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The Citric Acid Cycle
2
The Tricarboxylic Acid (TCA) Cycle
by Omni Ebow
Advanced Nutrition 456
The Tricarboxylic Acid (TCA) Cycle
- Also known as the Citric acid cycle or Kreb's cycle
Overview of TCA Cycle
- Pathway occurs in the mitochondrial matrix
- Primary function:
- generate high amounts of NADH & FADH2 that act as fuel for ATP synthesis in the electron transport chain
Net equation:
acetyl-CoA + 3 NAD+ + FAD + GDP + Pi -->
2CO2 + 3 NADH + FADH2 + GTP + CoA
Importance
The TCA Cycle is the center of energy metabolism
1. It's the final pathway by which fuel molecules (carbs, fatty acids, and amino acids) are completely oxidized to CO2 so that energy can be released and transferred to ATP
2. Intermediates of this cycle are used to synthesize purine and pyrimidine bases, hemeproteins, and steroid hormones
3. Regulatory factors of this cycle influence the regulation of other cycles
Regulatory Factors of TCA Cycle
Regulatory Factors
Regulation of pyruvate decarboxylation
Regulation of Pyruvate Dehydrogenase
In the presence of oygen, pyruvate moves into the matrix of the mitochondria and undergoes decarboxylation via pyruvate dehydrogenase
- Pyruvate dehydrogenase is an enzyme complex made of three enzymes
- This complex requires several cofactors and vitamin components including: Mg2+, pantothenic acid (coenzyme A), thiamin (pyrophosphate), niacin (NAD+), FAD, lipoic acid,
This is a regulatory factor by itself because
1) the activity of this enzyme occurs prior to citric acid cycle steps
2) this enzyme can be inhibited by citrate
3) conversion of pyruvate to acetyl-CoA is irreversible
Once acetyl-CoA is formed it has 1 of 2 ways to proceed: TCA cycle or fatty acid synthesis
Substrate availability
The major substrates of the TCA cycle are:
- Acetyl-CoA
- Amino acids converting to a-ketoglutarate
- Oxaloacetate
Acetyl-CoA, the starting substrate of the TCA cycle, converts to citrate in the first step of TCA cycle
- Under well-fed, high ATP conditions, citrate can build up and will exit mitochondria to begin fatty acid synthesis, slowing the TCA cycle by inhibiting citrate synthase enzyme
- Under starving states, amino acids can begin to break down and be converted into a-ketoglutarate and with increase of this substrate, the TCA cycle rate will increase to produce more ATP
Allosteric regulators
Citric acid cycle is always occcuring and therefore wants to readily respond to energy needs of the cell. This is accomplished by feedback of allosteric enzymes in 3 reactions
Allosteric regulators
Allosteric activation/Positive feedback: Enzyme activity increases with ADP & NAD+ binding to enzyme in each reaction
- Calcium (Ca2+), also gives positive feedback muscle cells require Ca to contract, so increase in muscle
Allosteric inhibition/Negative feedback: NADH binding to enzyme, as well as increased ratio of ATP, changes conformation of enzyme thus allosterically inhibiting (or inactivating) it
To summarize:
- allosteric activators are ADP, NAD+, acetyl-CoA, Ca2+
- allosteric inhibitors are citrate, NADH, and ATP
Regulatory Reactions of TCA Cycle
1. Citrate synthase
- In step 1 of TCA cycle, a condensation reaction catalyzed by citrate synthase adds acetyl-CoA to oxaloacetate forming citrate
Step 1:
Citrate synthase
Remember: High concentrations of citrate can inhibit pyruvate dehydrogenase-decreasing conversioin of pyruvate to acetyl-CoA
3. Isocitrate dehydrogenase
- Decarboxylation of isocitrate by isocitrate dehydrogenase to produce a-ketoglutarate
Step 3:
Isocitrate dehydrogenase
This reaction takes place in two parts:
When [ADP] is increased...
3a) ADP will bind to the enzyme to stimulate its activity increasing affinity for isocitrate substrate which increases overall rate of cycle
Isocitrate is oxidized into oxalosuccinate
3b) CO2 is released from oxalosuccinate forming a-ketoglutarate
4. a-ketoglutarate dehydrogenase
- Decarboxylation of a-ketoglutarate to produce succinyl-CoA
Step 4:
a-Ketoglutarate dehydrogenase
Succinyl-CoA, as an intermediate product, forms most of porphyrin('s carbon skeleton) which is major component of hemeproteins such as hemeglobin and myoglobin
Gluconeogenesis
is the pathway by which glucose is synthesized from non-carbohydrate metabolites that are intermediates of TCA cycle
Gluconeogenesis
- Oxaloacetate is constantly replenished by conversion of pyruvate to oxaloacetate(an anaplerotic process); stimulated with increase in levels of acetyl-CoA
Glucogenic amino acids can be catabolized into citric acid metabolites called a-ketoacids as 1) a-ketoglutarate, 2) succinyl CoA, and 3) fumarate
- The a-ketoglutarate produced in step 3 is used to synthesize: glutamate, glutamine, proline, arginine
- Oxaloacetate produced in step 8 is used to synthesize: /aspartate: lysine, asparagine, methionine, threonine, and isoleucine
Oxaloacetate in gluconeogensis and TCA cycle
- In mitochondria, oxaloacetate is reduced to malate and transported out of the mitchondrion
- In cytsol, malate is oxidized back to oxaloacetate and gets decarboxylated to phosphoenolpyruvate by phosphoenolpyruvate carboxykinase; which is the rate limiting step in for nearly all glucogenic precurors into pyruvate
Oxaloacetate
- via transamination reaction, a-keto acids aquire amino group a-ketoglutarate (from glutamate); pyridoxal phosphate is a cofactor
- forming glutamine, proline, and arginine