Biochem - Metabolism Module

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What is the catabolic pathway?

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163 Terms

1

What is the catabolic pathway?

Break down larger molecules into smaller substances

Extract H/e- → Deliver it to the electron transport chain

Controlled by demand

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What is the anabolic pathway?

Build larger molecules from smaller substances

  • Require ATP

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Dinitrophenol (DNP)

  • An uncoupler (a molecule that disrupts oxidative phosphorylation)

  • Prevent energy being stored as fat in the body (instead releasing as heat)

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ATP, ADP and AMP

Free energy required is produced by ATP hydrolysis, which makes them thermodynamically favourable.

  • The rate of ATP synthesis = The rate of ATP use

  • Cells can’t burn fuel without O2

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Energy demand

The rates of catabolic (ATP-demanding) and anabolic (ATP-utilising) pathways are regulated by the energy state within the cell.

  • A small change in AMP can significantly affect the whole energy charge.

<p>The rates of <u><strong>catabolic</strong></u> <strong>(ATP-demanding)</strong> and <u><strong>anabolic</strong></u> <strong>(ATP-utilising) pathways</strong> are regulated by the energy state within the cell.</p><ul><li><p>A small change in AMP can significantly affect the whole energy charge.</p></li></ul>
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What are kinases, phosphatases and phosphorylases?

  • Kinases Catalyse a phosphorylation reaction.

  • Phosphatases Catalyse a dephosphorylation reaction.

  • Phosphorylases Catalyse a phosphorolysis reaction.

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What are synthases and synthetases?

  • Synthases Catalyse condensation reactions/ synthetic process.

    • Without ATP

    • Reversible

  • Synthetases Catalyse condensation reactions.

    • With ATP

    • Irreversible

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What is Coenzyme A?

  • Carrier for acyl group

  • Great for trapping metabolites within the cell

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What are dehydrogenases?

  • Catalyse oxidation-reduction reactions

    • Transfer 2 H atoms from organic compounds to electron acceptors.

    • Involved NAD+ or FAD as cofactors.

  • NAD+ (Nicotinamide Adenine Dinucleotide)

    • NAD+ is reduced to NADH

    • Loves to oxidise -CH2-COH- to -CH-CO-

  • FAD (Flavin Adenine Dinucleotide)

    • Accept 2 H+ and 2 e-

    • Become FADH2

    • Loves to oxidise -CH2-CH2- to -CH=CH-

<ul><li><p>Catalyse <mark data-color="red"><u><strong>oxidation-reduction</strong></u></mark> reactions</p><ul><li><p>Transfer 2 H atoms from organic compounds to electron acceptors.</p></li><li><p>Involved <strong>NAD+</strong> or <strong>FAD</strong> as cofactors.</p></li></ul></li><li><p><strong>NAD+</strong> (Nicotinamide Adenine Dinucleotide)</p><ul><li><p>NAD+ is reduced to <strong>NADH</strong></p></li><li><p>Loves to oxidise <strong>-CH2-COH-</strong> to <strong>-CH-CO-</strong></p></li></ul></li><li><p><strong>FAD (Flavin Adenine Dinucleotide)</strong></p><ul><li><p>Accept 2 H+ and 2 e-</p></li><li><p>Become <strong>FADH2</strong></p></li><li><p>Loves to oxidise <strong>-CH2-CH2-</strong> to <strong>-CH=CH-</strong></p></li></ul></li></ul>
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What is the role of hydrogen/electron carriers?

  • H/e- carriers: NAD+ or FAD

    • They are also H/e-strippers.

    • Both are limited supply (once they’re carrying H/e-, they can’t do any more stripping)

<ul><li><p>H/e- carriers: <strong>NAD+</strong> or <strong>FAD</strong></p><ul><li><p>They are also H/e-strippers.</p></li><li><p>Both are limited supply (once they’re carrying H/e-, they can’t do any more stripping)</p></li></ul></li></ul>
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Strategy of Fuel Oxidation

Stage 1

  • Rip H/e- out of fuels

  • Fuels are broken up into 2-carbon pieces (acetate)

Stage 2

  • Rip H/e- out of acetate

  • Compete for oxidation of C atoms to CO2

Stage 3

  • Capturing the energy of H/e- as chemical/potential energy

    • Reaction between H and O liberates lots of energy

  • Formation of a proton gradient

  • Limited by oxidised NAD+ in resting muscle tissue

<p><u><strong>Stage 1</strong></u></p><ul><li><p>Rip H/e- out of fuels</p></li><li><p>Fuels are broken up into <strong>2-carbon</strong> pieces (acetate)</p></li></ul><p><u><strong>Stage 2</strong></u></p><ul><li><p>Rip H/e- out of acetate</p></li><li><p>Compete for oxidation of C atoms to CO2</p></li></ul><p><u><strong>Stage 3</strong></u></p><ul><li><p>Capturing the energy of H/e- as chemical/potential energy</p><ul><li><p>Reaction between H and O liberates lots of energy</p></li></ul></li><li><p>Formation of a <strong>proton gradient</strong></p></li><li><p>Limited by <strong>oxidised NAD+</strong> in resting muscle tissue</p></li></ul>
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How do we make ATP with H+ gradient?

H+ flows under pressure through a channel in the inner mitochondrial membrane.

They come in → Rotate another protein → Interact with subunits of ATP synthase → Generate ATP from ADP and phosphate

<p>H+ flows under pressure through a channel in the inner mitochondrial membrane.</p><blockquote><p>They come in → Rotate another protein → Interact with subunits of <strong>ATP synthase</strong> → Generate ATP from ADP and phosphate</p></blockquote>
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The 7 big concepts

  1. H/e- carriers are in short supply

  2. ADP is in short supply

    • [ATP] = 5 mM.

    • < 3 mM → Cells die

  3. ATP is stable

  4. Inner mitochondrial membrane is impermeable to H+

  5. H+ only flow into the matrix if the ATP is being made

  6. H+ pumps don’t work if the H+ gradient is very high

  7. No H+ pumping, no H/e- movement down the ETC

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Fatty acids and ß-Oxidation

Fatty Acids (FA)

  • Nearly all C atoms are fully reduced

  • Stored as Triglyceride

  • Hydrophobic

  • Very energy dense

  • Huge store

  • Can’t be used by brain

ß-Oxidation

  • 2 C atoms are removed in the form of acetyl-CoA at the carbonyl terminal

  • FAs trapped in the cytoplasm as Fatty Acyl-CoA

  • Transported into mitochondria by H/e- carrier: Carnitine

    Help transport long-chain FAs into mitochondria to oxidise them to produce ATP.

  • H/e- ripped out by FAD and NAD+

  • FA part loses an acetate chunk

  • Cycle repeats

<h3><span class="heading-content"><u><strong>Fatty Acids (FA)</strong></u></span></h3><ul><li><p>Nearly all C atoms are fully reduced</p></li><li><p>Stored as <strong>Triglyceride</strong></p></li><li><p>Hydrophobic</p></li><li><p>Very energy dense</p></li><li><p>Huge store</p></li><li><p>Can’t be used by brain</p></li></ul><h3><span class="heading-content"><u><strong>ß-Oxidation</strong></u></span></h3><ul><li><p><strong>2 C atoms</strong> are removed in the form of <strong>acetyl-CoA</strong> at the carbonyl terminal</p></li><li><p>FAs trapped in the cytoplasm as <strong>Fatty Acyl-CoA</strong></p></li><li><p>Transported into mitochondria by H/e- carrier: <strong>Carnitine</strong></p><blockquote><p>Help transport long-chain FAs into mitochondria to oxidise them to produce ATP.</p></blockquote></li><li><p>H/e- ripped out by <strong>FAD</strong> and <strong>NAD+</strong></p></li><li><p>FA part loses an acetate chunk</p></li><li><p>Cycle repeats</p></li></ul>
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Glucose and Glucose Oxidation

Glucose

  • Reasonably reduced

  • Stored as Glycogen

  • Hydrophilic

  • Low store (300g)

  • Used by all tissues (esp. by the brain)

  • Most readily available fuel (glucose transporters move to the cell surface)

Glucose Oxidation/Glycolysis

  • All tissues

  • Wholly cytosolic

  • No O2

  • Very fast but inefficient

  • Pyruvate must be transported into mitochondria for full oxidation.

<h3><span class="heading-content"><u><strong>Glucose</strong></u></span></h3><ul><li><p>Reasonably reduced</p></li><li><p>Stored as <strong>Glycogen</strong></p></li><li><p>Hydrophilic</p></li><li><p>Low store (300g)</p></li><li><p>Used by all tissues (esp. by the brain)</p></li><li><p>Most readily available fuel (glucose transporters move to the cell surface)</p></li></ul><h3><span class="heading-content"><u><strong>Glucose Oxidation/Glycolysis</strong></u></span></h3><ul><li><p>All tissues</p></li><li><p>Wholly cytosolic</p></li><li><p>No O2</p></li><li><p>Very fast but inefficient</p></li><li><p>Pyruvate must be transported into mitochondria for full oxidation.</p></li></ul>
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Protein

  • Channel into pyruvate, acetyl-CoA or Krebs cycle

  • Need to dispose of amine groups

  • Store 5-20 kg

  • Last alternative fuel source

  • Don’t store protein since all of it has its functions

  • Making protein requires lots of energy

<ul><li><p>Channel into pyruvate, acetyl-CoA or Krebs cycle</p></li><li><p>Need to dispose of amine groups</p></li><li><p>Store 5-20 kg</p></li><li><p>Last alternative fuel source</p></li><li><p>Don’t store protein since all of it has its functions</p></li><li><p>Making protein requires lots of energy</p></li></ul>
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Muscle contraction and ATP

  • Use ATP

    • Actin and Myosin interaction - Filaments sliding across each other

    • The faster the contraction, the faster ATP use

  • Use ATP even at rest

    • Maintain ion gradients

    • Sacroplasmic reticulum and CA2+

  • Compared to resting muscle cells, actively contracting muscle tissue has a higher rate of NAD+/NADH turnover

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How many types of muscle?

