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Introduction to Biochemistry > Metabolism and Lipids > Flashcards

Metabolism and Lipids Flashcards

ML Bellamy lectures 27-36

1
Q

Describe the structure of glycogen.

A

A helical branched polymer of α glucose made of a main chain of 1-4 and branches of 1-6.

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2
Q

How does glycogen store stuff?

A

Granules.

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3
Q

What are the three main steps of glycogenolysis?

A

Glycogen → (via Glycogen phosphorylase) G-1-P → (Via Phosphoglucomutase) G6P → Glycolysis occurs.

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4
Q

What do phosphorylases do?

A

Make or break bonds using Pi.

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5
Q

Why are phosphorylases used?

A

They do not use ATP which is a limited coenzyme.

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6
Q

What is special about the phosphorylase active site?

A

There is a deep cleft to the active site, which is a PLP (Pyridoxal phosphate) prosthetic group.

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7
Q

How does glycogen phosphorylase work?

A
  1. Hydrogen bond is broken
  2. Unstable intermediate produced, which is positive and attracted to negative Pi.
  3. Glucose 1 P is formed.
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8
Q

What is a processive enzyme and an example?

A

When an enzyme can have multiple reactions very close together. For example phosphorylase mobilises glucose very quickly.

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9
Q

What can phosphorylase not do?

A
  • Break 1-6 bonds
  • Break 1-4 bonds within 4 units of branch point
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10
Q

What is a limit dextrin?

A

A glucose that has been digested as much as it can have been by an enzyme, but not completely.

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11
Q

How is glycogen broken down further from limit dextrin (4 glycosyl units)?

A
  1. Debranching enzyme (Transferase) transfer 3 glycosyl units to the core of the molecule, shrinking the branch.
  2. This makes them available to phosphorylase to break up.
  3. α-1,6-Glucosidase hydrolyses the single glucose unit left into free glucose, releasing H₂O in the process.
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12
Q

How is G1P transformed into G6P?

A
  1. G1P goes into active site, P leaves serine and attaches to 6th carbon (two P on glucose)
  2. P is put back on serine, leaves carbon 1.
  3. It is now G6P. Tah dah. Leaves active site.
    - No ATP needed (reversible)
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13
Q

What happens to muscle glycogen?

A

It goes through glycolysis and then into ATP.

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14
Q

What happens to liver glycogen?

A

It goes through glucogenesis and then increases blood glucose.

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15
Q

Describe how G6P is turned into glucose.

(last step of glycogenolysis)

A
  1. G6P comes into the membrane.
  2. Glucose 6-Phosphatase (only found in liver) turns this into free glucose and Pi.
  3. They move out of the liver membrane into the blood.
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16
Q

What happens when we have too much glucose?

A

It gets converted into glycogen.

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17
Q

Why is the process of Glycogenolysis not reversed? What shows this?

A

Because the reactant (Pi) has so much more of a high concentration than G1P. McArdle’s disease shows this.

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18
Q

How is glucose turned into glycogen?

A
  1. Glucose → G1P via phosphoglucomutase.
  2. G1P → UDP Glucose producing UTP→PPi→2Pi via UDP glucose Pyrophosphorylase.
    This glucose is now activated.
  3. UDP Glucose → Glycogen via glycogen synthase.
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19
Q

How does glycogen synthase work?

A

UDP and proton is released, and is added onto the end of an existing chain. It bonds via a α 1-4 bond.

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20
Q

What are the two steps of initiation and branch synthesis of glycogenolysis?

A
  1. Glycogenin
  2. Branching enzyme
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21
Q

How does Glycogenin work?

A
  1. Builds initial 8 unit primer chain
  2. Primer extended by Glycogen Synthase
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22
Q

How does the branching enzyme of glycogenolysis work?

A
  1. Binds to chains 11+ units long
  2. Cuts off a heptamer of glucose units and reattaches heptamer via α1-6 bond (via glycosyltransferase)
    - Reattachment site is less than 4 units from the existing branch.
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23
Q

What are lipids?

A

Hydrophobic molecules.

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24
Q

What is the difference between a fat and an oil?

A

A fat is solid at room temperature, an oil is liquid at room temperature due to unsaturated bonds.

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25
Q

Describe the basic structure of a triglyceride.

A
  • 3 fatty acids linked to a glycerol backbone
  • Long chain of hydrocarbons (12-24C)
  • 0 or more double bonds (mono/polyunsaturated)
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26
Q

What sits at each side of the hydrocarbons in a triglyceride?

A

A methyl group (CH₃) and a COOH group.

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27
Q

What are the differences between cis and trans fats?

A

Cis - Have a bend in it caused by double bonds. Can be polycis (polyunsaturated)
Trans - No double bonds, a straight lipid.

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28
Q

What are the 3 naming systems for lipids?

A

Common
Systematic
Omega / n

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29
Q

Describe the systematic naming system. What could we learn about the lipid from the name ‘Cis-Δ⁹-Octadecenoic acid’?

