specific protein expression.

steroid hormones are lipophilic so go straight through the membrane

the stteroid hormone will bind to a receptor protein that is in the cytoplasm

Question 26

how are bile acids/salts related to cholesterol?

Answer 26

➢Synthesised from cholesterol in the liver
➢Essential for lipid digestion
➢Increase solubility as they are amphipathic
➢Increase surface area
bile acids are important for

Question 27

importance of cholesterol in digestion

Answer 27

Cholesterol is used to synthesise bile acids, in the liver.

Bile acids are amphiphilic so can enable solubilisation of dietary fats in a process called emulsification.

Emulsification is essential to enable uptake of dietary fats by enabling the formation of mixed micelles, which allow access of triacylglycerols to intestinal lipases for breakdown

Question 28

what is the function of bile?

Answer 28

The gallbladder stores bile ready for release.

First concentrates it for storage and then dilutes it in response to fats detected in the small intestine through the release of hormones cholecystokinin (chole-sisto-kinin).

Question 29

What happens when you mix oil and something aqueous?

Answer 29

When you mix oil and something aqueous (water-based), the two substances do not readily combine due to their incompatibility in polarity:

Question 30

what happens when bile acids are added to a fat globule?

Answer 30

When bile acids are added to a fat globule, they act as emulsifiers, breaking down large fat globules into smaller droplets. This process is essential for efficient fat digestion and absorption. Here’s what happens in detail:

1. Emulsification of Fat Globules by Bile Acids
   Bile acids are amphipathic molecules, meaning they have both a hydrophobic (fat-attracting) and hydrophilic (water-attracting) side.
   When bile acids are secreted into the small intestine, they surround the large fat globules with their hydrophobic side facing the fat and their hydrophilic side facing outward towards the water-based environment of the intestine.
   This action breaks up the large fat globule into smaller droplets in a process called emulsification. These smaller fat droplets have a much larger surface area compared to a single large globule, making them more accessible to digestive enzymes, particularly pancreatic lipase.
2. Formation of Micelles
   After emulsification, bile acids further help form structures called micelles. These micelles are tiny, water-soluble particles that carry fatty acids, monoglycerides, cholesterol, and fat-soluble vitamins (A, D, E, K) within their hydrophobic core.
   Micelles allow these fat products to be transported through the watery environment of the intestine to the brush border of the intestinal cells (enterocytes), where they can be absorbed.

Question 31

Effect of Bile Acids on Lipid Absorption

Answer 31

Increased Surface Area for Lipase Action: By breaking fat into smaller droplets, bile acids increase the surface area for the enzyme pancreatic lipase to act on. Lipase breaks down triglycerides into free fatty acids and monoglycerides, which are small enough to be absorbed.

Micelle Formation: Bile acids facilitate the formation of micelles, which are essential for transporting the products of lipid digestion (fatty acids, cholesterol, and fat-soluble vitamins) to the intestinal cells for absorption.

Improved Absorption of Fat-Soluble Vitamins: Bile acids are crucial for the absorption of fat-soluble vitamins (A, D, E, K). Without bile acids, these vitamins would not be efficiently absorbed, leading to potential deficiencies.

Recycling of Bile Acids: After aiding in fat digestion and absorption, most bile acids are reabsorbed in the ileum (the last part of the small intestine) and transported back to the liver in a process called enterohepatic circulation, allowing them to be reused.

Question 32

how does bile acid modification work?

Answer 32

Modified by conjugation: The formation of a link between an amino acid or other organic molecule with a waste or toxic product.

Makes the original product:
*Less toxic
*More hydrophilic
*Easier to excrete

Question 33

types of bile acids?

Answer 33

Primary:-Most toxic-Generated in the liver from cholesterol

Secondary:-Generated by oxidation reaction in the liver.

Tertiary:-Least toxic -Conjugated to glycine or taurine

Question 34

bile acids and emulsification

Answer 34

emulsification

Question 35

how many types of bile acids are there

Answer 35

there are 3, primary, secondary and tertiary

bile acids are very toxic so need to be quickly broken down once they are no longer of use

primary bile acids are the most toxic; then secondary bile acids and then tertiary are not very toxic to cells