Type 1 - Red + Slow

  • Contract slow

  • Many mitochondria

  • Good blood supply

Type 2b - White + Fast

  • Contract rapid

  • Few mitochondria

  • Poor blood supply

  • Packed full of contractile filaments

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Pathways of Fuel Oxidation

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What happen once ATP is used?

  • ↑ rate of ATP generation

  • Once ATP is used → Greater availability of ADP

    • ↑ ATP synthase

    • ↑ ETC

    • ↑ H/e- carriers/trippers

    • ↑ Fuel oxidation

    • Proton gradients diffuse faster, ie. H+ flow back into the matrix more quickly.

  • ↓ Blood glucose

    • Need to keep at 5 nM for brain

  • Glucose homeostasis

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What happen to energy in the body during gentle exercise?

  • Glucose is used → Cannot be recycled directly

  • After several minutes, fatty acids take over

  • Glucose stores (as glycogen) are limited

    • Cannot convert FAs into glucose

      • FAs substitute for glucose as a fuel

      • FAs prevent glucose from being wastefully oxidised

  • Glucose still gets into the muscles until lactate is reached

  • Lactate (produced from pyruvate) goes to the liver for re-synthesis of glucose

    • Gluconeogenesis

  • Low insulin and High glucagon → Stimulate

    • Glycogen breakdown in liver.

    • Fat breakdown in white adipose tissue.

<ul><li><p>Glucose is used → Cannot be recycled directly</p></li><li><p>After several minutes, <u><strong>fatty acids</strong></u> take over</p></li><li><p>Glucose stores (as glycogen) are <strong>limited</strong></p><ul><li><p>Cannot convert FAs into glucose</p><ul><li><p>FAs substitute for glucose as a fuel</p></li><li><p>FAs prevent glucose from being wastefully oxidised</p></li></ul></li></ul></li><li><p><u><strong>Glucose</strong></u> still gets into the muscles until lactate is reached</p></li><li><p><u><strong>Lactate</strong></u> (produced from pyruvate) goes to the liver for re-synthesis of glucose</p><ul><li><p><mark data-color="red"><strong>Gluconeogenesis</strong></mark></p></li></ul></li><li><p>Low insulin and High glucagon → Stimulate</p><ul><li><p>Glycogen breakdown in liver.</p></li><li><p>Fat breakdown in white adipose tissue.</p></li></ul></li></ul>
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What happen to energy in the body during moderate exercise?

  • ↑ Pace → ↑ Rate of FA utilisation

    ↳ Soon, FA oxidation enzymes are at their peak

    • FA oxidation cannot maintain ATP production alone (inhibition on glucose oxidation is removed)

  • Glucose oxidation occurs

    • Less glucose recycling

    • A faster depletion of liver glycogen

  • Mixture of FA oxidation and glucose oxidation

  • Further ↑ pace by ↑ glucose oxidation

    ↳ FA oxidation going at full speed

<ul><li><p>↑ Pace → ↑ Rate of FA utilisation</p><p>↳ Soon, FA oxidation enzymes are at their peak</p><ul><li><p>FA oxidation cannot maintain ATP production alone (inhibition on glucose oxidation is removed)</p></li></ul></li><li><p><u><strong>Glucose oxidation</strong></u> occurs</p><ul><li><p>Less glucose recycling</p></li><li><p>A faster depletion of liver glycogen</p></li></ul></li><li><p>Mixture of FA oxidation and glucose oxidation</p></li><li><p>Further ↑ pace by ↑ glucose oxidation</p><p>↳ FA oxidation going at full speed</p></li></ul>
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What happen to energy in the body during strenuous exercise?

  • Muscle glycogen is now broken down

    Endogenously stored

  • Limits on blood glucose oxidation

    • The supply and transport of blood cannot keep up with the demand

    • FAs are still going as fast as they can

<ul><li><p>Muscle glycogen is now broken down</p><p>↳ <strong>Endogenously stored</strong></p></li><li><p>Limits on blood glucose oxidation</p><ul><li><p>The supply and transport of blood cannot keep up with the demand</p></li><li><p>FAs are still going as fast as they can</p></li></ul></li></ul>
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What happen to energy in the body during very strenuous exercise?

  • ATP production cannot be met by oxidative phosphorylation

    ↳ Mitochondrial processes are too slow

  • Extra glycolysis boost needed

    • Glycolysis is very fast but inefficient

    • ↑ Blood lactate levels

  • Glucose must come from muscle glycogen

    • Transport already at max

<ul><li><p>ATP production cannot be met by oxidative phosphorylation</p><p>↳ Mitochondrial processes are too slow</p></li><li><p>Extra glycolysis boost needed</p><ul><li><p>Glycolysis is very fast but inefficient</p></li><li><p>↑ Blood lactate levels</p></li></ul></li><li><p>Glucose must come from muscle glycogen</p><ul><li><p>Transport already at max</p></li></ul></li></ul>
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What happen to energy in the body during sprinting?

  • Use Type 2b muscles → Very rapid ATP consumption.

  • Don’t use

    • FAS → Poor O2 supply, low mitochondria

    • Blood glucose → Delay in transporter recruitment, poor fuel supply

  • Glycolysis to lactate is very fast but creates a problem

    ↳ Lead to lactic acidosis due to lactate accumulation → Muscle fatigue and disrupt cellular processes

  • Lots of lactate produce very quickly

    • Poor blood supply takes away

  • ATP regeneration is so inefficient

    • Only 2 ATPs per glucose

  • Regeneration of H/e- carrier (NAD+)

<ul><li><p>Use Type 2b muscles → Very rapid ATP consumption.</p></li><li><p><strong>Don’t use</strong></p><ul><li><p>FAS → Poor O2 supply, low mitochondria</p></li><li><p>Blood glucose → Delay in transporter recruitment, poor fuel supply</p></li></ul></li><li><p>Glycolysis to lactate is very fast but creates a problem</p><p>↳ Lead to <strong>lactic acidosis</strong> due to lactate accumulation → Muscle fatigue and disrupt cellular processes</p></li><li><p>Lots of lactate produce very quickly</p><ul><li><p>Poor blood supply takes away</p></li></ul></li><li><p>ATP regeneration is so inefficient</p><ul><li><p>Only 2 ATPs per glucose</p></li></ul></li><li><p>Regeneration of H/e- carrier (NAD+)</p></li></ul>
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Why glycogen is important?

  • ATP can only be produced by FA oxidation when glycogen is depleted

    • Power output is lower when using only FAs

  • Cannot sprint if there’s no glycogen

    • Glucagon quickly provides glucose for energy production.

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Creatine Phosphate (CP)

  • An instant store of ATP (< 5 sec supply 15 nM)

  • Creatine supplements ↑ CP levels

    • Creatine increases the availability of creatine in the muscles, allowing higher levels of phosphocreatine.

Creatine Phosphate + ADP → ATP + Creatine

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Fatty Acid Oxidation/ß-Oxidation

Occurs in the ß-carbon atom

<p>Occurs in the ß-carbon atom</p>
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Transport of Fatty Acid

  • Transported through the bloodstream bound to a protein called albumin (ab).

  • The cells produce ATP after taking up fatty acids and undergoing beta-oxidation.

<ul><li><p>Transported through the bloodstream bound to a protein called <mark data-color="red"><strong>albumin (ab)</strong></mark>.</p></li><li><p>The cells produce ATP after taking up fatty acids and undergoing beta-oxidation.</p></li></ul>
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Transport of Fatty Acid: Mitochondria

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Trapping of Fatty Acid

  • FA trapped by attachment to CoA

    ↳ The CoA will always be attached from now on

    ➙ Activates FA

  • Requires lots of energy

    • ATP is not converted into ADP, but AMP

    • Pyrophosphate is hydrolysed, pulling reaction over

  • Coenzyme A

    • Carrier of acyl group

    • Great for trapping metabolites within the cell

<ul><li><p>FA trapped by attachment to CoA</p><p>↳ The CoA will always be attached from now on</p><p>➙ Activates FA</p></li><li><p>Requires lots of energy</p><ul><li><p>ATP is <u><strong>not</strong></u> converted into ADP, but <strong>AMP</strong></p></li><li><p><strong>Pyrophosphate</strong> is hydrolysed, pulling reaction over</p></li></ul></li><li><p><strong>Coenzyme A</strong></p><ul><li><p>Carrier of acyl group</p></li><li><p>Great for trapping metabolites within the cell</p></li></ul></li></ul>
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First and Second Stripping Steps

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ß-Oxidation

  • FAs trapped in the cytoplasm as Fatty Acyl-CoA

  • Transported into mitochondria - Carrier: Carnitine

  • H/e- ripped out by FAD and NAD+

  • FA part loses an acetate chunk

  • Cycle repeats

  • Each round of ß-oxidation gives

    • 1 acetyl CoA

    • 1 NADH

    • 1 FADH2

<ul><li><p>FAs trapped in the cytoplasm as <u><strong>Fatty Acyl-CoA</strong></u></p></li><li><p>Transported into mitochondria -  Carrier: <strong>Carnitine</strong></p></li><li><p>H/e- ripped out by FAD and NAD+</p></li><li><p>FA part loses an <strong>acetate chunk</strong></p></li><li><p>Cycle repeats</p></li><li><p>Each round of ß-oxidation gives</p><ul><li><p>1 acetyl CoA</p></li><li><p>1 NADH</p></li><li><p>1 FADH2</p></li></ul></li></ul>
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Glycolysis

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Glucose Uptake

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Early Glycolysis or Investment Phase

  • Requires two ATP molecules to prepare glucose for further breakdown.

  • It involves phosphorylation and rearrangement steps to convert glucose into fructose-1,6-bisphosphate.