A
  • Shows if it is cis/trans, the carbon the double bond is on and the name of the lipid.
    This measures from the COO- group being 1.
    So we know this is: A cis protein with a double bond on the 9th carbon, of which there are 18 (octadecene).
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30
Q

Describe the omega naming system. What could we learn about the lipid from the name ‘C18:1(n-9)’?

A
  • Shows the number of carbons, number of single and double bonds, and which carbon the double bond is on.
    In this system, the methyl group is counted as 1 rather than COO-.
    So we know this is: A lipid of 18 carbons with one double bond on carbon 9.
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31
Q

What are the two main enzyme groups we use to alter fatty acids?

A

Elongases: Elongate by two C
Desaturases: Add double bonds

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32
Q

Why do we alter fatty acids?

A
  • Fatty acid length alters bilayer thickness
  • Degree of unsaturation alters membrane fluidity
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33
Q

How are fatty acids digested?

A
  1. Digested by pancreatic lipase that hydrolyses 1 or 3 ester bonds between monoacylglycerol and free fatty acids.
  2. Crosses membrane into intestinal cells
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34
Q

What is the first step of triglyceride absorption?

A
  • FA is activated first using CoA
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35
Q

What is the second step of triglyceride absorption?

A

They are re-esterised in gut mucosa via acyl transferases to produce 2CoA-SH.

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36
Q

Why are triglycerides packed into lipoproteins?

A

They are too hydrophobic to pass through tissues on their own.

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37
Q

What is a lipoprotein?

A
  • Phospholipid and cholesterol outer layer
  • Triglyceride and cholesterol core
  • Includes chylomicrons (used for transport from gut to tissues)
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38
Q

How are lipoproteins taken up into the adipose tissue?

A
  1. Endothelial cells cleaves off fatty acids from lipoproteins. This is done via lipoprotein lipase, attached on the lumenal side of the endothelial cells.
  2. When chylomicron has offloaded most of the triglycerides, it is now known as a remnant. It is removed by the blood.
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39
Q

What are the starting molecules of lipogenesis?

A

G3P and 3x activated FA.

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40
Q

Where does the G3P in lipogenesis come from?

A

DHAP in glycolysis. This reaction goes both ways, producing NAD+ when making G3P or NADH+ + H+ when making DHAP.

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41
Q

How is the first fatty acid added in lipogenesis?

A

Via G3P acyltransferase to form lysophosphatidic acid. This makes it available for the second FA to attach.

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42
Q

How is the second fatty acid attached in lipogenesis?

A

Via 1-acyl-3-P acyltransferase to make phosphatidic acid.

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43
Q

What is phosphatidic acid and how is it modified in lipogenesis?

A

It is the most basic phospholipid. The phosphate is removed via phosphatidic acid phosphatase, making diacylglycerol.

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44
Q

How is the 3rd and final fatty acid added in lipogenesis?

A

Diacylglycerol has the final FA added to it via diacylglycerol acyltransferase.

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45
Q

Why do we metabolise fatty acids?

A
  1. They contain over double the energy that a glucose molecule can hold.
  2. Form dense energy stores as. Glucose needs 2x its mass in water, triglycerides do not.
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46
Q

Where are fatty acids stored?

A

Adipose tissue.

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47
Q

How are fatty acids accessed?

A
  1. Stored in a phosphorylated perilipin shell.
  2. TG binds to membrane protein, a fatty acid is removed and it leaves a free fatty acid.
  3. TG hydrolyses another FA leaving diacylglycerol, monoglycerol and then a glycerol with 3 FAs.
  4. FA’s bind to human serum albumin into the blood from high to low concentration.
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48
Q

What are the enzymes involved in fatty acids being accessed?

A

Step 2: Adipose TG lipase
Step 3: Human Sensitive HSL (to make a diacylglycerol) and monoglyceride lipase (to form a monoglycerol)

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49
Q

How do fatty acids move into cells?

A

Human Serum Albumin releases the fatty acids and travels to the outer membrane of the mitochondria, where they are activated.

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50
Q

What is the simple equation for fatty acid activation?

A

Fatty acid + CoA = Acyl CoA.

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51
Q

What provides the free energy for fatty acid activation?

A

The hydrolysis of pyrophosphate. .

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52
Q

Where is ATP used in fatty acid activation?

A
  1. Acyl CoA synthetase
  2. Conversion of AMP to ADP
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53
Q

How do fatty aids enter the mitochondria?

A
  1. Acyl CoA can cross outer mitochondrial membrane
  2. CoA swapped for carnitine to cross inner mitochondrial membrane.
  3. Acyl-Carnitine transported across the bilayer by a translocase antiporter.
  4. Acyl reattached to CoA in matrix.
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54
Q

What happens to Acyl CoA in the mitochondria?

