BIOC3006 - MOD1 - Converting Nutrients to Energy

What factors influence metabolism?

• Diet

• Activity levels

• Disease

• Body composition

• Microbiome

• Age

• Genetics

Why do we need to eat?

Because animals are heterotrophs. We obtain organic nutrients from plants and other animals for:

• Growth

• Structure - maintenance and reproduction

• Energy

BMI calculation

BMI = weight (kgs) / height (m²)

E.g. a person who weighs 50 kg and is 140 cm

BMI = 50/1.4²

What are risk factors for overweight/obesity?

• Coronary heart disease

• Cancer (breast, prostate, colon, uterine)

• Stroke

• Arthritis

• Gallbladder disease

• Sleep apnea

• Respiratory problems

• Metabolic syndrome (hypertension, diabetes mellitus, high cholesterol)

Characteristics of the metabolic syndrome

• Atherogenic dyslipidemia

  • A blood lipid profile characterised by high TAGs, low HDL, and high LDL. 

• Elevated blood pressure

• Elevated plasma glucose

• Pro-thrombic state 

  • Blood has increased tendency to form clots. 

• Pro-inflammatory state

Smaller babies have a higher adult risk of what?

• Hypertension

• Altered plasma lipids

• Raise plasma fibrinogen (blood clotting) and C-reactive protein (CRP) (inflammation)

  • Biomarkers of systemic inflammation and cardiovascular risk.

• Impaired glucose tolerance, type 2 diabetes, and central obesity

• Endothelial dysfunction

What are common claims of high protein diets?

• Lose weight quickly

• Decreased appetite

• Reverses insulin resistance

• Mitigates effects of high carb intake:

  • Increased appetite

  • Addiction to sugar - high BGLs

  • Increased body fat

What is the atkins diet?

A low carb, high protein, high fat diet.

Focuses on restricting carb intake to promote weight loss and improve health conditions. 

Does the atkins diet work?

It is the low calories part of the diet that causes weight loss, not the high protein. 

• Rapid weight loss experienced is water weight. 

Long term usage of this diet could lead to health problems. 

Results are temporary. 

What are the dangers of the atkins diet?

High saturated fat and cholesterol - can lead to CVD.

High protein - can lead to decline in renal function, urinary calcium losses → osteoporosis. 

Lack of fibre - increases colon cancer risk

Avoidance of carbs - decreased intake of essential vitamins and antioxidant phytochemicals. 

Enzymatic digestion of carbs in the small intestine

Starch is broken down into disaccharides by pancreatic amylase. 

Disaccharides are broken down into monosaccharides by their specific enzymes:

• Maltose → 2 x glucose (by maltase)

• Sucrose → glucose + fructose (by sucrase)

• Lactose → glucose + galactose (by lactase)

Enzymatic digestion of proteins in the small intestine

Polypeptides are broken down into smaller polypeptides by trypsin and chymotrypsin.

Smaller polypeptides and dipeptides are broken down into amino acids by:

• Aminopeptidase

• Carboxypeptidase

• Dipeptidase

Enzymatic digestion of nucleic acids in the small intestine

DNA and RNA are broken down into nucleotides by nucleases.

Nucleotides are broken down into nitrogenous bases, sugars, and phosphates by other enzymes. 

Enzymatic digestion of fats in the small intestine

Fats are emulsified (broken down) into fat droplets by bile salts.

Fat droplets are broken down into fatty acids and glycerol by lipase.

How is sugar transported into enterocytes? 

GLUT5 transports fructose across the apical membrane into the enterocyte via facilitated diffusion.

Na+/K+-ATPase hydrolyses ATP to transport Na+ out of the cell and bring K+ into the cell.

• This generates energy for SGLT1.

SGLT1 co-transports glucose and galactose into the enterocyte with Na+

How is protein digested in the small intestine?

1. Large proteins → small proteins and polypeptides (by pepsin and HCl)

2. Small proteins and polypeptides → polypeptides, tripeptides, dipeptides and AAs (by pancreatic pancreases

3. PPs, TPs, DPs, and AAs → TPs, DPs, AAs (by peptidases)

4. AAs are transported into the enterocyte/mucosal cell. 

What are micelles? How are they formed?

Bile acid salts solubilise lipids as micelles. 

A simple micelle is formed from 4 bile salts. 

They form when amphiphilic molecules (hydrophilic head and hydrophobic tail) aggregate in an aqueous environment. 

What are lipoproteins made up of?

