Carbohydrates –pyruvate oxidation & citric acid cycle (TCA cycle) Flashcards
briefly explain the complete oxidation of glucose
glucose-> 2 pyruvate ( leaving: 2 ATP and 2 NADH)
2 Pyruvate enters the mitochondria to form 2 acetyl coA ( expenditure: 2 NADH and 2 CO2)
2 Acetyl CoA enter the kreb cycle ( leaving: 6 NADH and 2 FADH2, 4 CO2, 2ATP)
All the NADH’s(10) and FADH2(2) enter the ETC in the inner mitochrondrial membrane to release H+ ions and all the H+ are brought back in through the 5th complex–> 28 ATP is generated
What are the alternate pathways of pyruvate other than entering the kreb cycle as acetly CoA?
It can turn in to lactate
What type of reaction occurs when pyruvate is becoming acetly CoA? What are the three components to pyruvate dehydrogenase complex? What are the 5 coenzymes?
•Oxidative decarboxylation reaction
•Links glycolysis with TCA cycle ‘link reaction’
•Three component enzymes
->Pyruvate dehydrogenase (pyruvate decarboxylase; E1)
->Dihydrolipoyl transacetylase (E2)
->Dihydrolipoyl dehydrogenase (E3)
•Five coenzymes
->Thiamine pyrophosphate (TPP), from thiamine (vitamin B1)
->Lipoic acid
->Coenzyme A (CoA), from pantothenic acid (vitamin B5)
->FAD from riboflavin (vitamin B2)
->NAD from niacin (vitamin B3)
(Tender Loving Care For Nancy)
What are other a-keto acid dehydrogenase similar to PDH?
- a-ketoglutarate dehydrogenase (TCA cycle)
- Branched chain a-keto acid dehydrogenase (metabolism of branched chain amino acids)
- E3 common to all the three dehydrogenases (coded by a single gene)
What are the reactions that occur when PDH is synthesized?
Decarboxylation
Oxidation
Transfer of Acetyl group to CoA
Site: Mitochondria
How is PDH regulated via allosteric and covalent modification? What si PDH kinase activated by? What is PDH kinase in activated by and what is PDH kinase inhibited by? What is PDH phosphotase activated by?
Allosteric
•Inhibited by NADH, Acetyl CoA (product inhibition)
Covalent modification
- Phosphorylated to inactive form by PDH kinase (cAMP independent)
- Dephosphorylated to active form by PDH phosphatase
- PDH kinase & phosphatase bound to the PDH complex
- PDH kinase activated by ATP, NADH, acetyl CoA (high energy signals)
- PDH kinase inhibited by pyruvate, ADP (low energy signal)
- PDH phosphatase is activated by Ca2+ (in muscle, during contraction); more oxidation of pyruvate
- Insulin activates PDH phosphatase in adipose tissue, causes activation of PDH (more acetyl CoA for lipogenesis)
Summarize the PDH regulation. what can be said about Acetyl CoA?
- Plenty of ATP, NADH, Acetyl CoA in the cell (high energy state) ® slow down PDH
- Plenty of ADP (low energy state), pyruvate (increased substrate) ® accelerate PDH
- PDH reaction is irreversible
- Acetyl CoA cannot be converted to pyruvate by PDH
- Acetyl CoA cannot enter gluconeogenesis to give rise to net synthesis of glucose
What component of PDH leads to PDH complex deficiency? What does this deficiency prevent? What happens to the excess pyruvate? What part of the body is most affected and why? When present in infants who does it present? What type of inheritance is it? What is the management/treatment for this deficiency?
- Deficiency of E1 component of PDH
- Inability to convert pyruvate to acetyl CoA, cannot enter TCA
- Pyruvate is converted to lactate; lactic acidosis, ¯ ATP synthesis
- Brain is most affected; relies on glucose oxidation through TCA cycle for energy, sensitive to acidosis
- Presents in infancy with delayed development, reduced muscle tone, ataxia & seizures
- Some infants may have congenital malformation of brain
- Neurodegeneration, muscle spasticity, early death (in the neonatal onset form)
- X-linked dominant inheritance (both males & females affected)
- Management: High fat, low carbohydrate & protein diet, supplementation with large doses of thiamine to activate residual PDH activity
Leigh syndrome:What is another name for leigh syndrome? Where is the defect for this disease seen? What are the signs? What type of DNA is affected? What component of PDH is the defect seen? Levels of ____ are elevated in the blood?