A
  • 2C at a time removed from Acyl CoAs as these are acetyl CoA molecules.
  • First cleavage is next to β carbon.
  • Fed into the TCA cycle.
    Known as β Oxidation.
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55
Q

Describe step 1 of β Oxidation.

A
  • Acyl CoA → trans-Δ²-Enoyl CoA
  • In this process, FAD is oxidised into FADH₂ (via dehydrogenase)
  • Hydrogen is fed into the electron transport chain from here
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56
Q

Describe step 2 of β Oxidation.

A
  • Water is added → trans-Δ²-Enoyl CoA to make L-3-Hydrocyacyl CoA, via hydratase.
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57
Q

Describe step 3 of β Oxidation.

A
  • L-3-Hydroxyacyl CoA → 3-Ketoacyl CoA via dehydrogenase.
  • This time only of the β carbon to make another double bonded oxygen.
  • NAD+ → H+NADH
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58
Q

Describe step 4 of β Oxidation.

A
  • 3-Ketoacyl CoA → Acyl CoA + Acetyl CoA
  • Via thiolase, as thiolysis occurs.
  • Sulfur becomes attached to a carbon and releases it.
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59
Q

What is thiolysis?

A

The splitting of a bond using sulfur.

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60
Q

What does each cycle of β Oxidation produce?

A

1 Acetyl CoA
1 NADH
1 FADH₂
Final cleavage yields 2x Acetyl CoA.

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61
Q

What changes if a different amino acid is being catabolised?

A
  • The process repeats if the chain is longer.
  • Additional isomerase enzymes are needed to convert double bonds into trans double bonds so they can be catabolised.
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62
Q

What is the role of a ketone body?

A
  • Under conditions of fasting/starvation, triglyceride hydrolysis and free fatty acid levels rise.
  • Ketone bodies are made, then Acetyl CoA builds up beyond the liver’s capacity.
  • They’re released into the blood and used as fuel
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63
Q

Why does the heart prefer using ketone bodies as fuel?

A

They require little conversion to enter the TCA cycle.

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64
Q

Describe ketogenesis overall.

A
  1. 3 Acetyl CoA’s are joined, a reversal of β oxidation step 4.
  2. Acetyl CoA is cleaved off
  3. Acetoacetate is the ketone body released into the blood
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65
Q

If acetoacetate is not released into the blood, which ketone body is?

A
  • Acetoacetate is converted into D-β -hydroxybutyrate via an oxidation reaction (gaining NAD+). D-β-Hydroxybutyrate is released.
  • OR it is converted into acetone, losing Co2.
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66
Q

Why is an acetone conversion unwanted?

A
  1. the conversion uses a Co2 that could otherwise be used to make more energy
  2. Acetone is toxic and lost as sweat/urine etc and not used as fuel.
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67
Q

What happens to the ketone when it arrives where it is needed?

A
  1. If not already, it is converted into acetoacetate.
  2. Then reacts with succinyl CoA to make an activated mini fatty acid
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68
Q

How are the processes of fatty acid metabolism mirrored?

A

For degradation and synthesis:
- Oxidation is mirrored by reduction
- Hydration is mirrored by dehydration
- Cleavage is mirrored by condensation

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69
Q

What are the two main differences between FA anabolism and catabolism?

A

In anabolism:
- Use of NADPH/NADP+ rather than NAD+/NADH
- Use of malonyl CoA rather than Acetyl CoA as a basic unit

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70
Q

How long is the process of fatty acid breakdown or synthesis?

A

7 cycles, as 2 double bonds are worked on at a time.

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71
Q

How is malonyl CoA created?

A

Acetyl CoA + ATP + HCO₃⁻ → Malonyl CoA +ADP + Pi + H⁺
- Uses the enzyme acetyl CoA carboxylase, which is very regulated as this reaction is irreversible

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72
Q

What stimulates and inhibits acetyl CoA carboxylase?

A

Stimulation: Citrate + insulin
Inhibition: Palmitic acid (the final product of this process) + glucagon + adrenaline

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73
Q

When should acetyl CoA carboxylase needed?

A

When the cell has lots of spare acetyl CoA. It should not be activated when the cell is in a starvation state with little acetyl CoA.

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74
Q

What enzyme joins all of the malonyl CoA?

A

Fatty acid synthase

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75
Q

Why does a fatty acid start with a 3C?

A

3C + 2C → 4C + 1C
The release of the 1C drives this reaction. Since That means we need 5C in the end to create a 4C fatty acid, we start with 3C and add 2.

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76
Q

Where is fatty acid synthase and acetyl CoA Carboxylase stored? Why is this a problem?

A

The cytoplasm. This is a problem because acetyl CoA is stored in the matrix of the mitochondria.

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77
Q

How does acetyl CoA travel into the cytoplasm to reach FAS And acetyl CoA carboxylase?

A
  1. Acetyl CoA + OAA → Citrate
  2. Citrate travels through membrane
  3. Citrate splits into Acetyl CoA and OAA again
78
Q

What happens to Acetyl CoA and OAA in the cytoplasm?

