BCH210H1 Lecture Notes - Lecture 35: Ketogenic Amino Acid, Acetyl-Coa, Citric Acid Cycle
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Lecture 35: Ketogenesis and Diabetes
Recall B-oxidation
• Fat reseres are a huge soure of Aetyl CoA ad geerate ore ATP ia β-oxidation than glucose alone
- Acyl CoA is dependant on oxaloacetate → need to do something else if not enough
• Catabolism of ketogenic amino acids can also produce Acetyl CoA (Atkins diet?)
- Atkins diet – high protein, low carb diet → lots of acetyl CoA but not enough oxaloacetate from glucose
• Fat and amino acid catabolism occurs when epinephrine and glucagon (GPCR signalling) dominate (activation of
certain enzymes)
• Acetyl CoA enters the Citric Acid Cycle but is limited by the amount of oxaloacetate present
• Ketogenesis occurs when acetyl CoA levels rise so that ketone bodies can be used as an alternate fuel source to
glucose
- Ketones can be used throughout the body after being released into the blood
- Amino acids → acetyl CoA → ketone bodies
Fates of acetyl CoA
• We need oxaloacetate to make citrate (generate energy through NADH,etc) where the energy created can go
back to inhibit CAC, causing citrate build up
- Citrate will be exported out of mitochondria for fat synthesis or can synthesize cholesterol
- Need to have oxaloacetate for this
• No oxaloacetate (aka no pyruvate carboxylase) then ketones made – can use to generate ATP in the liver
• Acetyl CoA → Citrate → Citric acid cycle → CO2 + energy
Amino acids and carbon metabolism
• We do’t at to reak aio aids or aro
but if we must we need to – proteases break
them into individual AAs
• AA can be used in liver to make ketone bodies
(ketogenic AA) or glucose (glucogenic AA)
• CAC will go all the way around oxaloacetate to
generate glucose via GNG
Ketone bodies produced in the liber
• Only two have ketone groups –
betahydroxybutyrate has carboxyl acid
• Structures resemble acetyl CoA – first two used as energy source but
contribute to acidosis
- Acetone is exhaled waste produce – can detect ketogenesis via this
• Because pKa of COO- group, proton will be released, creating acidosis
• At physiological pH, it is deprotonated and will contribute to acidosis
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Ketone body synthesis
• Made in the mitochondrial matrix in the liver –
3 acetyl CoA will come together to form 3
ketone bodies
1. Condensation reaction to bring together two
acetyl CoA molecules
2. HMB-CoA synthase will use another CoA – this
is made in the cholesterol synthesis
- Creates molecule HMG-CoA
3. Acetoacetate made from HMG-CoA lyase – first
ketone body
- Lost CoA molecule so it can be exported and used for energy in other cells
4. Dehydrogenase will metabolize further to create 3-hydroxy-butrate using NADH (optional)
- Reaction occurs because this molecule is more stable
- You can also decarboxylate it to create acetone (happens spontaneously)
• Pathway only makes one at a time, but it happens a lot causing the pool of ketones
• Oxaloacetate levels low when you have low carbohydrate concentrations
• Fored i lier itohodria usig aetyl CoA fro β-oxidation (& amino acid degradation)
• Ketone bodies leave the liver and enter the blood
• Aetoaetate ad β-hydroxybutyrate can be used as fuel by the brain, heart, muscle and kidney cells
• The production of acidic ketone bodies contributes to a drop in blood pH (acidosis)
• Acetone is a waste product and gives a characteristic fruity breath symptom
• Conversion back to Acetyl CoA can provide access to large amounts of ATP
Use of ketone bodies as fuel by brain or other tissues
• Reverse reaction to create 2 acetyl CoA via reaction beside – used to create energy
Blood pH, CO2 and bicarbonate
• H+ + HCO3- → H2CO3 → H2O + CO2
• CO2 decrease from exhaling deeply, [HCO2-] decreases
• Therer’s a uffer syste to help itigate the protoatio
- Bicarbonate combines with protons to break down into H2O and CO2
- CO2 exhaled to help buffer and remove protons from blood
• High exhale might be an indicator of acidosis, but consequence is that bicarbonate is
reduced – too much is problem because if you get rid of all bicarbonate, it will worsen
Keto(acido)sis
• Occurs when ketone levels rise in the body due to depleted liver glycogen stores
• Blood buffering system initially compensates along with H+ absorption by bone and tissue and renal secretion
• Acidosis occurs when blood pH drops below 7.35 (why is this bad?)
- Would cause dissociation of proteins that will get protonated → enzymatic sites
- Would cause denaturation of proteins that would be detrimental
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