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Ah, the TCA cycle! Also known as the citric acid cycle or the Krebs cycle. It's a fascinating process that occurs in the mitochondria of our cells, where it plays a crucial role in generating energy. Let's embark on a journey of discovery together, shall we?
Imagine you're a molecule of acetyl-CoA, eager to release your stored energy. You're about to enter a marvelous cycle that will help you do just that. Let's break it down into bite-sized steps, and I'll introduce you to the enzymes that will be your dance partners along the way.
Citrate formation: You, dear acetyl-CoA, will combine with a molecule of oxaloacetate to form citrate. The enzyme that helps you with this transformation is called citrate synthase.
acetyl-CoA+oxaloacetate→citrate synthasecitrate+CoA-SH
acetyl-CoA+oxaloacetate
citrate synthase
citrate+CoA-SH
Isomerization: Now that you're a citrate molecule, you'll undergo a little rearrangement to become isocitrate. Your dance partner for this step is the enzyme aconitase.
citrate→aconitaseisocitrate
citrate
aconitase
isocitrate
First oxidative decarboxylation: As isocitrate, you'll lose a carbon dioxide molecule and become alpha-ketoglutarate. The enzyme isocitrate dehydrogenase will guide you through this step, and you'll also produce a molecule of NADH.
isocitrate→isocitrate dehydrogenasealpha-ketoglutarate+CO2+NADH
isocitrate
isocitrate dehydrogenase
alpha-ketoglutarate+CO
2
+NADH
Second oxidative decarboxylation: Alpha-ketoglutarate, you'll now lose another carbon dioxide molecule and become succinyl-CoA. The enzyme alpha-ketoglutarate dehydrogenase will assist you, and you'll generate another molecule of NADH.
alpha-ketoglutarate+CoA-SH→alpha-ketoglutarate dehydrogenasesuccinyl-CoA+CO2+NADH
alpha-ketoglutarate+CoA-SH
alpha-ketoglutarate dehydrogenase
succinyl-CoA+CO
2
+NADH
Succinate formation: As succinyl-CoA, you'll say goodbye to your CoA-SH group and become succinate. The enzyme succinyl-CoA synthetase will help you with this transformation, and you'll produce a molecule of GTP.
succinyl-CoA→succinyl-CoA synthetasesuccinate+CoA-SH+GTP
succinyl-CoA
succinyl-CoA synthetase
succinate+CoA-SH+GTP
Fumarate formation: Now, as succinate, you'll be oxidized to fumarate with the help of the enzyme succinate dehydrogenase. In this step, you'll also produce a molecule of FADH₂.
succinate→succinate dehydrogenasefumarate+FADH2
succinate
succinate dehydrogenase
fumarate+FADH
2
Malate formation: As fumarate, you'll gain a water molecule and become malate. The enzyme fumarase will be your guide in this step.
fumarate+H2O→fumarasemalate
fumarate+H
2
O
fumarase
malate
Oxaloacetate regeneration: Finally, as malate, you'll be oxidized back to oxaloacetate with the help of the enzyme malate dehydrogenase. You'll also produce one last molecule of NADH.
malate→malate dehydrogenaseoxaloacetate+NADH
malate
malate dehydrogenase
oxaloacetate+NADH
And there you have it! You've completed the TCA cycle, and in the process, you've generated energy in the form of NADH, FADH₂, and GTP. The cycle can now begin anew with another molecule of acetyl-CoA. It's a beautiful dance of molecules and enzymes, isn't it?
Inhibitors of electron transport interfere with the normal flow of electrons along the electron transport chain. This disruption has far-reaching effects on cellular energy production.
1.1 Inhibition at Site I - Complex I
Alkyl Guanides: A hypotensive agent
Rotenone: An insecticide extracted from Derris elliptica plant roots
Chlorpromazine: A tranquilizing drug
Barbiturates: Sleep-inducing drugs
Progesterone: A hormone
Piericidin A: An antibiotic of microbial origin
Rotenone, for instance, is a strong inhibitor of complex I. It hinders the transport of electrons through the NADH-CoQ reductase complex, effectively disrupting electron flow. Some tribes use it as a fish poison due to its paralyzing effect on fish.