- Subacute necrotizing encephalomyelopathy
- Many variants seen; defects in mitochondrial ATP production due to mutations in genes coding for PDH complex, electron transport chain, ATP synthase, pyruvate carboxylase
- Rare, progressive neurodegenerative disorder, loss of coordination & muscle tone, can result in early death
- Both nuclear & mitochondrial DNA can be affected
- Defect in E3 component of PDH, a-ketoglutarate dehydrogenase & branched chain a-keto acid dehydrogenase complexes
- Impaired oxidation of pyruvate, a-ketoglutarate & branched chain amino acids
- Elevated blood lactate (acidosis), a-ketoglutarate & branched a.a
- Thiamine supplementation does not help
Vitamins deficiences & PDH:
What are the coenzymes and the diseases they cause? Without these enzymes which part of the body is mostly affected and how
What is seen in chronic alcoholics ? What is this syndrome called?
What is the management for chronic alcoholics?
- Thiamine deficiency (beri beri), niacin deficiency (pellagra) can cause serious CNS problems
- Brain cells unable to produce sufficient ATP without an active PDH & TCA due to lack of coenzymes
- Thiamine deficiency in chronic alcoholics- Wernicke-Korsakoff syndrome (encephalopathy, psychosis) due to ¯ energy production in neurons
Chronic alcoholics -> hypoglycemia & thiamine deficiency -> given IV glucose ->lactic acidosis (glucose + thiamine should be administered to avoid lactic acidosis)
what is the mechanism of arsenic poisoning?
Trivalent arsenic (arsenite) forms a stable complex with the thiol (-SH) groups of lipoic acid
Makes lipoic acid unavailable to serve as a coenzyme for E2 of PDH, a-KG DH & branched chain a-keto acid DH
Accumulation of pyruvate & lactate; ¯ ATP production
Pentavalent arsenic (arsenate) interferes with glycolysis, ¯ ATP production
Arsenic ¯ both aerobic & anaerobic ATP production
Affects brain, causes neurologic disturbances & death
Where does the TCA cycle occur? What does it start with? How does the cycle work? What is released? What type of pathway is TCA cycle?
Occurs in the mitochondrial matrix; in close proximity to the electron transport chain
Final common pathway for oxidation of carbohydrates, proteins & fats
Major source of ATP in cells (substrate-level & oxidative phosphorylation)
Starts by condensation of acetyl (2C) group of acetyl CoA with oxaloacetate (4C) to form citrate
In the end of the cycle, oxaloacetate is regenerated (cycle)
Two carbons are released as CO2
Intermediates used to synthesize other compounds (glucose, amino acids, heme, fatty acids)
Amphibolic pathway (functions in catabolism & anabolism)
Draw the TCA cycle and the enzymes involved ?
Explain the following enzymes of the TCA cycle :
Citrate synthase:
Isocitrate DH
a-Ketoglutarate DH
Succinyl-CoA synthetase/Succinate thiokinase:
Succinate DH:
Citrate synthase:
- Irreversible
- Citrate : Inhibits PFK-1 (glycolysis) & activates acetyl CoA carboxylase (fatty acid synthesis)
Isocitrate DH:
-Irreversible, Highly regulated
a-Ketoglutarate DH:
- Irreversible
- Reaction is similar to PDH (3 component enzymes)
- Coenzymes-TPP, Lipoic acid, CoA, FAD,NAD+
Succinyl-CoA synthetase/Succinate thiokinase:
-Substrate level phosphorylation(GDP + Pi ® GTP; can give rise to ATP)
Succinate DH:
- Inner mitochondrial membrane (generates FADH2)
- Complex II of ETC
With the following reactions , what are the coenzymes and number of ATP’s produced?
Isocitrate dehydrogenase
a-ketoglutarate dehydrogenase
Malate dehydrogenase
Succinate dehydrogenase
Succinate thiokinase
What is the total number of ATP produced?
What is the amphibolic nature of TCA cycle?
So citrate from the TCA cycle can form the acetyl CoA and eventually fatty acids, a-ketogluterate can form glutamate( Histidine, proline and Arginine can form glutamate and glutamine can form glutamate. Valine, Isoleucine and Methionine can enter the TCA to form succinyl-CoA. Phenylalamine and tyrosine can form fumerate . Asparagine can form aspartate to enter the TCA cycle to form oxalacetate . Oxalacetate can form PEP to go back to form Glucose and Glucose can form pyruvate to enter the TCA cycel to form oxaloacetate
What are the important compounds synthesized for the TCA intermediates ?
What are Anaplerotic reactions ? What are the 5 anaplerotic reactions of the TCA cycle and how are they formed? Which one is the most common?
Diversion of TCA intermediates for other pathways, depletes the cycle
Inability to regenerate oxaloacetate, ¯ ability to oxidize acetyl CoA
Reactions that replenish the intermediates are anaplerotic (‘filling up’)
1.Pyruvate carboxylase
2.Glutamate D.H (GDH)
3.Carboxylase, mutase
4.From phe, tyr
5.Transaminase
