Acetyl-CoA and CAC

Question 1

Characteristics of Acetyl-CoA

Answer 1

Thioester Bond= -7.5kcal/mol; contains B5 derivative pantothenic acid; important intermediate (formed from carbohydrates, FA’s of lipids); Substrate for CAC; metabolic precursor for FA’s, ketone bodies and cholesterol; formed from pyruvate; cannot cross inner mito membrane

Question 2

PDH complex: Location, Steps, Coenzymes

Answer 2

Found in inner mito matrix
3 steps: 1. pyruvate decarboxylase–EnA (binds hydroxyethyl group to TPP and releases CO2)
2. dihydrolipoyl transacetylase EnB (2 step rxn; accepts hydroxyethyl group from TPP and oxidizes/transfers it to CoASH); 3. dihydrolipoyl dehydrogenase, EnC ( 2 step rxn; regenerates active disulfide lipoamide for next rxn round, gives FADH2 and then regenerates FAD+ by NADH)
5 coenzymes: 2 soluble (NAD+ and CoA), 3 insoluble (TPP, FAD, lipoamide)

Question 3

4 B Vitamins

Answer 3

TPP-Thiamin (B1)
FAD- Riboflavin (B2)
NAD+-Niacin (B3)
Pantothenic Acid (B5)

Question 4

PDH Inhibition

Answer 4

causes build up of excess pyruvate; will be converted to lactate (lactate dehydrogenase)–causes metabolic acidosis–serum lactic acidemia

Question 5

Roles of CAC

Answer 5

1. Major “ATP generating” pathway (not RBCs)
2. Important source of metabolic precursors for biosynthesis
3. Catalyzes terminal phase of complete oxidation of glucose to CO2

Question 6

Energy Produced by CAC

Answer 6

1 GTP, 3 NADH (9 ATP’s), 1 FADH (2 ATPs)

Question 7

Importance of CAC Phase 1: Acetyl-CoA+OAO–> Citrate

Answer 7

Formation of Citrate (2C{acetyl-CoA}+ 4C [OAO] –> 6C citrate); IRREVERSIBLE!, citrate synthase

Question 8

Importance of CAC Phase 3: Isocitrate –> alpha-KG

Answer 8

oxidative decarboxylation (6C–>5C), isocitrate dehydrogenase, 1 C lost as CO2, 1 NADH is formed

Question 9

Importance of CAC Phase 4: alpha-KG–>succinate

Answer 9

Identical rxn to PDH complex (alpha-KG dehydrogenase very similar to PDH); 2 step rxn: 1) 1C is lost as CO2, 1 NADH is formed, 1 “high-energy” succinyl-CoA is formed, 2) 1 GTP is produced (substrate level phosphorylation)

Question 10

of ATP’s from each Acetyl-CoA, # from each molecule of pyruvate, and # from each molecule of glucose

Answer 10

12 (1 is GTP which is substrate level; rest are from oxidative phosphorylation), 15 ATPS from each molecule of pyruvate (remember one NADH from PDH complex) and 30 from each molecule of Glucose

Question 11

CAC Rxns which produce CO2

Answer 11

1. Isocitrate–>alpha-KG (isocitrate dehydrogenase)

2. alpha-KG—> succinyl-CoA (alpha-KG dehydrogenase)

Question 12

CAC rxns that produce NADH’s/FADH2

Answer 12

NADH: 1. Isocitrate–>alpha-KG (isocitrate dehydrogenase)
2. alpha-KG—> succinyl-CoA (alpha-KG dehydrogenase)
3. Malate–> OAO (malate dehydrogenase)
FADH2: 1. Succinate–>Fumarate (succinate dehydrogenase)

Question 13

What Happens if O2 is limited in cell?

Answer 13

pyruvate will be reduced to lactate; less ATP produced and this will lead to serum lactic acidemia

Question 14

Possible Anaplerotic Rxns for CAC

Answer 14

1. Pyruvate Carboxylase (pyruvate–>OAO); excess acetyl-CoA increases activity of enzyme; requires B-vitamin biotin; rxn in mito matrix
2. Glutamate dehydrogenase (glutamate–> alpha-KG);

Question 15

Regulation of PDH Complex

Answer 15

End Product Inhibition: acetyl-CoA, NADH

Phosphorylation/De-P: less active when -P and more active we De-P; all depends on activity of PDH-protein kinase

Question 16

PDH Protein Kinase

Answer 16

-P’s or De-P’s PDH complex
Activated by acetyl-CoA, NADH (which will inhibit PDH)
Deactivated by pyruvate, NAD+, CoASH, ADP (which will increase activity of PDH)

Question 17

Regulation of CAC Enzymes

Answer 17

Isocitrate dehydrogenase: activated by ADP, inhibited by NADH
alpha-KG dehydrogenase: inhibited by succinyl-CoA and NADH (take note it is NOT regulated by -P/De-P like PDH)

Question 18

PDH Deficiency

Answer 18

chronic lactic acidosis in infants and young children–severe neurological problems due to heavy reliance of brain on carb metabolism, also diminishes ATP production via CAC; pyruvate instead converted to lactate = serum lactic acidemia

Question 19

Thiamin Deficiency

Answer 19

B1 required by both PDH and alpha-KG dehydrogenase complexes–from poor diets, mental confusion, ataxia, neuromuscular problems, referred to as Wernicke-Korsakoff syndrome; Beri-Beri from populations that rely heavily on polished rice may also present w/ serum lactic acidemia

Question 20

CAC Deficiencies

Answer 20

mainly effect brain or muscle, serum lactic acidemia can occur

Question 21

Excessive Supply of Acetyl-CoA

Answer 21

ex. fasting/starvation in uncontrolled T1D, excess acetyl-CoA turned into ketone bodies, go into circulation, 2 acidic ketone bodies can lead to ketoacidosis–death/coma in diabetics

Question 22

4 Major Fates of Pyruvate

Answer 22

1. Lactate (3C–>3C) Lactate Dehydrogenase
2. OAO (3C–>4C) pyruvate carboxylase
3. Acetyl-CoA (3C–>2C) PDH
4. Alanine (3C–>3C)

Question 23

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Answer 23

Citrate, Isocitrate, Succinyl-CoA, Succinate, Fumarate, Malate, OAA

Question 24

Dehydrogenase, Synthetase

Answer 24

Dehydrogease= creating reducing equivalent; Synthetase= creating ATP/GTP