Acetyl-CoA Flashcards
What is the structure of acetyl-CoA?
Comprises coenzyme A (CoA) plus an acetyl group attached via a reactive thiol group
What are the sources of acetyl-CoA?
- Glucose to Pyruvate via glycolysis and pyruvate to acetyl-CoA via oxidative decarboxylation
- Certain amino acids to pyruvate via deamination and oxidation and pyruvate to acetyl-CoA via oxidative decarboxylation
- Fatty acids to acetyl-CoA via Beta-oxidation
- Certain amino acids to acetyl-CoA via deamination and oxidation
What are the fates of acetyl-CoA?
- Fat
- Ketone Bodies
- Oxidation via TCA cycle
- Cholesterol
Pyruvate dehydrogenase complex
Large enzymes that contains:
- pyruvate decarboxylase (E1)
- dihydrolipoyl transacetylase (E2)
- dihydrolipoyl dehydrogenase (E3)
- E3 binding protein
Converts pyruvate to acetyl-CoA via oxidative decarboxylation
Is pyruvate oxidized or reduced by pyruvate dehydrogenase?
Oxidized
What is a key point of metabolism involving pyruvate dehydrogenase complex? Why is this important?
Pyruvate dehydrogenase reaction is irreversible. No way back once pyruvate converts to acetyl-CoA
Where is the pyruvate dehydrogenase complex found?
Mitochondrial matrix
How is pyruvate brought to the mitochondria?
Pyruvate generated in cytoplasm and crosses outer mitochondrial membrane via non-selective pore protein and then into the inner mitochondrial membrane via specific carrier protein
What are the steps in the pyruvate dehydrogenase reaction?
- E1 decarboxylates pyruvate - intermediate forms with thiamine pyrophosphate (TPP)
- Intermediate oxidized to acetyl group and transferred to lipoamide group of E2
- Acetyl group transferred to CoA-SH by E2, forming acetyl-CoA
- Reduced lipoamide re-oxidized by E3 (FAD-dependent enzyme)
- FADH2 reoxidized by E3, electrons passing to NAD+ forming NADH
What four different B vitamins are required for pyruvate dehydrogenase reaction?
- Thiamine (B1) - formation of TPP
- Riboflavin (B2) - Generation of FAD
- Niacin (B3) - Formation of NAD
- Pantothenic Acid - component of CoA-SH
Thiamine deficiency
Dietary deficiency: polished rice lacks thiamine
alcoholism - inhibits thiamine uptake and conversion to TPP
Likely involves impairment of energy metabolism
What steps in energy metabolism is thiamine required for?
Pyruvate dehydrogenase
alpha-ketoglutarate dehydrogenase complex - TCA cycle
Branched chain alpha-keto acid dehydrogenase - amino acid metabolism
Transketolase - glucose metabolism
Beriberi
Dietary thiamine deficiency
Pain and paresthesia
Wet form - patient present with symptoms of congestive heart failure
Dry form - symmetric peripheral neuropathy
Wernicke encephalopathy
Thiamin deficient patient with chronic alcoholism
CNS impairment - mental impairment, cerebellar ataxia, horizontal nystagmus, ophthalmoplegia
Treatment by administration of thiamine
Can progress to Wernicke-Korsakoff syndrome (severe learning defect)
Pyruvate dehydrogenase deficiency
Causes chronic lactic acidosis - can cause fatal lactic acidemia in neonates
Most pts experience severe neurological problems
Most common mutations impact pyruvate decarboxylase (E1)
What products activate pyruvate dehydrogenase kinase?
Acetyl-CoA and NADH
What inactivates pyruvate dehydrogenase complex?
Pyruvate dehydrogenase kinase which phosphorylates the complex
What reactivates pyruvate dehydrogenase complex?
Pyruvate dehydrogenase phosphatase
What inhibits pyruvate dehydrogenase kinase?
ADP and Pyruvate
When is pyruvate dehydrogenase most active and least active?
Least active when energy needs are low and most active when energy needs are high
Tricarboxylic acid cycle
Acetyl-CoA completely oxidized and generates reduced electron carriers and GTP.
Source of biosynthetic intermediates
What is produced from TCA cycle?
2 Carbon dioxide
3 NADH
FADH2
GTP
3 H
CoA-SH
What is important to note about the carbons in the TCA cycle?
2 carbons come in as an acetyl group and 2 carbons leave as CO2
No net synthesis when acetyl-CoA is oxidized in TCA cycle
How much ATP is produced in TCA cycle?
Oxidation of 1 mol of acetyl-CoA could yield 10 mol of ATP
What regulates the TCA cycle?
Substrate availability
Citrate synthase
Isocitrate dehydrogenase
Alpha-ketoglutarate dehydrogenase complex
How does substrate availability regulate the TCA cycle?
Activity of Pyruvate dehydrogenase controls one route of substrates to TCA cycle
How does citrate synthase regulate the TCA cycle?
Citrate synthase regulated by available oxaloacetate
ATP, NADH, and succinyl-CoA inhibits citrate synthase
How does isocitrate dehydrogenase regulate the TCA cycle?
Allosteric Activation by ADP
Potential inhibition by NADH
How does alpha-ketoglutarate dehydrogenase complex regulate the TCA cycle?
Activation by ADP
Product inhibition by succinyl CoA and NADH
Fumarase deficiency
Grossly elevated urinary fumarate
Extremely rare and only well characterized TCA cycle defect
Is there any net synthesis of intermediates in TCA?
No! 2 carbons in as acetyl-CoA and two carbons out as CO2
Anaplerotic reaction
Replenish TCA intermediates
- Pyruvate carboxylase
- Glutamate dehydrogenase
- Generation of succinyl-CoA
Pyruvate carboxylase
Anaplerotic reaction
Coverts pyruvate to oxaloacetate
Enzyme of mitochondrial matrix. Activated by acetyl-CoA
Expressed at high levels in liver and nervous tissue - use of TCA cycle intermediates for gluconeogenesis and neurotransmitter synthesis
Contains prosthetic group formed from biotin which functions as carboxyl group carrier
Glutamate Dehydrogenase
Anaplerotic reaction
Catalyzes conversion of glutamate to alpha-ketoglutarate –> fed into the TCA cycle
Enzyme important for amino acid metabolism
Formation of succinyl-CoA
Propionyl-CoA produced by oxidation of odd chain fatty acids and certain amino acids. Converted to succinyl-CoA