• Phospholipids

• Free cholesterol

• Cholesterol ester

• Triglycerides

What are the causes of malabsorption?

• Reduced retention time 

  • Diarrhoea

• Reduced surface area

• Deficiency in digestive secretions

  • Enzymes

  • Bile salts

What is coeliac disease?

An autoimmune disease wherein transglutaminase modifies prolamin proteins which are found in gluten. This causes an inflammatory response in the GIT. 

Coeliac disease causes villus atrophy:

• Reduced surface area - causes malabsorption

• Reduced surface-bound enzymes (e.g. lactase)

It is treated by diet modification - gluten free diet.

What is an Exocrine Pancreatic Insufficiency?

Pancreatic dysfunction - a lack of digestive enzymes. 

Maldigestion (due to no digestive enzymes) leads to malabsorption. 

Causes:

• Cystic fibrosis

• Pancreatitis 

• Diabetes mellitis

What is substrate-level phosphorylation?

When ATP is synthesised as part of a single enzymatic reaction.

E.g. removing the phosphate group from phosphoenol pyruvate which can then be added to ADP to form ATP.

What is oxidative phosphorylation?

The moving of electrons from one entity to another yields energy.

REDOX

This is how energy is harvested in the ETC.

What does it mean if a transporter has a low K_M value?

Able to transport glucose at lower glucose concentrations. 

What does it mean if a transporter has a high K_M value?

Only transports glucose at (very) high glucose concentrations. 

Features of GLUT3

One of the main glucose transporters in the body. 

Able to transport glucose at low concentrations. 

K_M = 1.4 mmol/L

Features of GLUT1

One of the main glucose transporters in the body. 

Able to transport glucose at low concentrations. 

K_M = 3 mmol/L

Features of GLUT4

A particular transporter that exists inside vesicles within the cell. 

It remains floating in the cell (not transporting) until there is a large insulin signal. When this occurs, the vesicles come together and fuse with the plasma membrane, and starts transporting glucose. 

Present in insulin responsive tissues (skeletal muscle, cardiac muscle, adipose tissue).

Skeletal muscle is a good store of glycogen. Thus, when BGLs raise, we can enhance uptake of glucose to lower BGLs by fusing GLUT4 to the membrane. 

K_M = 5 mmol/L

• Humans maintain a BGL of ~ 5 mmol/L

Features of GLUT2

Primarily present in the pancreas - this is bc the pancreas is the body’s primary glucose monitor. 

• Also present in liver and enterocytes

K_M = 17 mmol/L

Bc there are primarily GLUT2 transporters in the pancreas, it knows that when GLUT2 are activated and transporting glucose that BGLs are too high. 

How do we maintain an ‘in gradient’ of glucose into the cell? 

Glucose transporters into the cell have a specificity for glucose, not glucose-6-phosphate. Hence, if we convert lots of glucose into G6P, it will no longer contribute to the gradient, maintaining the ‘in gradient’ rather than an ‘out gradient’. 

Intracellular regulation of glucose in the liver

We are primarily concerned with coordinating responses with gluconeogenesis.

If we have really efficient hexokinase IV (aka glucokinase), it will rapidly convert glucose → G6P, forcing it down the glycolytic pathway. 

However, if we are wanting to promote gluconeogenesis, this is counter-productive. 

Therefore, we do not want very efficient hexokinase so that glucose can accumulate within the cell. 

So, in situations where we have low BGLs, we will see a net movement of glucose out of the cell (lots of glucose inside cell) and into the bloodstream (not a lot of glucose). 

Intracellular regulation of glucose in the pancreas

We are primarily interested in glycolysis being a signal for the release of insulin. 

The main purpose of pancreatic B-cells is to release insulin when BGLs are high. However, it is very important that they only do so when BGLs are high (not when they’re low). 

• The trigger for the release of insulin is whether or not glycolysis is running quickly or not. 

Glycolysis is controlled via 2 main mechanisms:

1. GLUT2 only allows glucose into cells (pancreas) when BGLs are very high. 

2. Hexokinase only allows glycolysis to occur when glucose accumulates in the cell. 

These 2 mechanisms ensure that for a pancreatic B-cell, flux through glycolysis is quite small unless BGLs are high. 

How can we control where hexokinase is located within the cell?