A
  1. Acetyl CoA now available to be turned into malonyl CoA
  2. OAA turns into malate (oxidation of NADH) and that into pyruvate (reduction of NADP+) and produces Co2.
  3. Pyruvate then travels back across the membrane into OAA again.
79
Q

When is ATP used in the export of Acetyl CoA into the cytoplasm? Why is this not a problem for energy production?

A
  1. When citrate is turned into Acetyl CoA and OAA in the cytoplasm
  2. When pyruvate is turned back into OAA in the matrix.
80
Q

What is the basic structure of fatty acid synthase?

A

6 enzymes evolved to be connected together, with an Acyl Carrier Protein (ACP) in the middle of them.
- This is a flexible arm to transfer substrates to each active site

81
Q

What and how is the first step of fatty acid synthesis completed?

A
  • Joining of activated acyl and malonyl group (2C and 3C)
82
Q

What are the steps of this process?

A
  1. Acetyl group transferred to KS (one of the active sites on FAS) via ACP and MAT
  2. Malonyl is transferred onto ACP by MAT
  3. KS joins the acetyl and malonyl, losing a CO2 (driving the process)
83
Q

Describe the basic bonds of fatty acid anabolism.

A
  1. C-C bond
  2. C=O to CHOH (+2H reduction, KR site on FAS)
  3. C-C to C=C (Dehydration, DH site on FAS)
  4. CH to CH₂ (+2H reduction, ER site on FAS)
84
Q

How is a fatty acid elongated?

A
  1. 4C is transferred back to KS to start step 1
  2. Cycle is repeated until palmitic acid (16C) is made
  3. This is then released by thioesterase
85
Q

What happens to fatty acids when the body is in an anabolic state?

A

New FA will be converted to triglycerides and stored.
- If synthesised in the liver lipoproteins are used to export TG to adipose/other tissues

86
Q

What are the different types of lipoproteins?

A
  1. Chylomicrons
    Very low, Intermediate, Low and High Density Lipoprotein
87
Q

How can you find out the density of a lipoprotein? Are the larger ones more or less dense?

A

Centrifugation - the higher the density, the lower the lipoprotein will settle out.
The lower the density, the larger the lipoprotein.

88
Q

Why are there so many densities of lipoproteins?

A

It is a flow of sizes. They are the same molecule but just change in size and therefore density as they offload cargo. A LDL is just a VLDL that has offloaded almost all of its cargo.

89
Q

Which of the types of lipoproteins is unlike the others? Why?

A

High density lipoproteins are not a part of the flow of sizes. They are produced in a different part of the body with a different purpose.

90
Q

What four main things does a lipoprotein carry?

A
  1. Triglycerides
  2. Phospholipids
  3. Cholesterol
  4. Apoproteins
91
Q

What does a Very Low Density Lipoprotein carry?

A

Mostly triglycerides. Small quantities of everything else.

92
Q

What does an Intermediate Density Lipoprotein carry?

A

Mostly Triglycerides.

93
Q

What does a Low Density Lipoprotein carry?

A

Mostly cholesterol (‘bad cholesterol’)

94
Q

What does a High Density Lipoprotein carry?

A

Mostly Apoproteins, but it takes cholesterol back to the liver.

95
Q

What is the lifespan of each lipoprotein?

A

HDL: 3 - 6 days (longest)
LDL: 3 days
IDL: Minutes - Hours
VLDL: Minutes - Hours
Chylomicrons: Shortest (5 mins)

96
Q

What happens when there is a heterozygous defect in the LDR-R gene?

A

Familial Hypercholesterolaemia leading to Coronary Atherosclerosis.
- 50% reduction in LDL-R
- Double normal plasma LDL (2.5-5k)
- 1 in 2 chance of myocardial infarction by 50

97
Q

What happens when there is a homozygous defect in the LDL-R gene?

A

Familial Hypercholesterolaemia leading to Coronary Atherosclerosis.
- No LDL-R at all
- Even higher plasma LDL (Over 6k)
- High chance of death before age 20

98
Q

Describe the cycle of nitrogen balance.

A

From the amino acid pool:
- 250-300g of protein is synthesised and degraded every day.
- 100g of amino acids are introduced from diet and broken down a day.
Leads to a balance of amino acids (unless you eat a lot more protein)

99
Q

What are the three destinations for Amino Acids in the pool?

A
  1. Protein synthesis
  2. Direct use/minor modification
  3. Breakdown and redeployment
100
Q

What are the possible destinations for broken down amino acids?

A
  1. Ammonia/NH₃ (toxic)
  2. Carbon skeleton → Co2/H2O (Energy Production) OR biosynthesis (purines etc)
  3. Breakdown into urea
101
Q

Describe how amino acids are broken down.

A

Amino Acid → α-Ketoglutarate → Glutamate (Transamination) → Ammonia (Deamination) → Urea

102
Q

What is the function of an aminotransferase?