<ul><li><p>Requires two ATP molecules to prepare glucose for further breakdown.</p></li><li><p>It involves phosphorylation and rearrangement steps to convert glucose into <strong>fructose-1,6-bisphosphate</strong>.</p></li></ul>
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Second Glycolysis or Return Phase

  • Conversion of fructose-1,6-bisphosphate into 2 molecules of glyceraldehyde-3-phosphate (G3P).

  • Pyruvate is produced through an enzymatic reaction that converts G3P molecules into ATP and NADH.

<ul><li><p>Conversion of fructose-1,6-bisphosphate into 2 molecules of <strong>glyceraldehyde-3-phosphate (G3P)</strong>.</p></li><li><p>Pyruvate is produced through an enzymatic reaction that converts G3P molecules into ATP and NADH.</p></li></ul>
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What happen completing glycolysis?

  • 2 ATP, 2 pyruvate and 2 NADH (need to generate NAD+)

  • Fate of pyruvate (Aerobic and Anaerobic)

  • Get more ATP from full oxidation of pyruvate

    • Need to transport into mitochondria

    • Oxidise with pyruvate dehydrogenase (PDH)

  • Reoxidise NADH quickly → Important

    • Maintain the supply of NAD+

      • Lactate production

      • Alcohol production (in yeast)

    • Keep everything cytosolic

<ul><li><p>2 ATP, 2 pyruvate and 2 NADH (need to generate NAD+)</p></li><li><p>Fate of pyruvate (Aerobic and Anaerobic)</p></li><li><p>Get more ATP from full oxidation of pyruvate</p><ul><li><p>Need to transport into mitochondria</p></li><li><p>Oxidise with <strong>pyruvate dehydrogenase (PDH)</strong></p></li></ul></li><li><p>Reoxidise NADH quickly → Important</p><ul><li><p>Maintain the supply of NAD+</p><ul><li><p>Lactate production</p></li><li><p>Alcohol production (in yeast)</p></li></ul></li><li><p>Keep everything cytosolic</p></li></ul></li></ul>
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The Krebs Cycle

  • Substrate: Acetyl CoA

    ↳ From FA oxidation and/or glucose oxidation

  • Everything is in mitochondria

  • Strategy

    • Completely oxidise acetate carbons to CO2

    • Produce lots of NADH, FADH2 and even ATP (not directly)

    • Performing the reactions on a carrier molecule

      • Regenerate the carrier

<ul><li><p>Substrate: Acetyl CoA</p><p>↳ From FA oxidation and/or glucose oxidation</p></li><li><p>Everything is in mitochondria</p></li><li><p>Strategy</p><ul><li><p>Completely oxidise acetate carbons to CO2</p></li><li><p>Produce lots of NADH, FADH2 and even ATP (not directly)</p></li><li><p>Performing the reactions on a carrier molecule</p><ul><li><p>Regenerate the carrier</p></li></ul></li></ul></li></ul>
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What are the important features of Krebs Cycle?

  • 2C atoms come in and 2C atoms release

  • Generate:

  • 3 NADH, 1 reduced FAD + 1 GTP

    1 ADH → 2.5 ATP in oxidative phosphorylation

    1 FADH2 → 1.5 ATP

    With GTP, ≈ 10 ATP per acetyl CoA

  • ATP is not directly generated

  • Oxaloacetate is not net consume in the cycle (acts as carrier)

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Regulation pathways of the Krebs Cycle

  • Mainly by availability of cofactors

    • NAD+, FAD, ADP (more of these → Faster they go)

  • Inhibited by a high ‘energy charge’ – ATP : ADP ratio

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What happens if there is no proton gradient?

  • Will burn all of stored fuel

  • No driving force for ATP synthesis

    • No back-pressure to stop H+ pumping

    • No restriction, no H/e- movement down the transport chain to O2

  • Instant regeneration of NAD from NADH

    • Massive fuel oxidation rate

    • Massive O2 consumption

  • No ATP production → Low ATP synthesis and cell death (<3 mM)

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What does uncoupling mean?

ATP synthesis and electron transport chain are disrupted.

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Dinitrophenol (DNP)

  • An uncoupler

    • Disrupts the normal coupling between electron transport and ATP synthesis in oxidative phosphorylation.

    • Prevent energy from being stored as fat in the body (instead releasing as heat)

  • Hydrophobic when protonated

    ↳ Can move freely across membrane

  • Weak acid

    Part of molecule can take up or release H+, depending on surrounding pH

  • When H+ comes off → Negative charge can be delocalised (e- shared 2+ in a molecules)

    ↳ Still hydrophobic

<ul><li><p>An uncoupler</p><ul><li><p>Disrupts the normal coupling between <mark data-color="red"><strong>electron transport and ATP synthesis</strong></mark> in oxidative phosphorylation.</p></li><li><p>Prevent energy from being stored as fat in the body (instead releasing as heat)</p></li></ul></li><li><p>Hydrophobic when <strong>protonated</strong></p><p>↳ Can move freely across membrane</p></li><li><p>Weak acid</p><blockquote><p>Part of molecule can take up or release H+, depending on surrounding pH</p></blockquote></li><li><p>When H+ comes off → Negative charge can be delocalised (e- shared 2+ in a molecules)</p><p>↳ Still hydrophobic</p></li></ul>
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The mechanism of DNP

  • DNP is a protonophore, allowing protons to cross the inner mitochondrial membrane freely.

  • Protons leak back into the matrix without passing through ATP synthase, disrupting electron transport and ATP synthesis.

  • Dissipation of proton gradient

    • ↓ Rate of ATP synthesis (Prevent ATP production)

    • Proton gradient dissipates

    • ↑ Oxygen consumption.

    • ↑ Rate of ß-oxidation

  • Massive weight loss and heat production

  • Later used as a weight loss agent

<ul><li><p>DNP is a <u><strong>protonophore</strong></u>, allowing protons to cross the inner mitochondrial membrane freely.</p></li><li><p>Protons leak back into the matrix without passing through ATP synthase, disrupting electron transport and ATP synthesis.</p></li><li><p>Dissipation of proton gradient</p><ul><li><p>↓ Rate of ATP synthesis (Prevent ATP production)</p></li><li><p>Proton gradient dissipates</p></li><li><p>↑ Oxygen consumption.</p></li><li><p>↑ Rate of ß-oxidation</p></li></ul></li><li><p>Massive weight loss and heat production</p></li><li><p>Later used as a weight loss agent</p></li></ul>
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Natural uncoupler - Uncoupling Protein 1 (UCP-1)

  • UCP-1 or Thermogenin

  • Found only in brown adipose tissue

  • Function: Generate heat

    • Esp in small mammals and hibernating animals

  • Under hormonal control

    • Noradrenaline binds to ß-receptors (only in white adipose tissue) on the cell surface.

    • Stimulates FA secretion

    • Open proton channel

    ➜ Targeted and controllable

High in neonates, less as we grow up

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What are e- transport and H+ pumping?

  • The strippers and carriers of H/e-

  • Components of the ETC

    • H/e- carriers in the chain

    • Proteins that support them

  • Matrixed fuel system

    • Movement of protons out of the matrix

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What does Electron Transport Chain (ETC)?

  • Contains 4 complexes

    • All embedded in the inner mitochondrial membrane

    • Complex I skip complex II (I and II are distinct entries)

I → III → IV, and II → III → IV

  • Each complex consists of many proteins

    • Structural - Maintain the shape of complex

    • Prosthetic group (a subset of cofactor) - Bits that transport H/e-

  • Proteins are arranged so that

    • H+ expelling reactions on the outside

    • H+ consuming reactions on the matrix side

  • ≈ 10 H+ are pumped out for each NADH

<ul><li><p>Contains 4 complexes</p><ul><li><p>All embedded in the inner mitochondrial membrane</p></li><li><p>Complex I skip complex II (I and II are distinct entries)</p></li></ul></li></ul><h3><span class="heading-content">I → III → IV, and II → III → IV</span></h3><ul><li><p>Each complex consists of many proteins</p><ul><li><p><strong>Structural -</strong> Maintain the shape of complex</p></li><li><p><strong>Prosthetic group</strong> (a subset of cofactor) <strong>-</strong> Bits that transport H/e-</p></li></ul></li><li><p>Proteins are arranged so that</p><ul><li><p><strong>H+ expelling reactions</strong> on the outside</p></li><li><p><strong>H+ consuming reactions</strong> on the matrix side</p></li></ul></li><li><p>≈ 10 H+ are pumped out for each NADH</p></li></ul>
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Nicotinamide Adenine Dinucleotide (NAD+) in ETC

  • Donates H/e- to complex I (re-deoxides NADH to NAD+)

  • NAD+ accepts a H+ and 2 e- = A hydride ion H

  • NAD+ likes to rip H/e- off from the -CH-OH group converting them to -C=O groups

  • Nicotinamide group derived from nicotic acid (niacin)

<ul><li><p><u><strong>Donates</strong></u> H/e- to <mark data-color="red"><strong>complex I</strong></mark> (re-deoxides NADH to NAD+)</p></li><li><p>NAD+ accepts a H+ and 2 e- = A hydride ion H</p></li><li><p>NAD+ likes to rip H/e- off from the -CH-OH group converting them to -C=O groups</p></li><li><p>Nicotinamide group derived from <strong>nicotic acid (niacin)</strong></p></li></ul>
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Why NADH but not NADH2?

  • NADH is the reduced form of NAD+.

  • In cellular respiration, it carries 2 high-energy electrons and 1 proton.

