Citric Acid Cycle

• Fatty acids are Beta Oxidized to be converted to Acetyl CoA
• Pyruvate with CoASH and NAD+ is cleaved to CO2, Acetyl CoA, and NADH by the pyruvate dehydrogenase complex for it to enter the citric acid cycle
• The citric acid cycle is the central pathway for energy recovery from several metabolic fuels like carbohydrates, lipids and amino acids
• Acetyl CoA is processed with Glucose, Fatty acids, or amino acids
• The citric acid cycle is an amphibolic process
• The citric acid cycle is a multistep catalytic process that converts acetyl groups from fuels producing 2 CO2, 3 NADH, 1 FADH2, and 1 GTP
• Oxaloacetate must be regenerated for a continuous aerobic metabolism
• Acetyl CoA has an Adenosine, Panthothenic acid from vitamin B5 and Cysteine bound to the acetyl group via thioester bond, a high energy bond
• Acetyl CoA has a high transfer potential as acetyl group is released, it has a thiol group
• The Citric acid cycle happens in the matrix of mitochondria
• The mitochondria has an inner and outer mitochondrial membrane with a intermembrane space in the middle
• The citric acid cycle harvests high energy electrons from carbon fuels and are stored in the form of reduced coenzymes such as NADH, and FADH2
• The electrons is relayed in the electron transfer complexes in the ETC, which are embedded in the inner membrane of the mitochondria
• When electrons from reduced coenzymes are passed from one complex to another complex, it generates a proton gradient
• The proton gradient is created between the inner and outer mitochondrial membranes when there are differences in concentrations
• The enzyme dihydrolipoyl dehydrogenase is in the inner membrane that produces FADH2, and can easily pass the FADH2 to the electron transport chain
• TCA stands for tricarboxylic acid cycle
• The six carbon atom citrate undergoes 2 consecutive oxidative decarboxylation to yield 2 NADH, and 2 CO2
• The 4 carbon compound malate is then converted to oxaloacetate yielding with products GTP, FADH2, and NADH
• The citric acid cycle proceeds with oxidative phosphorylation through its high energy electrons/reduced cofactors, and they reduce 2 O2 producing 4 H2O and a proton gradient makes H+ flow to synthesize ATP with ATP synthase
• The link between glycolysis and citric acid cycle is through pyruvate dehydrogenase complex which also happens in the mitochondria
• Pyruvate dehydrogenase complex is a large, highly integrated complex that utilizes 3 distinct enzymes
• In a multienzyme complex, the enzyme reaction reacts are limited by the frequency with which enzymes collide with their substrates. When a series of reactions occur in an multienzyme complex, their distance on the substrates that diffuses between active sites is minimized, thereby enhancing reaction rate
• In a multienzyme complex, there is a structure that can transfer from one enzyme to another through its products formed
• In a multienzyme complex, they can be coordinately controlled
• Pyruvate dehydrogenase complex is a member of a homologous complex that include Alpha ketoglutarate dehydrogenase
• These enzymes have molecular masses ranging from 4 to 10 million daltons
• In a multienzyme complex, the core of the enzyme are connected by tethers
• In the pyruvate dehydrogenase complex, there is a substrate that is bound to the enzyme, and it would allow its group to travel from one active site to another
• The synthesis of Acetyl-CoA from pyruvate requires 3 Enzymes and 5 Co-Enzymes
• The coenzyme Thiaminepyrophosphate (TPP), lipoic acid, and FAD serves as catalytic co-factors as they are bound to the enzyme while CoA and NAD+ are stoichiometric co-factors that can either enter or leave the enzyme
• In the pyruvate dehydrogenase complex, E1 is pyruvate dehydrogenase, E2 is dihydrolipoyl transacetylase or the core, and E3 is dihydrolipoyl dehydrogenase
• Pyruvate dehydrogenase facilitates oxidative decarboxylation of pyruvate, while dihydrolipoyl transacetylase facilitates transfer of acetyl group to CoASH
• In reaction 1, thiamine pyrophosphate is the cofactor bound to E1 that decarboxylates pyruvate, yielding a hydroxyethyl-TPP carbanion and CO2
• TPP has a positive N which serves as the electron sink, while the carbon between nitrogen and sulfur is acidic which can be ionized to form a carbanion which can bind to acetyl CoA
• Lipoamide is lipoid acid binded to lysine side chain in E2. Yielding to an 8 carbon arm
• Reaction 2 is where the hydroxyethyl group is transferred to the lipoamide arm of dihydrolipoyl transacetylase, which is oxidized to form an Acetyl dihydrolipoamide, eliminating TPP and regenerating the coenzyme for E1
• Reaction 3 is where Acetyl dihydrolipoamide is transferred to CoA catalyzed by the active site of E2 and producing an transesterified Acetyl CoA and a reduced form of dihydrolipoamide
• Reactions 1 and 2 are catalyzed by E1 which is pyruvate dehydrogenase
• Reactions 3 are catalyzed by E2 or dihydrolipoyl transacetylase, while Reactions 4 and 5 are catalyzed by E3 or dihydrolipoyl dehydrogenase