A

To transfer an amino acid into something that can be used for energy production. Examples:
Asp → OAA
Ala → Pyruvate

103
Q

How does an aminotransferase work?

A

Using a vitamin B6 derived prosthetic group called Pyridoxal phosphate.
1. PLP attaches to enzyme, alongside amino acid.
2. Hydrolysis of carbon skeleton from enzyme. Now called PMP.
3. α-Ketoglutarate comes in, condensation reaction removes water from the molecule. Now a single bond nitrogen like before.
4. Re-arrangement of molecule, α-Ketoglutarate and NH₂ leave the enzyme. Back to PLP.

104
Q

How is Glutamate + H2O transformed into α-ketoglutarate?

A

A reaction in which NH₄⁺ is produced, as well as NADH from NAD⁺ via glutamate dehydrogenase.

105
Q

What activates and inhibits this reaction?

A

Inhibits: GTP
Activates: ADP

106
Q

What is the cost of producing 1 urea?

A

1 CO2
1 H₂O
1 NH₄
1 NH₂ (Aspartate)
4 ATP.

107
Q

What is the function of Extra-Hepatic tissues?

A

They catabolise Amino acids to NH₃ (ammonia)
- Cant make urea

108
Q

How and where is amino acid catabolised into NH₃ (Ammonia) ?

A
  1. (Extra Hepatic tissues) α-Ketoglutarate + NH₃ → Glutamate (Glu)
  2. Glutamate + Ammonia → Glutamine (Gln)
  3. In the kidney, Gln is deaminated back into Glu to release NH₃ into the urine for acid neutralisation
109
Q

How is sulphur disposed of in methionine?

A

Just turned into Cys which is why Cys isn’t an essential amino acid. This reaction also produces Succinyl CoA.

110
Q

How is sulphur disposed of in cysteine?

A

Cysteine → Pyruvate because cysteine has the carbon skeleton of pyruvate.

111
Q

What is the first pathway of cysteine conversion into pyruvate?

A
  1. Cys → Cysteinesulphinate
    - Produces H₂O from O₂ and NADP⁺ from NADPH
  2. Cysteinesulphinate → β-sulphinylpyruvate (deamination reaction)
  3. β-sulphinylpyruvate → Pyruvate , losing all of its sulphur in the process (goes into urine)
112
Q

What is the second pathway of cysteine conversion into pyruvate?

A
  1. Cys → β-mercaptopyruvate (deamination reaction)
  2. β-mercaptopyruvate → Pyruvate, losing its sulphur (H₂S) in the process. Goes into urine.
113
Q

What amino acids can we not synthesise?

A

The essential amino acids (histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine)
We gotta eat these

114
Q

How are purines biosynthesised?

A

From the carbon skeletons from Aspartate (N), Glycine (CCN) and Glutamine (NN) + C from CO2.

115
Q

What is gluconeogenesis? What is its purpose?

A

The synthesis of glucose from other molecules.
- Glucose is needed for the brain and red blood cells (rest of the body is happy on fatty acids)
- Glycogen in the liver is limited and muscles cant release glucose

116
Q

What is the best solution to decreasing glucose levels? Why don’t we do it?

A
  1. Convert fatty acids into glucose, however we do not have the enzymes to do this (although glycerol can be converted)
  2. Reversing glycolysis however it is not reversible (big ΔG)
117
Q

Describe the first step of gluconeogenesis.

A
  1. HCO₃⁻ + ATP → HOCO₂-P + ADP
  2. Biotin + HOCO₂-P → Biotin-CO₂ + Pi
  3. Biotin-CO₂ + Pyruvate (3C) → Biotin + OAA (4C)
    - Catalysed by pyruvate carboxylase (a biotin prosthetic group)
118
Q

What is the second step of gluconeogenesis?

A
  1. OAA(4C) + GTP → PEP(3C) + GDP + CO₂
    - Catalysed by PEP Carboxykinase (PEPCK)
    - Driven by release of the CO₂
119
Q

What is the first thermodynamic barrier in gluconeogenesis?

A

Pyruvate → PEP
- Spontaneous conversion of enol form of pyruvate to keto form has very large negative ΔG∘’,so it is irreversible

120
Q

What reaction is carried out to go from pyruvate to PEP?

A

Pyruvate (3C) + CO₂ + ATP + GTP → PEP (3C) + CO₂ + ADP + GDP

121
Q

What is the second thermodynamic barrier of gluconeogenesis?

A

F-1,6 Biphosphate → F-6-Biphosphate
- ATP would have to be created for this to work

122
Q

What reaction takes place to go from F-1-6-BP to F-6-BP?

A

F-1-6-Biphosphate + H₂O → F-6-P + Pi
- Via F-1-6-Biphosphatase
- Simple hydrolysis of attached phosphate
- Occurs in the cytoplasm

123
Q

What is the 3rd thermodynamic barrier in gluconeogenesis?