<ul><li><p>NADH is the reduced form of NAD+.</p></li><li><p>In cellular respiration, it carries 2 high-energy electrons and 1 proton.</p></li></ul>
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Flavin Adenin Nucleotide (FAD) in ETC

  • Present inside and stuck in Complex II

  • Acceptor and donator of Hs

  • Rip H from a saturated hydrocarbon chain

    • 2 H ripped out and being carried

  • Built-up ADP

<ul><li><p>Present inside and <u><strong>stuck</strong></u> in <mark data-color="red"><strong>Complex II</strong></mark></p></li><li><p>Acceptor and donator of Hs</p></li><li><p>Rip H from a saturated hydrocarbon chain</p><ul><li><p>2 H ripped out and being carried</p></li></ul></li><li><p>Built-up ADP</p></li></ul>
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Ubiquinone (UQ or Q pool) in ETC

  • Reduced form: UQH2 (transfers Hs to Complex III)

  • Electrons move around in Complex I from 1 prosthetic group to another until they reach the Q pool.

  • Very hydrophobic

    • Lives in the inner mitochondrial membrane

  • Accept all H and e- from Complex II

  • Never sees the light

<ul><li><p>Reduced form: <strong>UQH2</strong> (<u><strong>transfers</strong></u> Hs to <mark data-color="red"><strong>Complex III</strong></mark>)</p></li><li><p>Electrons <u><strong>move</strong></u> around in <mark data-color="red"><strong>Complex I</strong></mark> from 1 prosthetic group to another until they reach the <strong>Q pool.</strong></p></li><li><p>Very hydrophobic</p><ul><li><p>Lives in the inner mitochondrial membrane</p></li></ul></li><li><p>Accept <strong>all</strong> H and e- from Complex II</p></li><li><p>Never sees the light</p></li></ul>
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Cytochrome C (Cyt C) and Iron in ETC

  • Cyt C picks up e- from Complex III and gives e- to Complex IV.

  • Cyt C has a prosthetic group that contains a Fe atom

    • Changes from ferrous (Fe2+) to ferric (Fe3+) as it loses, and vice versa, as it accepts e-

    • Fe does not carry Hs

  • Only deal with e-

    Very good at moving e- from 1 place to another

  • How are Fe atoms held in place?

    • In mid of porphyrin rings

    • In Iron-Sulphur complexes

<ul><li><p>Cyt C picks up e- from <mark data-color="red"><strong>Complex III</strong></mark> and gives e- to <mark data-color="red"><strong>Complex IV.</strong></mark></p></li><li><p>Cyt C has a prosthetic group that contains a Fe atom</p><ul><li><p>Changes from ferrous (Fe2+) to ferric (Fe3+) as it loses, and vice versa, as it accepts e-</p></li><li><p>Fe does not carry Hs</p></li></ul></li><li><p>Only deal with e-</p><blockquote><p>Very good at moving e- from 1 place to another</p></blockquote></li><li><p>How are Fe atoms held in place?</p><ul><li><p>In mid of <strong>porphyrin rings</strong></p></li><li><p>In <strong>Iron-Sulphur complexes</strong></p></li></ul></li></ul>
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What is the proton motive force?

  • Local pH is important

  • Proton motive force has a charge and [component]

  • Energy in the gradient is based on both charge, conc, chemical and electrical gradient

  • 2 components come together to make free energy in gradient that much greater

<ul><li><p>Local pH is important</p></li><li><p><strong>Proton motive force</strong> has a charge and [component]</p></li><li><p>Energy in the gradient is based on both charge, conc, chemical and electrical gradient</p></li><li><p>2 components come together to make free energy in gradient that much greater</p></li></ul>
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Getting Cytoplasmic NADH to the ETC

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What does Glycerol 3-Phosphate Shuttle do?

  • Effectively bypassing Complex I

  • After glycolysis, dihydroxyacetone phosphate is converted to NAD+ by reacting with NADH → Glycerol 3-Phosphate.

    • Then oxidised by FAD in the mitochondrial membrane.

    • Allow e- to pass through the chain to Q and then through the chain again.

  • Losing H+ pumping potential

  • Functions:

    • Transfers e- between cytosolic NADH and mitochondria, producing ATP through oxidative phosphorylation.

    • Maintains energy production in tissues where NADH is efficiently produced in the cytosol and transported to the mitochondria.

<ul><li><p>Effectively bypassing <strong>Complex I</strong></p></li><li><p>After glycolysis, <mark data-color="red"><strong>dihydroxyacetone phosphate</strong></mark> is converted to NAD+ by reacting with NADH → <mark data-color="red"><strong>Glycerol 3-Phosphate.</strong></mark></p><ul><li><p>Then oxidised by FAD in the mitochondrial membrane.</p></li><li><p>Allow e- to pass through the chain to Q and then through the chain again.</p></li></ul></li><li><p>Losing H+ pumping potential</p></li><li><p><strong>Functions:</strong></p><ul><li><p>Transfers e- between cytosolic NADH and mitochondria, producing ATP through oxidative phosphorylation.</p></li><li><p>Maintains energy production in tissues where NADH is efficiently produced in the cytosol and transported to the mitochondria.</p></li></ul></li></ul>
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What does Malate Aspartate Shuttle do?

  • Moves e- around to get them across the inner mitochondrial membrane

  • Purpose:

    • Take NADH from the cytoplasm and make NADH in the matrix

      ↳ e- transferred into the matrix with no loss of H+ potential

  • Function:

    • Transfers reducing equivalents from the cytosol to mitochondria by oxidative phosphorylation, where NADH contributes to ATP production.

    • Allows efficient energy utilization and maintains redox balance.

<ul><li><p>Moves e- around to get them across the inner mitochondrial membrane</p></li><li><p><strong>Purpose:</strong></p><ul><li><p>Take NADH from the cytoplasm and make NADH in the matrix</p><p>↳ e- transferred into the matrix with <u><strong>no</strong></u> loss of H+ potential</p></li></ul></li><li><p><strong>Function:</strong></p><ul><li><p>Transfers reducing equivalents from the cytosol to mitochondria by oxidative phosphorylation, where NADH contributes to ATP production.</p></li><li><p>Allows efficient energy utilization and maintains redox balance.</p></li></ul></li></ul>
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Organise the four separate routes that feed into UQ (Complex I, Complex II, G3P shuttle and beta-oxidation)

  1. From Complex I (NADH dehydrogenase)

    • Transfers electrons from NADH to ubiquinone (UQ) in the ETC.

  2. From Complex II (Succinate dehydrogenase)

    • Directly transfers electrons from succinate to UQ in the ETC.

  3. From the 1st step of ß-oxidation

  4. From the Glycerol 3-P shuttle

    • Generates NADH and FADH2 during the breakdown of fatty acids, which transfer electrons to UQ in the ETC.

  • Once in the Q pool, the e- will always go to complex III

<ol><li><p>From <strong>Complex I (NADH dehydrogenase)</strong></p><ul><li><p>Transfers electrons from NADH to ubiquinone (UQ) in the ETC.</p></li></ul></li><li><p>From <strong>Complex II (Succinate dehydrogenase)</strong></p><ul><li><p>Directly transfers electrons from succinate to UQ in the ETC.</p></li></ul></li><li><p>From the 1st step of <strong>ß-oxidation</strong></p></li><li><p>From the <strong>Glycerol 3-P shuttle</strong></p><ul><li><p>Generates NADH and FADH2 during the breakdown of fatty acids, which transfer electrons to UQ in the ETC.</p></li></ul></li></ol><ul><li><p>Once in the <strong>Q pool</strong>, the e- will <u><strong>always</strong></u> go to <strong>complex III</strong></p></li></ul>
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The mechanisms involved in the generation and destruction of free radicals

  • Free radicals: Very dangerous → Mutations to DNA

  • Electron Leakage:

    • Electrons leak and react with molecular oxygen, forming superoxide anion (O2·−).

    • This primarily occurs at Complex I and Complex III.

  • Ubiquinone (Coenzyme Q) Reaction:

    • After electrons pass through the ETC, the ubiquinone (UQH2) reduced form can react with molecular oxygen to produce superoxide anion (O2)→ Escape ETC → Free radicals

      • Things getting out of ETC before getting to O2

        ↳ Problems bc things in ETC are very reactive (environment in chain keep it safe

<ul><li><p><strong>Free radicals:</strong> Very dangerous → Mutations to DNA</p></li><li><p><u><strong>Electron Leakage:</strong></u></p><ul><li><p>Electrons leak and react with molecular oxygen, forming superoxide anion (O2·−).</p></li><li><p>This primarily occurs at Complex I and Complex III.</p></li></ul></li><li><p><u><strong>Ubiquinone (Coenzyme Q) Reaction:</strong></u></p><ul><li><p>After electrons pass through the ETC, the ubiquinone (UQH2) reduced form can react with molecular oxygen to produce superoxide anion (O2)→ Escape ETC → Free radicals</p><ul><li><p>Things getting out of ETC before getting to O2</p><p>↳ Problems bc things in ETC are very reactive  (environment in chain keep it safe</p></li></ul></li></ul></li></ul>
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ATP Synthase and its structure

  • Using H+ gradient to make ATP

  • Movement of 3 H+ → 1 ATP per 1 rotation

  • F0 channel: composed of 12 cylindrical proteins

    • As protons enter →  γ subunit rotates

  • Causes ß subunit of F1 to change its conformation in 3 ways:

    • Accepting ADP + Pi

    • Reacting them together to give ATP

    • Releasing ATP

<ul><li><p>Using H+ gradient to make ATP</p></li><li><p>Movement of 3 H+ → 1 ATP per 1 rotation</p></li><li><p><u><strong>F0 channel:</strong></u> composed of 12 cylindrical proteins</p><ul><li><p>As protons enter →  <strong>γ subunit</strong> rotates</p></li></ul></li><li><p>Causes <strong>ß subunit</strong> of <u><strong>F1</strong></u> to change its conformation in 3 ways:</p><ul><li><p>Accepting ADP + Pi</p></li><li><p>Reacting them together to give ATP</p></li><li><p>Releasing ATP</p></li></ul></li></ul>
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The alternate states of the ß-subunit