1.2 Inhibition at Site II - Complex III
Antimycin: An antibiotic from Streptomyces species
BAL "British Anti-Lewisite" (Dimer Caprol): Antidote to an old war gas
Naphthoquinone
Antimycin interferes with electron flow from cytochrome b to cytochrome c1 within Complex III. This inhibition affects the overall energy production process.
1.3 Inhibition at Site III - Complex IV
Azide ion (N)
Cyanide ion (CN)
CO (Carbon Monoxide)
H2S (Hydrogen Sulfide)
These substances inhibit the transfer of electrons at Complex IV, preventing their movement to oxygen.
2.1 Oligomycin
Oligomycin blocks both oxidation and phosphorylation in intact mitochondria. It binds to the stalk of ATP synthase, closing the H+ ion channels and preventing protons from re-entering the matrix. As a result, pH and electrical gradients cannot dissipate, and electron flow is disrupted.
2.2 Atracycloside
Atracycloside inhibits the translocase and transport of adenine nucleotides across the inner mitochondrial membrane, leading to a decrease in the availability of ADP for ATP synthesis.
Uncouplers disrupt the coupling of oxidation and phosphorylation by increasing the permeability of protons through the inner mitochondrial membrane. This leads to a disruption in the proton gradient, preventing ATP synthesis and causing increased oxygen consumption.
2,4-dinitrophenol (DNP)
2,4-dinitrocresol (DNC)
Pentachlorophenol (PCP)
Dicoumarol
M-chloro carbamoyl cyanide phenyl hydrazone (CCCP)
Trifluoro carbamoyl cyanide phenyl hydrazone (FCCP)
Free salicylate (metabolite of aspirin)
These compounds act as proton carriers, disrupting the normal functioning of oxidative phosphorylation.
Uncoupling plays a significant role in certain physiological contexts, such as maintaining body temperature in hibernating animals, newborn babies, and animals adapted to cold temperatures. Additionally, the disruption caused by uncouplers is useful in studying metabolic processes and their regulation.
The enzymes or proteins within the electron transport chain are organized into five separate complexes. Let's explore each complex's structure and function:
Complex I, also known as NADH-CoQ reductase or NADH dehydrogenase, is responsible for removing two electrons from NADH and transferring them to ubiquinone (Q). This transfer results in the formation of ubiquinol (QH2) and the pumping of four protons across the complex from the mitochondrial matrix into the intermembrane space. This complex is pivotal for creating a proton gradient, driving ATP synthesis.
Complex II, also called succinate-Q reductase or succinate dehydrogenase, is a unique enzyme as it's a membrane-bound component of the Krebs cycle. It receives electrons from the oxidation of succinate and transfers them via flavin (FAD) and an iron-sulfur cluster to the ubiquinol (QH2) pool. Unlike Complex I, Complex II generates only one QH2 per oxidized succinate and doesn't actively pump protons.
Complex III, or cytochrome reductase, transfers electrons from Coenzyme Q (ubiquinone) to cytochromes. The heme groups of cytochrome b and c undergo a change in iron's oxidation state, contributing to the overall electron transfer process. The redox potential difference between CoQ and Cyt c results in a free energy change that drives the electron flow.
Complex IV, also known as cytochrome oxidase, receives electrons from cytochrome-c, a small mobile protein that diffuses from Complex III. The electrons are passed through various cytochrome-a and copper ion centers, ultimately leading to the reduction of molecular oxygen (O2) to water (H2O). Each NADH that is oxidized yields enough electrons to reduce half a molecule of O2 to H2O.
The components are strategically arranged in the order of increasing redox potentials, ensuring a seamless flow of electrons from donors like NADH to acceptors like oxygen. This flow results in the establishment of a proton gradient across the inner mitochondrial membrane.
The movement of electrons through the ETC and the pumping of protons generate a proton motive force across the inner mitochondrial membrane. This force is harnessed by the ATP synthase enzyme to convert ADP and inorganic phosphate into ATP. Thus, the components of the ETC are not only responsible for energy transfer but also for the production of ATP, the cellular energy currency.