A
  • G-6-P to Glucose
    Cant be reversed
124
Q

What reaction takes place to go from G-6-P to Glucose?

A

G-6-P + H₂O → Glucose + Pi
- Via glucose-6-phosphatase
- Occurs in Endoplasmic reticulum

125
Q

Why cant tissues without glucose-6-phosphatase export glucose?

A
  • G6P cannot cross the plasma membrane
126
Q

What is the problem with maintaining gluconeogenesis?

A

There are no stores of pyruvate to maintain gluconeogenesis.

127
Q

What is the first solution to not being able to store pyruvate?

A

Cori Cycle.
Glucose → Pyruvate → (via Lactate Dehydrogenase) Lactate
- travels to liver
Lactate → (Via Lactate Dehydrogenase again) Pyruvate → Glucose

128
Q

What is the second solution to not being able to store pyruvate?

A

Glucogenic amino acids.
- Alanine is the most important
-Only leucine and lysine are purely ketogenic (not glucogenic)

129
Q

Why is alanine the most important glucogenic amino acid?

A
  1. Muscle catabolism releases alanine into the blood
  2. Alanine is transformed into pyruvate via alanine aminotransferase
  3. Pyruvate is transformed into glucose (gluconeogenesis)
    - At the same time, α-ketoglutarate is transformed into glutamate via the same enzyme
130
Q

Does the conversion of alanine to pyruvate consume energy? Why?

A

No, because their forms are very similar. Their carbon skeleton is the same but:
- Alanine has a CH, not a C
- Alanine has a NH₂ group with a single bond, pyruvate has an O with a double bond

131
Q

How is glycerol transformed into glucose? Is it efficient?

A
  • Consumes 1 ATP but produces 1 NADH which is 3ATP so
    1. Glycerol → Glycerol 3 Phosphate via glycerol kinase
    2. Glycerol 3 Phosphate → Dihydroxyacetone phosphate via glycerol phosphate dehydrogenase
    3. Dihydroxyacetone phosphate ↔ D-Glyceraldehyde 3-Phosphate
  • Either gluconeogenesis (from dihydroxyacetone P or DG3P) or glycolysis (only from DG3P)
132
Q

What are the gluconeogenesis entry points?

A
  1. Alanine into pyruvate
  2. Lactate into pyruvate
  3. Amino acids into OAA
  4. Glycerol into DHA
133
Q

Where does fructose integrate into gluconeogenesis?

A

(fruit) = Fructose 6 Phosphate (from non liver tissues) or Gly-3-P (from the liver)
- Via hexokinase which uses an ATP

134
Q

Where does mannose integrate into gluconeogenesis?

A
  • Into Fructose-6-P
  • Via hexokinase into M-6-P which uses an ATP
  • Then M-6-P into F-6-P via Phospomannose Isomerase
135
Q

Where and how does galactose integrate into gluconeogenesis?

A
  1. Galactose → Gal-1-P via galactokinase (uses ATP)
  2. Gal-1-P → G-1-P (powered by cycle of UDP Galactose ↔ UDP Glucose)
  3. G-1-P → G-6-P via phosphoglucomutase
136
Q

What are the characteristics of a rate limiting step?

A
  1. Slowest reaction in pathway
  2. Determines flux through pathway by acting as a bottleneck
  3. Usually first unique enzyme in a pathway (such as after a branch so products will be made independently of one another)
137
Q

How do we identify a rate limiting step?

A
  1. Measure Vmax for enzymes in the pathway (lowest is probably RLS)
  2. Compare Keq and mass action ratios
  3. Test if step is at a crossover point
138
Q

How do we compare the Keq and mass action ratios?

A

Keq = Ratio of product to substrate at equilibrium
MAR = Ratio of product to substrate within a cell
- If reaction has little regulation the numbers will be close together. For the RLS, MAR is usually 100-1000 times smaller than Keq.

139
Q

How do we test if a step is at a crossover point?

A

Perturb the system, increasing/decreasing the flux through the pathway.
- E.g. treat tissue with hormone.
- If pathway flux increases activity of enzyme controlling flux must have increased (+ P -S)

140
Q

What is the RLS in glycolysis? Why is this beneficial?

A

It is hexokinase. This is beneficial because it is the first enzyme, so it prevents any waste which would occur if the slowest reaction was 1/2 of the way through glycolysis.

141
Q

Why do we need metabolic regulation?

A
  1. Ensure a metabolic pathway is active when a product is needed.
  2. Ensures competing pathways are not simultaneously active (Such as gluconeogenesis and glycogenolysis)
  3. Ensure co-ordinating activity in multiple pathways (Such as gluconeogenesis and glycogen breakdown).
142
Q

Why is it essential that competing pathways don’t occur simultaneously?

A
  • Futile cycling (constant conversion of a molecule) wastes lots of energy.
  • However this is utilised by brown adipocytes in order to produce heat to warm up the body
143
Q

What are the three ways to regulate metabolism using enzyme regulation?