  • Every time 3 H+ come in → ß-subunit change conformation

  • Start at any point and follow the ß-subunit ways

  • 3 ß-subunits

<ul><li><p>Every time 3 H+ come in → ß-subunit change conformation</p></li><li><p>Start at any point and follow the ß-subunit ways</p></li><li><p>3 ß-subunits</p></li></ul>
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The contribution of the proton gradient to processes other than the ATP synthase

  • Swapping of ATP/ADP (brings ADP + Pi) takes negative charge outside

    • ATP goes out of into the cytoplasm

    • 3- charges come in, 4- go out

    • Need positive charge to do movement → Use a H+ (proton gradient)

  • The import of Pi consumes H+

<ul><li><p>Swapping of ATP/ADP (brings ADP + Pi) takes negative charge outside</p><ul><li><p>ATP goes out of into the cytoplasm</p></li><li><p>3- charges come in, 4- go out</p></li><li><p>Need positive charge to do movement → Use a H+ (proton gradient)</p></li></ul></li><li><p>The import of Pi consumes H+</p></li></ul>
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Counting ATP

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Inhibitors and Acceptors in ETC

  • Rotenone

    • Inhibit at Complex I

    • Whole chain stops → H+ pumping stops

    • Everything downstream is oxidised (stop consuming O2)

  • Cyanize, Azide and CO

    • Inhibit at Complex IV

    • Whole chain stops → H+ pumping stops

    • Everything upstream is reduced

  • Alternative receptors, e.g. Methylene blue

    • Accepts e- from Complex IV before cyanine blockage point

    • Allow transport to continue

<ul><li><p><u><strong>Rotenone</strong></u></p><ul><li><p>Inhibit at Complex I</p></li><li><p>Whole chain stops → H+ pumping stops</p></li><li><p>Everything <strong>downstream</strong> is <strong>oxidised</strong> (stop consuming O2)</p></li></ul></li><li><p><u><strong>Cyanize, Azide and CO</strong></u></p><ul><li><p>Inhibit at Complex IV</p></li><li><p>Whole chain stops → H+ pumping stops</p></li><li><p>Everything <strong>upstream</strong> is <strong>reduced</strong></p></li></ul></li><li><p><u><strong>Alternative receptors</strong></u>, e.g. Methylene blue</p><ul><li><p>Accepts e- from Complex IV before cyanine blockage point</p></li><li><p>Allow transport to continue</p></li></ul></li></ul>
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Starvation and Some rules

Starvation

  • Begin at the start of the post-absorptive period

    • When all food digested

    • No substrates coming in from gut

  • Reliant on blood and stored fuel

Some Rules

  • Need to keep [blood glucose] ≈ 5 mM (> 4 mM)

    • Euglycemia or Normoglycemia (normal [blood glucose])

  • Under normal circumstances, brain can only use glucose

    • Cannot use FAs which cannot cross Blood Brain Barrier (BBB)

    • Uses ≈ 120g glucose/day

    • Transported by GLUT-1

  • Although we store most of our energy as fat, we cannot convert FA into CHO (carbohydrate/glucose)

    • Acyl CoA can’t be made into Gluconeogenic precursors.

    • Pyruvate (3C) → Acetyl CoA (2C → Glucose is lost) is Irreversible

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Glucose requirements during the first few hours and what happens to them

  • Parts of the kidney, skin and RBCs have obligatory requirements for glucose

    ↳ Cannot use anything else but glucose

  • Other tissues (primarily muscle)

    ↳ Can switch to FAs as an alternate fuel during starvation

General Strategy

  • Glucose conservation: Don’t use it unless you must to

  • Glucose recycling: Don’t fully oxidise it - Generate from Lactate

  • New glucose formation: Make it from other things

First Few Hours

  • Tissues are using glucose → ↓ [blood glucose]

  • Prevent hypoglycemia, liver releases glucose into bloodstream

    • [blood glucose] stays constant to at least euglycemia at ≈ 4 mM

<ul><li><p>Parts of the kidney, skin and RBCs have obligatory requirements for glucose</p><p>↳ Cannot use anything else but glucose</p></li><li><p>Other tissues (primarily muscle)</p><p>↳ Can switch to FAs as an alternate fuel during starvation</p></li></ul><h3><span class="heading-content"><strong>General Strategy</strong></span></h3><ul><li><p><u><strong>Glucose conservation:</strong></u> Don’t use it unless you must to</p></li><li><p><u><strong>Glucose recycling:</strong></u> Don’t fully oxidise it - Generate from <strong>Lactate</strong></p></li><li><p><u><strong>New glucose formation:</strong></u> Make it from other things</p></li></ul><h3><span class="heading-content"><strong>First Few Hours</strong></span></h3><ul><li><p>Tissues are using glucose → ↓ [blood glucose]</p></li><li><p>Prevent hypoglycemia, liver releases glucose into bloodstream</p><ul><li><p>[blood glucose] stays constant to at least euglycemia at ≈ 4 mM</p></li></ul></li></ul>
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What happen at first 24 hours?

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Glycogen Mobilisation or Glycogenolysis

  • Breakdown of glycogen to release glucose.

  • Signal: The binding of glucagon to the receptor on liver cell membrane

  • Glycogen phosphorylase

    • Cleaves glucose units from the glycogen molecule, and a branching enzyme removes branch points using Phosphates.

    • Produce G-1P

    • Rapidly converted into G 6-P

<ul><li><p>Breakdown of glycogen to release glucose.</p></li><li><p><u><strong>Signal:</strong></u> The binding of <strong>glucagon</strong> to the receptor on liver cell membrane</p></li><li><p><strong>Glycogen phosphorylase</strong></p><ul><li><p>Cleaves glucose units from the glycogen molecule, and a branching enzyme removes branch points using <strong>Phosphates.</strong></p></li><li><p>Produce <strong>G-1P</strong></p></li><li><p>Rapidly converted into <strong>G 6-P</strong></p></li></ul></li></ul>
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Phosphorylase Activation by Glucagon

  • Glucagon activates glycogen phosphorylase via cAMP and protein kinase A (PKA).

  • The PKA activates glycogen phosphorylase, leading to glycogen breakdown and glucose release.

<ul><li><p>Glucagon activates <strong>glycogen phosphorylase</strong> via cAMP and protein kinase A (PKA).</p></li><li><p>The PKA activates glycogen phosphorylase, leading to glycogen breakdown and glucose release.</p></li></ul>
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How much ATP is used?

  • Not much ATP is consumed

  • The amount of ATP being used and amount of cAMP being made are very tiny → Not really affect [ATP]cell

    • cAMP is the 2nd messenger in the pathway

    • Tiny changes in conc are detected by PKA (Protein Kinase A)

  • PKA is activated by removing a regulatory inhibitory subunit

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Why it’s so complicated?

  • Amplification through 2nd messenger and cascade, rather than directed binding

    • Massive response from small signal

      ↳ Each step catalysed by an enzyme

    • More control over the whole process

      ↳ Each enzyme can be further influenced by other factors (e.g. Ca2+ and AMP)

  • ≠ in muscle → Adrenaline is the stimulant

<ul><li><p>Amplification through 2nd messenger and cascade, rather than directed binding</p><ul><li><p>Massive response from small signal</p><p>↳ Each step catalysed by an enzyme</p></li><li><p>More control over the whole process</p><p>↳ Each enzyme can be further influenced by other factors (e.g. Ca2+ and AMP)</p></li></ul></li><li><p>≠ in muscle → Adrenaline is the stimulant</p></li></ul>
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Branch points of Glucose

  • Debranching enzyme

  • At the branch points, a simple hydrolysis is used

  • ≈ 10% of the glucose residues are released as glucose (not glucose 1-P)

<ul><li><p><u><strong>Debranching enzyme</strong></u></p></li><li><p>At the branch points, a simple hydrolysis is used</p></li><li><p>≈ 10% of the glucose residues are released as glucose (<u>not</u> glucose 1-P)</p></li></ul>
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Does muscle contribute to blood glucose?

  • Muscle doesn’t breakdown glycogen much in starvation, bc

    • NO glucagon receptors

    • NO G6Pase (only liver has)

      ↳ Cannot convert G6P to glucose → Cannot release glucose into blood.

  • However, some glucose residues in glycogen are released as neat glucose

    • B/c debranching enzyme uses water to hydrolysed the glycosidic linkages, not phosphate

    • ≈ 10% potentially released

  • Muscle is selfish with its glucagon, but what if PDH is inhibited, G6P will go to lactate

<ul><li><p>Muscle <u>doesn’t</u> breakdown glycogen much in starvation, bc</p><ul><li><p>NO glucagon receptors</p></li><li><p>NO <strong>G6Pase</strong> (only liver has)</p><p>↳ Cannot convert G6P to glucose → Cannot release glucose into blood.</p></li></ul></li><li><p>However, some glucose residues in glycogen are released as neat glucose</p><ul><li><p>B/c debranching enzyme uses water to hydrolysed the <strong>glycosidic linkages</strong>, not phosphate</p></li><li><p>≈ 10% potentially released</p></li></ul></li><li><p>Muscle is selfish with its glucagon, but what if PDH is inhibited, G6P will go to lactate</p></li></ul>
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White Adipose Tissue (WAT) Lipolysis

  • WAT lipolysis is the breakdown of stored fat in white adipose tissue.

  • Accessing the large reserves of fat in WAT

  • Glucagon → ↑ [cAMP] → ↑ activity of PKA

  • PKA then phosphorylates Hormone Sensitive Lipase (HSL) (breakdown fat) → Cleaves triglycerides into fatty acids and glycerol.

