The Citric Acid Cycle Flashcards
What does TCA cycle stand for and what are other names for this?
Tricarboxylic Acid Cycle
-Krebbs cycle, citric acid cycle
What kinds of metabolism enter the TCA cycle?
-Carbohydrate metabolism
-Fatty acid metabolism
-Amino Acid metabolism
What is the purpose of the TCA cycle?
-All catabolism of fuels converge here
-It is a cycle so nothing is lost
-Generates energy rich signals - citrate
-Generates further reducing power (NADH, FADH, FMN)
-Components for ETC
-CENTRAL HUB OF METABOLISM
What is citric acid cycle and what does it do?
-Central converging pathway by which all fuels oxidised in cellular respiration
-Carbon skeletons of fatty acids, glucose, other sugars and many amino acids degraded to acetyl-CoA
-Many amino acids also convert to citric acid cycle intermediates
-Catabolic and anabolic cycle - many intermediates used in biosynthetic/anabolic pathways
-Occurs in mitochondria
What kind of pathway is the TCA cycle?
Open pathway
What is the entry point into TCA?
Acetyl-CoA
Formation of Acetyl-CoA?
-Coenzyme A adds on covalently to acetyl group making thiol bond to form acetyl CoA
-CoA is an acyl carrier molecule in metabolism
How does pyruvate enter the TCA cycle?
-In presence of O2, pyruvate enters the mitochondria via Mitochondrial Pyruvate Carrier Protein (MPC)
-Pyruvate is oxidised and decarboxylated to acetyl-CoA by enzyme PDH (Pyruvate Dehydrogenase) and this occurs in the mitochondrial matrix of euks
(v complex w multiple copies of 3 enzyme subunits which need cofactors)
(highly regulated allosteric/ covalent - so PDH off when ample fuel available and on when cells energy s low)
How many copies of enzymes does PDH have?
PDH contains multiple copies of 3 enzymes E1, E2, E3
-human form 50nm diameter - large - can be viewed by EM
What can a build up of pyruvate lead toß
Energy dysfunction - loss of brain function
What organic anions did Hans Krebs discover stimulate pyruvate oxidation?
Dicarboxylic acid COO-x2
4 carbon molecules : succinate, fumarate, malate, oxaloacetate
5 carbon molecule: alpha-ketoglutarate
Tricarboxylic acids COO-x3
6 carbon molecules: citrate and isocitrate
What is the slogan to remember citric acid cycle and what does each letter stand for?
Our City Is Kept Safe and Secure From Monsters
-Oxaloacetate ( with acetyl CoA)
-Citrate
-Isocitrate
-alpha Ketoglutarate
-Succinyl-CoA
-Fumarate
-Malate
What happens in the citric acid cycle?
- 4C oxaloacetate and 2C acetyl group of acetyl CoA condense to form 6C citrate which is 3 x COO- tricarboxylic acid
- 6C citrate (high energy reduced biomolecule)
Oxidised and recabroxylated back to 4C oxaloacetate in a cycle
7 enzymes catalysed reactions loses Hs with its electrons which collect on 3 NADH and 1 FADH2
What is the point of the TCA cycle?
Overall for one acetyl CoA condensation with oxaloacetate the reactions ‘produce’
3NADH, 1 FADH2, 1GTP, and 2CO2
What are the enzymes used in citric acid cycle?
Citric Acid Cycle Steps? Step 1
-Condensation rxn - Acetyl CoA (2C) condenses with oxaloacetate (4C) to form 6C citrate by citrate synthase
-Tricarboxylate and reduced (H) high energy nature of citrate
-Strong oxidation potential for energy transfer in rest of cycle
Citric Acid Cycle Steps? Step 2?
Isomerisation rxn - citrate to isocitrate
-Citrate isomerises to isocitrate by removal and addition of H20 enzyme (citrate aconitase)
-Sets up bong structrure so next rxn can happen
Citric Acid Cycle Steps? Steps 3 and 4?
3) 1st oxidative decarboxylation (exergonic step)
-Oxidaton of isocitrate (&C) to alpha-ketoglutarate (5C) using isocitrate dehydrogenase
-First CO2 released and NADH formed
4) 2nd oxidative decarboxylation (2nd key exergonic step)
-Addition of CoA and oxidation of alpha-ketoglutarate (5C) to succinyl-CoA (4C) by using alpha-ketoglutarate dehydrogenase complex
-Second CO2 released and second NADH formed
Citric Acid Cycle Steps? Steps 5 and 6?
5) Conversion of succinyl-CoA synthetase
-Removal of CoA so then the energy of this forms GTP which converts to 1 ATP
6) Oxidation of succinate (4C) to furmarate (4C) by succinate dehydrogenase (SDH)
-Removal of 2H formation of 1FADH2
Citric Acid Cycle Steps? Steps 7 an d8?
7) Hydration - addition of H20 to fumerate (4C) to malate (4C) by hydratase
8) Oxidation of malate (4C) to oxaloacetate (4C) using malate dehydrogense
Removal of 2H formation of NADH and H+
How many CO2s are emerge?
2 Cs emerge as CO2 waste
What energy molecules are produced iun the citric acid cycle and what happens these?
3NAD+ reduced to 3 NADH
1 FAD+ reduced to 1 FADH2
1 GTP - 1 ATP generated
3NADH and 1FADH2 deliver electrons to stage 3 respiratory chin - OXPHOS
What do NAD and FAD do?
Nicotinamide Adenine Dinucleotide
Flavin Adenine Dinucleotide
-Coenzymes
-Accept electrons from energy rich molecules
-Donate electrons to electron transport chain
(all macromolecules will enter TCA cycle and create reducing power)
How many ATPs does the cell make per glucose molecule?
10 NADH = 30 ATP
2 FADH2 = 4 ATP
Substrate level phosphorylation = 4 ATP
-1 glucose will yield a max of 38 ATP if completely oxidized to CO2 and H2O
Is the ccitric acid cycle confined to oxidation/ catabolism?
No
-Has major function in anabolic/biosynthetic pathways where citric acid cycle intermediates are ‘siphoned off’
-Metabolites are cntantly feeding in for degradation and constantly feeding out for synthesis
Examples of metabolites that feed in?
-Other 4C, 5C end products feed in like oxaloacetate and alpha-ketoglutarate can be produced from amino acid catabolism of aspartate and glutamate respectively
What are intermediates of the cycle?
-Biosynthetic precursors
e.g they can make amino acids, heme, sterols etc
-Anaeobic bacteria have a rudimentary TCA cycle used for biosynthesis
What affect do metabolites have on the system?
-Metabolites e.g acetyl-CoA, succinate, fumarate can alter the response of both the innate and adaptive immune systems
-Succinate and fumarate build-up are oncometabolites that can promote tumorigenesis
-Citrate can leave mitochondria and degrade to Acetyl-CoA and oxaloacetate where acetyl CoA can acetylate histones/regulate gene expression
How is the citric acid cycle regulated?
By controlling the activity of the 3 exergonic irreversible enzymes:
-Citrate synthase
-Isocitrate dehydrogenase
-Alpha-ketoglutarate- dehydrogenase
-Regulation of pyruvate dehydrogenase also important
How are these enzymes regulted allosterically?
-Energy indicators - if high conc of NADH, ATP then turned off
-Product accumulation
-Substrate availability