We can control whether hexokinase is located:

1. In the cytosol (where it can see the glucose its trying to work with)

2. Sequestered in the nucleus (distant from the glucose its working with)

This is determined by:

1. An accumulation of glucose will stimulate glucose to be located in the cytosol.

   1. Glucose accumulates when there is flux through glycolysis.

2. An accumulation of fructose-6-phosphate will stimulate glucose to be sequestered in the nucleus. 

   1. Fructose accumulates when glycolysis is inhibited / there is increased flux through gluconeogenesis.

What is the fate of pyruvate when we have adequate oxygen?

Pyruvate is converted to acetyl-coA. 

• This acetyl-coA is then passed onto the TCA cycle. 

What is the fate of pyruvate when we have inadequate oxygen?

Converted to lactate

• Lactate dehydrogenase is bidirectional and regulates pyruvate ↔ lactate.

• When we convert P→ L, we also oxidise NAH → NAD+

  • Thus, if we just have lots of P, it will impede upon the availability of NAD+ in the cytosol - we won’t be able to yield ATP. 

What is the Pentose Phosphate pathway?

A metabolic pathway that runs parallel to glycolysis. 

Its primary purpose it to synthesise:

• Ribose-5-phosphate

• NADPH

• Nucleotides, coenzymes, DNA, RNA

The pathway is controlled via negative feedback. 

• If we have an adequate amount of NADPH, we will not excessively consume G6P. 

How is the flux through glycolysis vs gluconeogenesis determined?

Insulin:glucagon ratio.

Relative enzymatic activity controls flux:

• Phosphofructokinase-1 controls (promotes) glycolysis

• Fructose-1,6-bisphosphate-1 controls (promotes) gluconeogenesis

What is fructose-2,6-bisphosphate? What is its role in glycolysis/gluconeogenesis?

F-2,6-BP is an allosteric inhibitor/stimulator of glycolysis/gluconeogenesis. 

Relative levels of F-2,6-BP are determined by hormonal inputs to the cell. 

1. High levels of F-2,6-BP - glycolytic cell (undergoes more glycolysis than gluconeogenesis). 

2. Low levels of F-2,6-BP - gluconeogenic cell (undergoes more gluconeogenesis than glycolysis). 

How do insulin and glucagon influence phosphorylation and dephosphorylation?

Insulin drives phosphorylation

Glucagon drives dephosphorylation

What is the primary consequence in a deficiency of one/any of the intermediates of glycolysis?

Haemolytic anaemia

How does do muscle and liver differ in terms of being glycogen stores?

Glycogen in the liver is very useful for the rest of the body. 

Glycogen in the muscle is not useful for the rest of the body. 

• This is bc once muscle make glycogen, it keep it. 

• The muscle only uses glycogen from its own store, thus, it doesn’t take glycogen from elsewhere, allowing the rest of the body to use the other stores. 

• Muscles can break and create glycogen, however, it cannot provide glycogen back to the bloodstream, thus just keeps it for itself. 

What is the difference between connecting glucose molecules with 1,4 vs 1,6 linkages. 

1,4 linkages makes a nice long string. 

1,6 linkages makes a branched arrangement. 

What affect does glycogen phosphorylase have on glycogen?

Glycogen phosphorylase attacks the non-reducing ends of glycogen, breaking it down into glucose. 

• If we have high demand for lots of glucose, if we have lots of glycogen phosphorylase, we will be able to produce a large amount of glucose to meet that demand. 

What are the fates of glucose-6-phosphate

1. Down the glycolytic pathway (to produce pyruvate)

2. Conversion to become glycogen

3. Back to the liver

4. Stolen by the Pentose Phosphate Pathway

How do we control (synthesis/breakdown of) glycogen stores?

1. Altering activity of:

   1. Glycogen phosphorylase (promotes breakdown)

      1. Form B is active and phosphorylated

   2. Glycogen synthase (promotes synthesis)

      1. Form A is active and dephosphorylated

2. Hormonal signals

   1. Insulin (promotes synthesis)

   2. Glucagon (promotes breakdown)

What does C18:1:ω9 mean?

A fatty acid with:

• 18 carbons

• 1 double bond

• 9 carbons from the end is where you’ll find the double bond. 

What is acetyl-coA carboxylase (ACC)?

An enzyme that is critical for:

1. The formation of fatty acids

2. The control of fatty acid synthesis.

Insulin and glucagon exert their influence on ACC. 

What is malonyl-coA?

A key intermediate for fatty acid synthesis.

Also functions as an inhibitor of fatty acid oxidation.

It regulates whether a cell creates new fats or breaks down existing ones for energy. 

High levels indicate that the body is storing fat. 

Low levels indicate that the body needs to burn fat for fuel.