    • PKA also phosphorylates perilipin (shell surrounding the vacuole)

      ↳ Allow the activated HSL to interact with the fat

  • FAs released into the bloodstream

  • Glycerol can return to liver → Convert back to glucose (small amount)

<ul><li><p>WAT lipolysis is the breakdown of stored fat in white adipose tissue.</p></li><li><p>Accessing the large reserves of fat in WAT</p></li><li><p>Glucagon → ↑ [cAMP] → ↑ activity of PKA</p></li><li><p>PKA then phosphorylates <u><strong>Hormone Sensitive Lipase (HSL)</strong></u> (breakdown fat) → Cleaves <strong>triglycerides</strong> into fatty acids and glycerol.</p><ul><li><p>PKA also phosphorylates <strong>perilipin</strong> (shell surrounding the vacuole)</p><p>↳ Allow the activated HSL to interact with the fat</p></li></ul></li><li><p>FAs released into the bloodstream</p></li><li><p>Glycerol can return to liver → Convert back to glucose (small amount)</p></li></ul>
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What are the effects of FA oxidation?

  • FAs will be oxidised to provide the acetyl CoA for the Krebs Cycle

    • But need to avoid oxidation

    • PDH ( pyruvate → AcCoA) is Irreversible

  • GLUT-1 is still present in muscle

    • Even though GLUT-4s were endocytosed due to a lack of insulin

      ↳ Muscle can still take up glucose

  • Need to preserve glucose

    • Get tissues to stop oxidising glucose

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Activating PDH

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Glucose-Fatty Acid Cycle

In starvation, PDH needs to be off

  • PDH Kinase activity >> PDH phosphate activity

  • Acetyl CoA stimulates PDH

  • PDH is inactive when phosphorylated

  • Prevents wasteful oxidation of pyruvate

  • Pyruvate only converted into lactate

When PDH is off

  • Pyruvate cannot be oxidised to acetyl CoA

    • Then, there is only 1 fate for pyruvate in the muscle to be converted into lactate by LDH.

  • Lactate can be taken up by liver.

    • Remade into glucose by gluconeogenesis

  • Called Cori-cycle

    • Muscle glucose → Pyruvate → Lactate → Liver → Glucose (via gluconeogenesis) → Glucose into bloodstream again

  • Gluconeogenesis can also happen from glycerol

    • Made by 30g glucose per day

    • Glycerol (from lipolysis) is the only source of de novo gluconeogenesis

      • Lactate-fueled gluconeogenesis is recycling

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What is Proteolysis?

  • The process of breaking down proteins into smaller peptide fragments or individual amino acids.

  • After a few a hrs, [blood glucose] < 5 mM → Insulin secretion stops

    • Important in stimulating lipolysis

  • HypoinsulinemiaProteolysis

    • Release of amino acids from tissues (mainly muscles)

  • Many amino acid ‘carbon skeletons’ are used for gluconeogenesis

    • Need to get amino acids to the liver

    • Need to do sth with an amine group (Ammonia is poisonous)

  • Carbon skeletons – the portion of the molecule remaining after the removal of nitrogen

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What are Processing Amino Acids and the Fate of Amine Groups?

Processing Amino Acids

  • Channel amine groups to 3 amino acids

    Alanine, Glutamate and Aspartate

  • 3 acceptors are all found in the main pathways

    • Pyruvate Alanine

    • α-ketoglutarate Glutamate

    • Oxaloacetate Aspartate

  • Result in α-keto acids used in gluconeogenesis

Fate of Amine Groups

  • Urea Cycle – Only in liver

    • The body’s way of converting toxic ammonia into urea.

  • Ammine groups are channelled into urea.

    • Synthesised from aspartate and glutamate

    • Consume lots of ATP

  • Urea is non-toxic

<h3><span class="heading-content"><strong>Processing Amino Acids</strong></span></h3><ul><li><p>Channel amine groups to 3 amino acids</p><p>↳ <strong>Alanine</strong>, <strong>Glutamate</strong> and <strong>Aspartate</strong></p></li><li><p>3 acceptors are all found in the main pathways</p><ul><li><p><mark data-color="red"><u><strong>Pyruvate</strong></u></mark> <strong>→</strong> <mark data-color="red"><strong>Alanine</strong></mark></p></li><li><p><mark data-color="yellow"><u><strong>α-ketoglutarate</strong></u></mark> <strong>→</strong> <mark data-color="yellow"><strong>Glutamate</strong></mark></p></li><li><p><mark data-color="red"><u><strong>Oxaloacetate</strong></u></mark> <strong>→</strong> <mark data-color="red"><strong>Aspartate</strong></mark></p></li></ul></li><li><p>Result in <strong>α-keto acids</strong> used in gluconeogenesis</p></li></ul><h3><span class="heading-content"><strong>Fate of Amine Groups</strong></span></h3><ul><li><p><u><strong>Urea Cycle</strong></u> – Only in liver</p><ul><li><p>The body’s way of converting toxic ammonia into urea.</p></li></ul></li><li><p>Ammine groups are channelled into urea.</p><ul><li><p>Synthesised from aspartate and glutamate</p></li><li><p>Consume lots of ATP</p></li></ul></li><li><p>Urea is non-toxic</p></li></ul>
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What is Gluconeogenesis?

  • A reversal of Glycolysis

    • Amino acids and glycerol are converted into glucose.

  • Maintains blood glucose levels during fasting or low carbohydrate intake.

  • Except 3 ‘rate limiting ‘ steps bypassed

    • Hexokinase Glucose trapping step

    • Phosphofructokinase Rate limiting step

    • Pyruvate Kinase Final and Energy releasing step

  • Completing the pathway only in liver

    • Mainly cytoplasmic → Pyruvate carboxylase

  • Substrates:

    • Lactate Enter as pyruvate at the bottom

    • Glycerol Enter as dihydroxyacetone phosphate

    • Amino acid carbon skeletons Enter as various places

<ul><li><p>A reversal of Glycolysis</p><ul><li><p>Amino acids and glycerol are converted into glucose.</p></li></ul></li><li><p>Maintains blood glucose levels during fasting or low carbohydrate intake.</p></li><li><p><strong>Except</strong> 3 ‘rate limiting ‘ steps bypassed</p><ul><li><p><mark data-color="red"><u><strong>Hexokinase</strong></u></mark> <strong>→</strong> <mark data-color="red"><strong>Glucose trapping step</strong></mark></p></li><li><p><mark data-color="yellow"><u><strong>Phosphofructokinase</strong></u></mark> <strong>→</strong> <mark data-color="yellow"><strong>Rate limiting step</strong></mark></p></li><li><p><mark data-color="red"><u><strong>Pyruvate Kinase</strong></u></mark> <strong>→</strong> <strong>Final</strong> and <mark data-color="red"><strong>Energy releasing step</strong></mark></p></li></ul></li><li><p>Completing the pathway <u>only</u> in liver</p><ul><li><p>Mainly cytoplasmic → <strong>Pyruvate carboxylase</strong></p></li></ul></li><li><p><u>Substrates:</u></p><ul><li><p><u><strong>Lactate</strong></u> <strong>→</strong> Enter as <strong>pyruvate</strong> at the bottom</p></li><li><p><u><strong>Glycerol</strong></u> <strong>→</strong> Enter as <strong>dihydroxyacetone phosphate</strong></p></li><li><p><u><strong>Amino acid carbon skeletons</strong></u> <strong>→</strong> Enter as various places</p></li></ul></li></ul>
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Can all amino acid skeleton make glucose?

  • Not all AA skeletons can make glucose

  • A carbon skeleton can be converted into an intermediate for gluconeogenesis.

  • Cost for lots of energy to make proteins (made for reasons)

    • Lots of ATP is required to dispose of the amine groups

  • Not all amino acids made into glucose

  • Many amino acids from proteolysis are burnt before release from tissue.

  • Need extra 90g glucose (breakdown 180g) per day

<ul><li><p>Not all AA skeletons can make glucose</p></li><li><p>A carbon skeleton can be converted into an intermediate for gluconeogenesis.</p></li><li><p>Cost for lots of energy to make proteins (made for reasons)</p><ul><li><p>Lots of ATP is required to dispose of the amine groups</p></li></ul></li><li><p>Not all amino acids made into glucose</p></li><li><p>Many amino acids from proteolysis are burnt before release from tissue.</p></li><li><p>Need extra 90g glucose (breakdown 180g) per day</p></li></ul>
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Lipolysis + ß-Oxidation

  • After 2-3 days of starvation, the rate of lipolysis will be at max.

    • FA released into bloodstream → ↑ [FA] in blood → More FA than is needed

  • ß-Oxidation in Liver

    • Rate depends on the demand of ATP by the tissues

      • Generation of CoA by Krebs Cycle needed to keep FA oxidation going

      • Rate of Krebs Cycle strictly regulate by demand for ATP

    • BUT ß-oxidation can occur even if ATP isn't required

      • Other pathways can regenerate CoA from acetyl-CoA

<ul><li><p>After 2-3 days of starvation, the rate of lipolysis will be at max.</p><ul><li><p>FA released into bloodstream → ↑ [FA] in blood → More FA than is needed</p></li></ul></li><li><p>ß-Oxidation in Liver</p><ul><li><p>Rate depends on the demand of ATP by the tissues</p><ul><li><p>Generation of CoA by Krebs Cycle needed to keep FA oxidation going</p></li><li><p>Rate of Krebs Cycle strictly regulate by demand for ATP</p></li></ul></li><li><p>BUT ß-oxidation can occur even if ATP isn&apos;t required</p><ul><li><p>Other pathways can regenerate CoA from acetyl-CoA</p></li></ul></li></ul></li></ul>
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What is the function of Fate of Acetoacetate (Ketone body)?

  • Acetoacetate, or a Ketone body, is used as an alternative energy source by various tissues for energy.

  • It can be converted

    • Back into acetyl-CoA to generate ATP or

    • Into other ketone bodies like beta-hydroxybutyrate and acetone.

