Metabolism 9 - Integration

Question 1

What is energy intake tightly coordinated with

Answer 1

Energy expenditure

Question 2

Describe the metabolic features of muscles

Answer 2

Can have a high ATP requirement during vigorous contraction- relies upon carbohydrate and fatty acid oxidation.

Question 3

Describe the metabolic features of the brain and nervous tissue

Answer 3

continuously high ATP requirement (20% of resting metabolic rate)- cannot utilise fatty acids

Question 4

Describe the metabolic features of adipose tissue

Answer 4

Long term storage site for fatty acids in the form of triglycerides.

Question 5

Describe the metabolic features of the heart

Answer 5

10% of resting metabolic rate- can oxidise fatty acids and carbohydrates

Question 6

Describe the metabolic features of the liver

Answer 6

20% of resting metabolic rate- the body’s main carbohydrate store (glycogen) and a source of blood glucose

Question 7

What happens to the skeletal muscle during light contraction

Answer 7

ATP consumption is met by oxidative phosphorylation (O2, blood-borne glucose and fatty acids are used as fuel).

Question 8

What happens to the skeletal muscle during vigorous contraction

Answer 8

ATP consumption is faster than ATP supply by oxidative phosphorylation (O2 and blood-borne substrate diffusion is limiting). Muscle stores of glycogen are consequently broken down to produce ATP.

Question 9

What happens to the skeletal muscle in anaerobic conditions

Answer 9

Pyruvate is converted into lactate, which can leave the muscle and reach the liver via the blood.

Question 10

What is a key feature of skeletal muscle

Answer 10

It is capable of large and rapid increases in ATP demand during exercise

Question 11

What substrates can the brain metabolise

Answer 11

Ketone bodies and glucose

Question 12

What can be a consequence of hypoglycaemia

Answer 12

Faintness and coma

Question 13

What can be a consequence of hyperglycaemia

Answer 13

Coma and irreversible damage

Question 14

Why is the heart rich in mitochondria

Answer 14

The heart needs to beat constantly and hence is designed for complete aerobic metabolism. The heart utilises TCA substrates ( free fatty acids and ketone bodies).

Question 15

What are the consequences of a loss of o2 supply to the heart

Answer 15

Cell death and myocardial infarction

Energy demand&raquo_space;» supply.

Question 16

What metabolic processes does the liver participate in

Answer 16

Glycolysis, gluconeogenesis and transamination- this reflects in the high metabolic rate of the liver. It also plays a central role in maintaining blood glucose at 4.0-5.5nM. It stores glucose as glycogen, can interconvert nutrient types and plays a key role in lipoprotein metabolism ( transport of triglycerides and cholesterol).

Question 17

What does glucose need to be converted to before being stored as glycogen

Answer 17

Glucose-6-phosphate.

Question 18

What happens during fasting

Answer 18

Rather than enter the TCA cycle, much of the acetyl-coA-produced results in ketone body production.

Question 19

How can glucose 6 phosphate be used in nucleotide production

Answer 19

Via the pentose phosphate pathway in a pathway that generates the bulk of NADPH needed for anabolic pathways ( cholesterol synthesis).

Question 20

How does the body avoid hypoglycaemia (<3nM)

Answer 20

Breakdown liver stores to maintain plasma glucose levels
Release free fatty acids from adipose tissue
convert acetyl coA into ketone bodies via the liver.
Both fatty acids and ketone bodies can be respired by the muscles, making more of the plasma glucose available for the brain.

However, within 12-18hrs all the glycogen stores will be exhausted, hence the need for another pathway to generate glucose- gluconeogenesis.

Question 21

What is the purpose of gluconeogenesis

Answer 21

To produce glucose from non-carbohydrate sources (lactates, amino acids and glycerol).

Question 22

When is gluconeogenesis important

Answer 22

During intense exercise and times of starvation

Question 23

Where does gluconeogenesis occur

Answer 23

The liver (small activity in kidney cortex too)

Question 24

Is gluconeogenesis a direct reversal of glycolysis

Answer 24

No- different enzymes are needed to bypass the irreversible reactions of glycolysis

Question 25

What does gluconeogenesis require

Answer 25

An investment of ATP.

Question 26

Where does lactate enter the gluconeogenesis pathway

Answer 26

Lactate is generated by the muscle during strenuous exercise, when the rate of glycolysis exceeds the rate of the TCA cycle and the ETC. Lactate can be taken up by the liver and utilised to regenerate pyruvate by lactate dehydrogenase- cori cycle.