A
  1. Allosterism/inhibitors = Very quick but limited effect.
  2. Phosphorylation = Quick with on/off effect.
  3. Gene expression = Slow but sustained effect, increases/decreases Vmax. If a mutation occurs Vmax will become 0 (not good).
144
Q

How are enzymes regulated by metabolites via product inhibition?

A

When the product of a reaction is an inhibitor for an enzyme earlier in the reaction, so it stops further product being made.
e.g. G6P inhibits its own production

145
Q

How are enzymes regulated by metabolites via allosterism?

A

Produce a second metabolite which is an allosteric regulator of the enzymes.
- Very quick but limited effect

146
Q

How can hormones alter the activity of enzymes?

A

Via dephosphorylation:
- Rapid
- Short lived effect

147
Q

How can hormones alter the number of enzymes?

A

Via gene expression changes:
- Slowly
- Longer lived effect
- Mutations cause a Vmax of 0

148
Q

How do hormones alter enzymes via phosphorylation?

A
  • Kinases attach P, phosphatase removes it
  • Different enzymes react differently
  • Phosphorylation overrides allosterism
149
Q

How does phosphorylation occur during glycogen metabolism using phosphorylase?

A

Phosphorylase has two states: inactive and active.
- In muscles AMP will switch it to its active form, allowing glycogen to be broken down. If G6P is high it will be shifted to active form.
- In the liver glucose makes it inactive.

150
Q

What are the affects of insulin on glycogen metabolism?

A

Insulin is a dephosphorylation hormone.
- Phosphorylase kinase
- Glycogen phosphorylase
+ Glycogen synthase

151
Q

What are the affects of adrenaline/glucagon on glycogen metabolism?

A

These are phosphorylating enzymes, via protein kinase A.
+ Phosphorylase kinase
+ Glycogen phosphorylase
- Glycogen synthase

152
Q

What is the affect of insulin on lipid metabolism?

A
  • Dephosphorylated hormone sensitive lipase have very little activity.
  • Perilipin coats triglyceride so no fat can be broken down.
153
Q

What is the affect of adrenaline on lipid metabolism?

A

Phosphorylation via protein kinase A
- When perilipin is phosphorylated a confirmational change occurs and it opens gaps for hormone sensitive lipase to reach the triglyceride.

154
Q

Describe the side reaction that occurs when Fructose-6-Phosphate builds up.

A
  1. F-6-P → F-2-6-P₂ via phosphofructokinase-2 (INSULIN)
  2. F-2-6-P₂ → F-6-P via Fructobiphosphate-2 (the first reaction backwards so it can be used in glycolysis again) (ADRENALINE/GLUCAGON)
  3. As normal, F-6-P → F-1-6-BP₂ via Phosphofructokinase-1, forming ATP.
155
Q

What is the role of AMP-activated Protein Kinase (AMPK)?

A
  • Energy sensor as AMP is the starvation signal within a cell.
  • AMP binds cooperatively and allosterically causing a 1000 fold increase in activity of AMPK.
  • Phosphorylates enzymes and transcription factors
  • Activated by Metformin.
156
Q

How is enzyme activity regulated by gene expression?

A

Transcription factors bind genes and through this increase/decrease expression by increasing/decreasing enzymes, and therefore Vmax.
- Some transcription factors are metabolite receptors so genes bind after the metabolite binds.

157
Q

What is the effect of dephosphorylation on the link reaction?

A
  1. Active Pyruvate Dehydrogenase → Inactive Pyruvate Dehydrogenase via PDH Kinase
    Inhibited by: ATP and NADH and Ca+ (from muscles)
    Activated by: CoA, NAD+, ADP
158
Q

What is the effect of phosphorylation on the link reaction?

A
  1. Inactive Pyruvate Dehydrogenase → Active Pyruvate Dehydrogenase
    - Activated by Acetyl CoA, ATP, NADH and Ca+ (from muscles)
    - Inhibited by CoA, ADP, NAD+
159
Q

What is AMP-Activated Protein Kinase? (AMPK)

A
  • Enzyme that links allosterism to phosphorylation
  • Phosphorylates enzymes and transcription factors
  • Activated by AMP, the starvation signal (Is usually converted into ADP by ATP)
  • Activated by metformin.
160
Q

How are enzymes controlled by expression?

A
  • Transcription factors can bind and ↑↓ expression, therefore ↑↓ enzymes, Vmax and V.
  • Some TFs are metabolic receptors (Gene binds after metabolite binds)
  • Phosphorylation of TFs → gene binding
161
Q
A
162
Q

How does caffeine give us more energy?

A
  • It is a purine, similar to adenine and guanine.
  • Inhibits cAMP phosphodiesterase
  • More protein kinase A
  • Increasing glycogenolysis and lipolysis
163
Q

Describe the metabolic profile of the brain.