  • Split in the mitochondria to acetyl CoA

    • An instant source of fuel for the Krebs Cycle

    • AcCoA inhibits PDH and stimulates PDH kinase

  • Reduces brain glucose consumption

<ul><li><p><u><strong>Acetoacetate,</strong></u> or a <u><strong>Ketone body</strong></u>, is used as an alternative energy source by various tissues for energy.</p></li><li><p>It can be converted</p><ul><li><p>Back into <strong>acetyl-CoA</strong> to generate ATP or</p></li><li><p>Into other ketone bodies like <strong>beta-hydroxybutyrate</strong> and <strong>acetone</strong>.</p></li></ul></li><li><p>Split in the mitochondria to acetyl CoA</p><ul><li><p>An instant source of fuel for the Krebs Cycle</p></li><li><p>AcCoA inhibits PDH and stimulates PDH kinase</p></li></ul></li><li><p>Reduces brain glucose consumption</p></li></ul>
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Functions of Acetoacetate (Ketone body)

Inefficiency in Ketone Body Metabolism

  • Nothing inefficient about the oxidation

  • But ketone body

    • Lost in the urine

    • Spontaneously decarboxylate

Have Ketone Bodies Saved Us?

  • Make 30g glucose per day from glycerol

  • After 2 days of starvation

    • Brain using 120g glucose a day

    • Protein loss > 100g protein/day

  • After 3-4 days

    • Ketone bodies are lowering the brain’s need for glucose

    • Protein losses ≈ 75g/day

  • By day 5

    • Brain using 30g glucose/day

<h3><span class="heading-content"><strong>Inefficiency in Ketone Body Metabolism</strong></span></h3><ul><li><p>Nothing inefficient about the oxidation</p></li><li><p>But ketone body</p><ul><li><p>Lost in the urine</p></li><li><p>Spontaneously decarboxylate</p></li></ul></li></ul><h3><span class="heading-content"><strong>Have Ketone Bodies Saved Us?</strong></span></h3><ul><li><p>Make 30g glucose per day from glycerol</p></li><li><p>After 2 days of starvation</p><ul><li><p>Brain using 120g glucose a day</p></li><li><p>Protein loss &gt; 100g protein/day</p></li></ul></li><li><p>After 3-4 days</p><ul><li><p>Ketone bodies are lowering the brain’s need for glucose</p></li><li><p>Protein losses ≈ 75g/day</p></li></ul></li><li><p>By day 5</p><ul><li><p>Brain using 30g glucose/day</p></li></ul></li></ul>
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How is the protein related to tissues' demand performing?

  • Proteins are lost from all tissues

    • Inactive muscles slightly preferentially degraded

  • Will reach equilibrium

    • The loss of body protein is ultimately what kills us

    • Loss of function

    • Much more prone to infection

Amount of protein breakdown = (amount of glucose needed - 30) x ≈ 2

<ul><li><p>Proteins are lost from all tissues</p><ul><li><p>Inactive muscles slightly preferentially degraded</p></li></ul></li><li><p>Will reach equilibrium</p><ul><li><p>The loss of body protein is ultimately what kills us</p></li><li><p>Loss of function</p></li><li><p>Much more prone to infection</p></li></ul></li></ul><h3><span class="heading-content">Amount of protein breakdown = (amount of glucose needed - 30) x ≈ 2</span></h3>
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The importance of Glucagon

  • Glucagon promotes glycogen breakdown (glycogenolysis) and stimulates gluconeogenesis, which raises blood glucose.

  • Maintains glucose homeostasis during fasting.

<ul><li><p>Glucagon promotes glycogen breakdown (glycogenolysis) and stimulates gluconeogenesis, which raises blood glucose.</p></li><li><p>Maintains glucose homeostasis during fasting.</p></li></ul>
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Energy Charge and ATP

  • ATP is not the most energy-containing molecule in metabolism

  • Need to keep at 5 mM

  • Instant reserves

    • Compounds that phosphorylate substrates

  • Only few seconds supply

    • Still need ↑ catabolic pathway

ATP

  • Energy released when any of the terminal phosphates are hydrolysed

  • ATP → ADP or ADP → AMP releasing energy

Adenylate Kinase (AK)

  • Converts ATP to ADP, helping to buffer energy fluctuations.

  • 2ADP ↔ ATP + AMP

  • Translate small change in ATP and large change in AMP

  • Ratio of [Adenine molecule] = Energy charge

    • Key molecule: AMP

    • ATP:ADP kept high

  • Key enzymes very sensitive to [ADP]

<ul><li><p>ATP is <u><strong>not</strong></u> the most energy-containing molecule in metabolism</p></li><li><p>Need to keep at 5 mM</p></li><li><p>Instant reserves</p><ul><li><p>Compounds that phosphorylate substrates</p></li></ul></li><li><p>Only few seconds supply</p><ul><li><p>Still need ↑ catabolic pathway</p></li></ul></li></ul><h3><span class="heading-content"><strong>ATP</strong></span></h3><ul><li><p>Energy released when any of the terminal phosphates are hydrolysed</p></li><li><p>ATP → ADP or ADP → AMP releasing energy</p></li></ul><h3><span class="heading-content"><strong>Adenylate Kinase (AK)</strong></span></h3><ul><li><p>Converts ATP to ADP, helping to buffer energy fluctuations.</p></li><li><p>2ADP ↔ ATP + AMP</p></li><li><p>Translate small change in ATP and large change in AMP</p></li><li><p>Ratio of [Adenine molecule] = <strong>Energy charge</strong></p><ul><li><p><u>Key molecule:</u> AMP</p></li><li><p>ATP:ADP kept high</p></li></ul></li><li><p>Key enzymes very sensitive to [ADP]</p></li></ul>
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Which enzymes are controlled these?

Rate-limiting step (RLS)

  • Slowest enzyme-catalysed reaction in a metabolic pathway.

  • Control the overall rate of metabolic activity

  • Irreversible

    • Need alternative enzymes to go back

    • NOT equilibrium under physiological conditions

  • Saturated (bao hoa) with substrate.

    • Low Km or [S] > Km

    • Working at Vmax

Flux generating step

  • Contributes significantly to the overall flux or rate of metabolite flow through the pathway.

  • Often associated with the rate-limiting step, as it determines the overall speed of the pathway.

  • 3 major ways to regulate

    • Make the rate-limiting enzyme go faster/slower

    • Turn the rate-limiting enzyme on/off or make it work the other way

    • ↑ rate of transcription/translation of the RLS or change its rate of degradation

<h3><span class="heading-content"><strong>Rate-limiting step (RLS)</strong></span></h3><ul><li><p>Slowest enzyme-catalysed reaction in a metabolic pathway.</p></li><li><p>Control the overall rate of metabolic activity</p></li><li><p>Irreversible</p><ul><li><p>Need alternative enzymes to go back</p></li><li><p>NOT equilibrium under physiological conditions</p></li></ul></li><li><p>Saturated (bao hoa) with substrate.</p><ul><li><p>Low Km or [S] &gt; Km</p></li><li><p>Working at Vmax</p></li></ul></li></ul><h3><span class="heading-content"><strong>Flux generating step</strong></span></h3><ul><li><p>Contributes significantly to the overall flux or rate of metabolite flow through the pathway.</p></li><li><p>Often associated with the rate-limiting step, as it determines the overall speed of the pathway.</p></li><li><p>3 major ways to regulate</p><ul><li><p>Make the rate-limiting enzyme go faster/slower</p></li><li><p>Turn the rate-limiting enzyme on/off or make it work the other way</p></li><li><p>↑ rate of transcription/translation of the RLS or change its rate of degradation</p></li></ul></li></ul>
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Overall catabolic pathway

knowt flashcard image
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Allosteric PFK (Phosphofructokinase)

  • Involved in the anabolic pathway of glycolysis.

  • Catalyses the breakdown of glucose for energy by converting fructose-6-phosphate to fructose-1,6-bisphosphate.

    F6P + ATP → F1,6BP

  • In the catabolic pathway, PFK acts as an allosteric regulator of glycolysis and ATP production.

  • The binding of ATP and AMP to PFK ensures efficient energy use.

    • Has binding sites for AMP away from the active site.

      ↳ Biniding AMP changes the way PFK responds to ATP

  • Also binds Citrate allosterically

    • Citrate inhibits PFK

    • [Citrate] high → ↑ PFK → ↓ Glycolysis

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Hexokinase – Feedback Inhibition

  • Involved in the first step of glycolysis, it catalyses glucose phosphorylation to produce glucose-6-phosphate (G6P).

    • G6P levels control the activity of hexokinase through feedback inhibition.

  • In feedback inhibition, G6P acts as an allosteric inhibitor of hexokinase.

  • ↑ G6P levels = Sufficient glucose or saturated downstream metabolic pathways.

    ↳ Hexokinase is inhibited → Slowing down the phosphorylation of glucose and ↓ the flux of glucose through glycolysis → ↓ Glycolysis

  • Prevent unnecessary accumulation of G6P and ensures that glucose is utilized efficiently.

    • Prevent waste of ATP

    • Allow glucose to go back out of the cell

  • If G6P is not used, glucose is not trapped

<ul><li><p>Involved in the first step of glycolysis, it catalyses glucose phosphorylation to produce <strong>glucose-6-phosphate (G6P)</strong>.</p><ul><li><p>G6P levels control the activity of <u><strong>hexokinase</strong></u> through <strong>feedback inhibition</strong>.</p></li></ul></li><li><p>In feedback inhibition, G6P acts as an allosteric inhibitor of hexokinase.</p></li><li><p>↑ G6P levels = Sufficient glucose or saturated downstream metabolic pathways.</p><p>↳ Hexokinase is inhibited → Slowing down the phosphorylation of glucose and ↓ the flux of glucose through glycolysis → ↓ Glycolysis</p></li><li><p>Prevent unnecessary accumulation of G6P and ensures that glucose is utilized efficiently.</p><ul><li><p>Prevent waste of ATP</p></li><li><p>Allow glucose to go back out of the cell</p></li></ul></li><li><p>If G6P is not used, glucose is not trapped</p></li></ul>
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PDH – Covalent Modification

  • Inactivated by phosphorylation (totally OFF)

    • Phosphorylation inhibits PDH activity, while dephosphorylation activates it.