Question 27

Where do amino acids enter the gluconeogenesis pathway

Answer 27

Pyruvate or oxaloacetate

Question 28

Where does glycerol enter the gluconeogenesis pathway

Answer 28

Hydrolysis of triglycerides yields fatty acids and glycerol. The glycerol backbone is used to generate dihydroxyacetone phosphate- which is converted to G3P.

Question 29

Which enzymes catalyse the irreversible reactions of glycolysis

Answer 29

The kinases

Question 30

Describe the process of gluconeogenesis.

Answer 30

``` Mitochondrial matrix: Pyruvate --- oxaloacetate (pyruvate carboxylase) Cytoplasm: Oxaloacetate --- phosphoenolpyruvate (phosphoenolpyruvate carboxykinase) Phosphoeneolpyruvate --- G3P G3P -- F16BP F16BP --- F6P (F16BP phosphatase) F6P--- G6P G6P -- Glucose (G6P phosphatase) ```

Question 31

What is the purpose of the addition of 4 high energy bonds

Answer 31

To turn an energetically unfavourable process into an energetically favourable one delta G is -38kJ/mol

Question 32

What are the breakdown products of glucogenic amino acids

Answer 32

pyruvate, a-ketoglutarate, succinyl coA, fumerate and oxaloacetate

Question 33

What is meant by a glucogenic amino acids

Answer 33

An amino acids who's carbon skeleton can be used in glucogenesis to produce glucose

Question 34

What are the breakdown products of ketogenic amino acids

Answer 34

acetyl coA, acetoacetyl coA.

Question 35

What is meant by ketogenic amino acids

Answer 35

The amino acids give rise to skeletons which cannot enter gluconeogenesis but can be used for the synthesis of fatty acids and ketone bodies.

Question 36

Can fatty acids be used in gluconeogenesis

Answer 36

no- they are broken down to form acetyl coA, which can be used in the TCA cycle or used to produce ketone bodies.

Question 37

Describe what happens during aerobic respiration

Answer 37

When O2 supply is adequate- ATP demands of muscle can be met by oxidative phosphorylation, using glucose and other substrates as fuel. Glucose is transported from the blood into muscle cells where it can undergo metabolism by glycolysis and the TCA cycle to ultimately generate ATP by the re-oxidation of cofactors. As the muscle contracts, the demand for ATP increases (actomyosin ATPase, Ca2+ ATPase for cation balance). The increase demand for glucose is met by an increase in the number of glucose transporters in the membrane of muscle cells. Adrenaline plays a key role in meeting the demand for ATP by increasing the rate of gluconeogenesis by the liver and increasing the release of fatty acids from adipocytes.

Question 38

What are the effects of adrenalin on skeletal muscle contraction during aerobic respiration

Answer 38

Increases muscle glycolysis Increases gluconeogenesis Increases the release of fatty acids.

Question 39

What are the three ATPases found in muscle cells

Answer 39

Actomyosin ATPase Ca2+ ATPase Na+K+ ATPase

Question 40

What happens during anaerobic respiration

Answer 40

Under anaerobic conditions, the demands of the contracting muscle for ATP cannot be met by oxidative phosphorylation and similarly, the transport of glucose from the blood cannot keep up with the demands of glycolysis. Glycogen in the muscle is therefore broken down to meet these demands. Pyruvate is produced, which is converted into lactate, to replenish NAD+. Lactate is taken up by the liver and is converted back to pyruvate by lactate dehydrogenase. The pyruvate can be used by the liver to generate glucose by gluconeogenesis (recovery).

Question 41

What is the control of metabolic pathways typically centred around

Answer 41

Metabolic control is typically centred around reactions that are irreversible, at these points, increases in the rate of enzyme activity greatly increases the rate of the downstream steps. For the greatest steps it is desirable that these steps occur early in the pathway.

Question 42

What are the levels of metabolic control

Answer 42

Product inhibition | Under the influence of signalling molecules such as hormones.

Question 43

What concentration is blood glucose concentration usually maintained around

Answer 43

4mM

Question 44

What is the key difference between the isoforms of hexokinase found in the liver and muscle cells

Answer 44

Both isoforms catalyse the same reaction, but they are maximally active at different concentrations of glucose

Question 45

Describe the characteristics of hexokinase 1 found in muscle cells

Answer 45

Km of 0.1- active at low concentrations of glucose and is essentially working at Vmax all the time. It is also highly sensitive to inhibition by G6P. This means that under anaerobic conditions when the rate of the TCA cycle drops, glycolysis slows, Hexokinase 1 is inhibited by accumulating levels of G6P.

Question 46

Describe the characteristics of hexokinase IV found in liver cells.

Answer 46