A

Energy usage: 100kJ/kg/day
Storage form: None
Preferred substrate: Glucose (Ketone bodies during starvation)
Substrates exported: None

164
Q

Describe the metabolic profile of the liver.

A

Energy usage: 835kJ/kg/day
Storage form: Glycogen/triglyceride
Preferred substrate: Lipid or glucose or
Substrates exported: Glycerol or lipid (Ketone Bodies during starvation)

165
Q

Describe the metabolic profile of adipose tissue.

A

Energy usage: 19kJ/kg/day
Storage form: Triglycerides
Preferred substrate: Lipid
Substrates exported: Lipid and glycerol

166
Q

Describe the metabolic profile of muscles.

A

Energy usage: 54/kJ/kg/day
Preferred substrate: Lipid (rest) glucose / (intense)
Substrate exported: None (rest/during starvation) / lactate (intense)

167
Q

What is the preferred fuel of the heart?

A

Ketone bodies.

168
Q

What is the preferred fuel of Erythrocytes (red blood cells)?

A

Glycolysis only, generate lactate

169
Q

What is the preferred fuel of cancer cells?

A

Aerobic lactate production.

170
Q

What is the preferred fuel of the kidneys?

A

Use 8g a day of lactate for ATP production.

171
Q

What is the preferred fuel of the intestines and immune cells? (it is the same)

A

Glutamine.

172
Q

What is the preferred fuel of spermatozoa?

A

Only fuel source is fructose.

173
Q

Where does glucose end up in an Anabolic state?

A

50-60% → Glycolysis
10% → Glycogen
30-40% → Triglycerides

174
Q

Where do Amino Acids end up in an Anabolic state?

A
  1. Protein
  2. Carbon skeletons
175
Q

Where do fatty acids end up in an Anabolic state?

A

Just triglycerides.

176
Q

What are isozymes?

A

Different enzymes with the same substrate.

177
Q

What is the rate of GLUT and Hexokinase in most tissues?

A

GLUT1+3= Low Km
HK I-III= Low Km
- Meaning most cells take up glucose just fine even when levels are low.

178
Q

What is the rate of GLUT and Hexokinase in the liver + beta cells in pancreas?

A

GLUT2 = High Km
HK IV (Glucokinase) = High Km (Not inhibited by G6P, its own product)
- Only when glucose levels get high do these tissues bind to glucose.

179
Q

What is the rate of GLUT and Hexokinase in muscles and adipose tissue?

A

GLUT4 = Medium Km (Induced by insulin)
HK II = Medium Km

180
Q

What is the first step of Ethanol → Acetyl CoA?

A

Ethanol → Acetaldehyde via Alcohol Dehydrogenase
- Produces NADH + H+ (From NAD+)

181
Q

What is the second step of Ethanol → Acetyl CoA?

A

Acetaldehyde → Acetate via Aldehyde Dehydrogenase
- Produces NADH + H + (from NAD+ + H20)

182
Q

What is the third step of Ethanol → Acetyl CoA?

A

Acetate → Acetyl CoA via Acetyl-CoA synthetase
- Produces PPi + GMP (From CoA-SH + GTP)

183
Q

What is the problem with having no regulation of ethanol metabolism?

A
  • It is oxidised in preference to surrounding nutrients (i.e. Glucose)
  • ↑NADH⁺ + H⁺ = ↓NAD⁺ (Inhibits TCA cycle, producing lactate and inhibiting pyruvate)
184
Q

What does excess NADH⁺ , H⁺ and Lactate cause?

A

H⁺ + Lactate = Acidosis, causing a drop in pH + death.
NADH⁺ = ATP excess, inhibiting glycolysis allosterically.

185
Q

What does a lack of NAD+ and Pyruvate cause?

A

↓Pyruvate = Gluconeogenesis → Hypoglycaemia
↓NAD⁺ = β oxidation inhibited.
- This + ↑Acetyl CoA (=↑TG Synthesis) = fatty liver as it cannot be broken down.

186
Q

How is ATP rapidly replaced during short term, intense exercise?

A

ADP + Creatine P ↔ ATP + Creatine
- Via creatine kinase
ADP + ADP ↔ ATP + AMP
- Via adenylate kinase

187
Q

How is ATP produced during long duration, low intensity exercise?

A

Fatty acids (Aerobic metabolism)
Lactate (Anaerobic metabolism)

188
Q

How is heat generated from metabolic processes?

A
  1. Shivering
  2. Uncoupled respiration (Either via Thermogenic or attaching a fatty acid to an amino acid)
189
Q

What is brown adipose tissue?

A

Modified adipocytes which generate heat by wasting the energy in stored fats.

190
Q

What are the differences between normal and brown adipose tissue?

A

Brown adipose tissue have:
- Many small TG droplets
- More mitochondria
- Noradrenaline which activates Thermogenin, uncoupling the ETC and ATP synthesis
- N-Acyl amino acid synthase, joining FA to AA to make an N-acyl AA

Introduction to Biochemistry (5 decks)

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