Acetyl-CoA and CAC Flashcards
Characteristics of Acetyl-CoA
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
PDH complex: Location, Steps, Coenzymes
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)
4 B Vitamins
TPP-Thiamin (B1)
FAD- Riboflavin (B2)
NAD+-Niacin (B3)
Pantothenic Acid (B5)
PDH Inhibition
causes build up of excess pyruvate; will be converted to lactate (lactate dehydrogenase)–causes metabolic acidosis–serum lactic acidemia
Roles of CAC
- Major “ATP generating” pathway (not RBCs)
- Important source of metabolic precursors for biosynthesis
- Catalyzes terminal phase of complete oxidation of glucose to CO2
Energy Produced by CAC
1 GTP, 3 NADH (9 ATP’s), 1 FADH (2 ATPs)
Importance of CAC Phase 1: Acetyl-CoA+OAO–> Citrate
Formation of Citrate (2C{acetyl-CoA}+ 4C [OAO] –> 6C citrate); IRREVERSIBLE!, citrate synthase
Importance of CAC Phase 3: Isocitrate –> alpha-KG
oxidative decarboxylation (6C–>5C), isocitrate dehydrogenase, 1 C lost as CO2, 1 NADH is formed
Importance of CAC Phase 4: alpha-KG–>succinate
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)
of ATP’s from each Acetyl-CoA, # from each molecule of pyruvate, and # from each molecule of glucose
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
CAC Rxns which produce CO2
- Isocitrate–>alpha-KG (isocitrate dehydrogenase)
2. alpha-KG—> succinyl-CoA (alpha-KG dehydrogenase)
CAC rxns that produce NADH’s/FADH2
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)
What Happens if O2 is limited in cell?
pyruvate will be reduced to lactate; less ATP produced and this will lead to serum lactic acidemia
Possible Anaplerotic Rxns for CAC
- Pyruvate Carboxylase (pyruvate–>OAO); excess acetyl-CoA increases activity of enzyme; requires B-vitamin biotin; rxn in mito matrix
- Glutamate dehydrogenase (glutamate–> alpha-KG);
Regulation of PDH Complex
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
PDH Protein Kinase
-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)
Regulation of CAC Enzymes
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)
PDH Deficiency
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
Thiamin Deficiency
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
CAC Deficiencies
mainly effect brain or muscle, serum lactic acidemia can occur
Excessive Supply of Acetyl-CoA
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
4 Major Fates of Pyruvate
- Lactate (3C–>3C) Lactate Dehydrogenase
- OAO (3C–>4C) pyruvate carboxylase
- Acetyl-CoA (3C–>2C) PDH
- Alanine (3C–>3C)
Can I Keep Selling Sex For Money, Officer
Citrate, Isocitrate, Succinyl-CoA, Succinate, Fumarate, Malate, OAA
Dehydrogenase, Synthetase
Dehydrogease= creating reducing equivalent; Synthetase= creating ATP/GTP