Higher Km of 4mM- less sensitive to blood glucose concentrations. It is also less sensitive to the inhibitory effects of G6P. Liver cells also contain glucose-6-phosphatase which can catalyse the reverse reaction to hexokinase, producing glucose from G6P.

Question 47

When is insulin secreted and what is its function

Answer 47

it stimulates uptake and use of glucose and storage as glycogen and fat.

Question 48

When is glucagon secreted and what is its function

Answer 48

When blood glucose levels fall, it stimulates the production of glucose by gluconeogenesis and breakdown of glycogen and fat.

Question 49

What are the effects of adrenalin (epinephrine)

Answer 49

strong and fast metabolic effects to metabolise glucose for flight or fight.

Question 50

What are the effects of glucocorticoids

Answer 50

steroid hormone which increases synthesis of metabolic enzymes concerned with glucose availability.

Question 51

Where is adrenalin and glucocorticoids secreted from

Answer 51

The adrenal medulla.

Question 52

What happens when blood glucose levels increase after eating a meal

Answer 52

High glucose stimulates insulin release from the pancreas. Increases glucose uptake by liver- glycogenesis, glycolysis (to produce acetyl coA for FA synthesis). Increased glucose uptake ang glycogenesis in muscle Increased triglyceride synthesis in adipocytes Increased usage of metabolic intermediates throughout the body to a stimulatory effect on anabolic pathways.

Question 53

What happens when blood glucose levels start to fall after eating a meal.

Answer 53

Increased glucagon secretion from the islets. Glucose production in liver from glycogenolysis and gluconeogenesis utilisation of fatty acid respiration as alternative substrate for ATP production ( important in preserving glucose for the brain). Adrenaline has similar effects on the liver, but also stimulates skeletal muscle towards glycogen breakdown and glycolysis, and adipose tissue towards fat lipolysis to provide other tissues with alternative substrates to glucose.

Question 54

What happens after prolonged fasting (longer than can be covered by glycogen reserves)

Answer 54

Glucagon/Insulin ratio increases further Adipose tissue begins to hydrolyse triglyceride to provide FAs for metabolism TCA cycle intermediates are reduced in amount to provide substrates for gluconeogenesis Protein breakdown provides amino acid substrates for gluconeogenesis ketone bodies are produced from fatty and amino acids in liver to substitute partially for brain's requirement for glucose.

Question 55

What is diabetes mellitus

Answer 55

A disorder of insulin release and signalling, resulting in an impaired ability to regulate blood glucose concentrations. The overall effects is that metabolism is controlled as if the person is undergoing starvation, regardless of dietary glucose intake.

Question 56

Distinguish between the two types of diabetes mellitus

Answer 56

Type 1- individuals fail to secrete enough insulin- beta cell dysfunction Type 2- individuals respond inappropriately to insulin levels (insulin resistance)

Question 57

What are the complication of diabetes

Answer 57

Hyperglycaemia with progressive tissue damage (retina, kidney, peripheral nerves). Increase in plasma fatty acids and lipoprotein levels with possible cardiovascular complications Increase in ketone bodies with risk of acidosis. Hypoglycaemia with consequent coma if insulin dosage is imperfectly controlled

Question 58

Why is glucagon important in protecting against hypoglycaemia

Answer 58

Major site of action is liver where glucagon stimulates gluconeogenesis and glycogenolysis. Insulin deficiency and relative excess of glucagon leads to increased hepatic output of glucose, and thus, hyperglycaemia.

Question 59

How does a cell decide to synthesis glucose or degrade it

Answer 59

Phosphofructokinase is allosterically regulated by the binding of a variety of metabolites, which provide both positive and negative feedback regulation. The enzyme is activated by byproducts of ATP hydrolysis, including ADP, AMP and Pi, and is inhibited by ATP. Thus when ATP is depleted and its metabolic byproducts accumulate, phosphofructokinase is turned on and glycolysis proceeds to generate ATP. The enzymes that catalyses the reverse reaction, Fructose,1,6- bisphosphatase is regulated by the same molecules but in the opposite direction. Thus is activated when phosphofructokinase is turned off.

Question 60

Describe the energetic costs of the reactions in gluconeogenesis

Answer 60

Production of a single molecule of glucose consumes 4 molecules of ATP and 2 molecules of GTP. Thus a cell must tightly regulate the balance between glycolysis and gluconeogenesis. If both processes were to proceed simultaneously, they would shuttle metabolites back and forth in a futile cycle that would consume large amounts of energy and generate heat for no purpose.