  • Help control the conversion of pyruvate to acetyl-CoA based on energy demands.

  • The total amount of enzyme doesn’t change

    • Phosphorylated : Dephosphorylated ratio

  • Reactivation by phosphate

    • Release of phosphate

    • Totally ON

  • PDH activity balance between kinase and phosphate

<ul><li><p>Inactivated by phosphorylation (totally OFF)</p><ul><li><p>Phosphorylation inhibits PDH activity, while dephosphorylation activates it.</p></li></ul></li><li><p>Help control the conversion of pyruvate to acetyl-CoA based on energy demands.</p></li><li><p>The total amount of enzyme doesn’t change</p><ul><li><p><strong>Phosphorylated : Dephosphorylated ratio</strong></p></li></ul></li><li><p>Reactivation by phosphate</p><ul><li><p>Release of phosphate</p></li><li><p>Totally ON</p></li></ul></li><li><p>PDH activity balance between kinase and phosphate</p></li></ul>
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<p>Fuel Selection</p>

Fuel Selection

  • Catabolism vs. Anabolism

    • Glycolysis vs. Gluconeogenesis

    • ß-Oxidation vs. FA synthesis

  • When 1 pathway is stimulated, the opposite is inhibited

  • When they both occur at the same time → Futile Cycle

    • A net loss of energy without any productive outcome.

    • Regulatory purposes but generally leads to wasteful energy expenditure.

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Gluconeogenesis and its pathway

  • Getting from 3C to 6C

    • Bypassing hexokinase and PFK → PFK-1

  • G6Pase (only in liver) and F1

  • NO ATP gained from the loss of phosphate at these steps

  • PC (Pyruvate Carboxylase)

    • In the mitochondria.

    • Crucial role in gluconeogenesis, converting pyruvate into oxaloacetate

      ↳ Further converted into glucose.

    • Stimulated by acetyl-CoA (FA oxidation)

    • Acetyl-CoA levels high when ß-Oxidation prominent

    • Inhibition of PDH → Prevenr wasteful oxidation of glucose

  • PEPCK (phosphoenolpyruvate carboxykinase)

    • Involved in gluconeogenesis, converting oxaloacetate to phosphoenolpyruvate (PEP).

    • Crucial role in maintaining blood glucose levels during fasting

    • Regulated by hormones such as glucagon and cortisol.

    • Stimulated by ↑ transcription/translation of gene

  • These enzymes can exist in tissues other than liver

    • Enables glycerol to be made from pyruvate

<ul><li><p>Getting from 3C to 6C</p><ul><li><p>Bypassing hexokinase and PFK → <strong>PFK-1</strong></p></li></ul></li><li><p><u><strong>G6Pase</strong></u> (only in liver) and <u><strong>F1</strong></u></p></li><li><p>NO ATP gained from the loss of phosphate at these steps</p></li><li><p><mark data-color="red"><u><strong>PC (Pyruvate Carboxylase)</strong></u></mark></p><ul><li><p>In the mitochondria.</p></li><li><p>Crucial role in gluconeogenesis, converting pyruvate into oxaloacetate</p><p>↳ Further converted into glucose.</p></li><li><p>Stimulated by <strong>acetyl-CoA (FA oxidation)</strong></p></li><li><p>Acetyl-CoA levels high when ß-Oxidation prominent</p></li><li><p>Inhibition of PDH → Prevenr wasteful oxidation of glucose</p></li></ul></li><li><p><mark data-color="red"><u><strong>PEPCK (phosphoenolpyruvate carboxykinase)</strong></u></mark></p><ul><li><p>Involved in gluconeogenesis, converting oxaloacetate to <strong>phosphoenolpyruvate (PEP)</strong>.</p></li><li><p>Crucial role in maintaining blood glucose levels during fasting</p></li><li><p>Regulated by hormones such as glucagon and cortisol.</p></li><li><p>Stimulated by ↑ transcription/translation of gene</p></li></ul></li><li><p>These enzymes can exist in tissues other than liver</p><ul><li><p>Enables glycerol to be made from pyruvate</p></li></ul></li></ul>
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Synthesis of PEP from Pyruvate

  • Pyruvate is carboxylated to form oxaloacetate by pyruvate carboxylase (PC).

  • Oxaloacetate is then converted to PEP by phosphoenolpyruvate carboxykinase (PEPCK).

  • Essential for gluconeogenesis, allowing the body to generate glucose from non-carbohydrate sources.

<ul><li><p>Pyruvate is carboxylated to form oxaloacetate by <mark data-color="red"><u><strong>pyruvate carboxylase (PC)</strong></u></mark>.</p></li><li><p>Oxaloacetate is then converted to PEP by <mark data-color="red"><u><strong>phosphoenolpyruvate carboxykinase (PEPCK)</strong></u></mark>.</p></li><li><p>Essential for gluconeogenesis, allowing the body to generate glucose <strong>from non-carbohydrate sources</strong>.</p></li></ul>
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Why 2-deoxy glucose can’t be used in glycolysis

  • B/c it lacks a hydroxyl group (OH-) at the C2 position

  • Preventing it from being efficiently phosphorylated by hexokinase.

  • A key step in glycolysis.

  • Acts as a competitive inhibitor of hexokinase and blocks the entry of glucose into the glycolytic pathway.

<ul><li><p>B/c it lacks a hydroxyl group (OH-) at the C2 position</p></li><li><p>Preventing it from being efficiently phosphorylated by hexokinase.</p></li><li><p>A key step in glycolysis.</p></li><li><p>Acts as a <strong>competitive inhibitor of hexokinase</strong> and <strong>blocks</strong> the entry of glucose into the glycolytic pathway.</p></li></ul>
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F26BP affects PFK-1 and FBPase-1

  • Reversal of F6P → F16BP

  • PFK-2 and FBPase-2 are the same enzyme

    • Swapping from 1 form to another after reversible phosphorylation

  • Interconversion catalysed by Protein Kinase A (PKA) and [glucagon] and [insulin]

    • Sensitive to cAMP

<ul><li><p>Reversal of <strong>F6P → F16BP</strong></p></li><li><p><strong>PFK-2</strong> and <strong>FBPase-2</strong> are the same enzyme</p><ul><li><p>Swapping from 1 form to another after reversible phosphorylation</p></li></ul></li><li><p>Interconversion catalysed by <strong>Protein Kinase A (PKA)</strong> and [glucagon] and [insulin]</p><ul><li><p>Sensitive to cAMP</p></li></ul></li></ul>
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Gluconeogenesis & Glycolysis

  • During starvation

    • ↑ Glucagon → ↑ [cAMP)

    • ↓ [F2,6]

      • NO stimulus for PFK → NO glycolysis

      • NO inhibition of F1,6BPase → Gluconeogenesis

  • F6O → F16BP stimulated by allosteric effector F26BP

    • F26BP made by PFK-2

    • F26BP inhibits F16BPase and stimulates PFK

    • When F26BP is highGlycolysis is favoured

  • Phosphorylation of PFK-2 converts it into F26BPase

    • ↓ [F26BP]

    • PFK is inhibited

    • ↑ F16BPase activity

    • When F26BP is lowGluconeogenesis is favoured

  • Phosphorylation is catalysed by cAMP-dependant protein kinase (or PKA)

    • cAMP stimulates PKA

    • cAMP are high when glucagon bound to receptors on liver cell

  • F16BPase is more active when [glucagon] high

    • As in starvation

<ul><li><p>During starvation</p><ul><li><p>↑ Glucagon → ↑ [cAMP)</p></li><li><p>↓ [F2,6]</p><ul><li><p>NO stimulus for PFK → NO glycolysis</p></li><li><p>NO inhibition of F1,6BPase → Gluconeogenesis</p></li></ul></li></ul></li><li><p><strong>F6O → F16BP</strong> stimulated by allosteric effector <u><strong>F26BP</strong></u></p><ul><li><p>F26BP made by PFK-2</p></li><li><p>F26BP inhibits F16BPase and stimulates PFK</p></li><li><p>When F26BP is <mark data-color="red"><strong>high</strong></mark> → <mark data-color="red"><strong>Glycolysis</strong></mark> is favoured</p></li></ul></li><li><p>Phosphorylation of PFK-2 converts it into <u><strong>F26BPase</strong></u></p><ul><li><p>↓ [F26BP]</p></li><li><p>PFK is inhibited</p></li><li><p>↑ F16BPase activity</p></li><li><p>When F26BP is <mark data-color="yellow"><strong>low</strong></mark> → <mark data-color="yellow"><strong>Gluconeogenesis</strong></mark> is favoured</p></li></ul></li><li><p>Phosphorylation is catalysed by cAMP-dependant protein kinase (or PKA)</p><ul><li><p>cAMP stimulates PKA</p></li><li><p>cAMP are high when glucagon bound to receptors on liver cell</p></li></ul></li><li><p>F16BPase is more active when [glucagon] high</p><ul><li><p>As in starvation</p></li></ul></li></ul>
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Anaplerosis

  • In the citric acid cycle, anaplerotic reactions refill oxaloacetate after consumption.

  • Maintain adequate ATP levels for continuous cellular respiration.

<ul><li><p>In the citric acid cycle, <u><strong>anaplerotic reactions</strong></u> refill oxaloacetate after consumption.</p></li><li><p>Maintain adequate ATP levels for continuous cellular respiration.</p></li></ul>
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Is Glucose toxic?

  • Brain can’t live without it

    • Need to keep [blood glucose] at 4-5 mM

  • Very reactive in vivo

    • Glycation: Non-enzymatic glycosylation of protein

    • Destroys protein function

    • Rate is directly proportional to [glucose]

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