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Electron Transport Chain

 Electron Transport Chain

Definition-The electron transport chain (ETC or respiratory chain) is a series of protein complexes that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples this electron transfer with the transfer of protons (H⁺ ions) across a membrane. The electron transport chain is built up of peptides, enzymes, and other molecules.

Introduction- The flow of electrons through the electron transport chain is an exergonic process. The energy from the redox reactions creates an electrochemical proton gradient that drives the synthesis of adenosine triphosphate (ATP). In aerobic respiration, the flow of electrons terminates with molecular oxygen being the final electron acceptor. In anaerobic respiration, other electron acceptors are used, such as sulfate.

In the electron transport chain, the redox reactions are driven by the Gibbs free energy state of the components. Gibbs free energy is related to a quantity called the redox potential. The complexes in the electron transport chain harvest the energy of the redox reactions that occur when transferring electrons from a low redox potential to a higher redox potential, creating an electrochemical gradient. It is the electrochemical gradient created that drives the synthesis of ATP via coupling with oxidative Phosphorylation with ATP synthase.

In eukaryotic organisms the electron transport chain, and site of oxidative Phosphorylation, is found on the inner mitochondrial membrane. The energy stored from the process of respiration in reduced compounds (such as NADH and FADH) is used by the electron transport chain to pump protons into the inter membrane space, generating the electrochemical gradient over the inner mitochondrial membrane.

Most eukaryotic cells have mitochondria, which produce ATP from products of the citric acid cycle, fatty acid oxidation, and amino acid oxidation. At the inner mitochondrial membrane, electrons from NADH and FADH₂ pass through the electron transport chain to oxygen, which is reduced to water. 

The electron transport chain comprises an enzymatic series of electron donors and acceptors. Each electron donor will pass electrons to a more  electronegative acceptor, which in turn donates these electrons to another acceptor, a process that continues down the series until electrons are passed to oxygen, the most electronegative and terminal electron acceptor in the chain.

Passage of electrons between donor and acceptor releases energy, which is used to generate a proton gradient across the mitochondrial membrane by "pumping" protons into the inter membrane space, producing a thermodynamic state that has the potential to do work. This entire process is called oxidative Phosphorylation since ADP is phosphorylated to ATP by using the electrochemical gradient established by the redox reactions of the electron transport chain.

Mitochondrial redox carriers

Energy obtained through the transfer of electrons down the electron transport chain is used to pump protons from the mitochondrial matrix into the inter membrane space, creating an electrochemical proton gradient (ΔpH) across the inner mitochondrial membrane. This proton gradient is largely but not exclusively responsible for the mitochondrial membrane potential (ΔΨ_M). It allows ATP synthase to use the flow of H⁺ through the enzyme back into the matrix to generate ATP from adenosine diphosphate (ADP) and inorganic phosphate.

Complex I (NADH coenzyme Q reductase; labeled I) accepts electrons from the Krebs cycle electron carrier nicotinamide adenine dinucleotide (NADH), and passes them to coenzyme Q (ubiquinone; labeled Q), which also receives electrons from complex II (succinate dehydrogenase; labeled II). Q passes electrons to complex III (cytochrome bc₁ complex; labeled III), which passes them to cytochrome C. cytochrome C passes electrons to complex IV (cytochrome coxidase; labeled IV), which uses the electrons and hydrogen ions to reduce molecular oxygen to water.

Four membrane-bound complexes have been identified in mitochondria. Each is an extremely complex transmembrane structure that is embedded in the inner membrane. Three of them are proton pumps. The structures are electrically connected by lipid-soluble electron carriers and water-soluble electron carriers.

The overall electron transport chain:

Complex I

In complex I (NADH ubiquinone oxireductase, Type I NADH dehydrogenase, or mitochondrial complex I; EC 1.6.5.3), two electrons are removed from NADH and transferred to a lipid-soluble carrier, ubiquinone (Q). The reduced product, ubiquinol (QH₂), freely diffuses within the membrane, and Complex I translocates four protons (H⁺) across the membrane, thus producing a proton gradient. Complex I is one of the main sites at which premature electron leakage to oxygen occurs, thus being one of the main sites of production of superoxide.

The pathway of electrons is as follows-

NADH is oxidized to NAD⁺, by reducing Flavin mononucleotide  FMN to FMNH₂ in one two-electron step. FMNH₂ is then oxidized in two one-electron steps, through a semiquinone intermediate. Each electron thus transfers from the FMNH₂ to a Fe-S cluster, from the Fe-S cluster to ubiquinone (Q). Transfer of the first electron results in the free-radical (semiquinone) form of Q, and transfer of the second electron reduces the semiquinone form to the ubiquinol form, QH₂. During this process, four protons are translocated from the mitochondrial matrix to the inter membrane space.  As the electrons become continuously oxidized and reduced throughout the complex an electron current is produced along the 180 Angstrom width of the complex within the membrane. This current powers the active transport of four protons to the inter membrane space per two electrons from NADH.

Complex II

In complex II (succinate dehydrogenase or succinate-CoQ reductase) additional electrons are delivered into the quinone pool (Q) originating from succinate and transferred (via flavin adenine dinucleotide (FAD)) to Q. Complex II consists of four protein subunits: succinate dehydrogenase, (SDHA); succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial, (SDHB); succinate dehydrogenase complex subunit C,(SDHC) and succinate dehydrogenase complex, subunit D,(SDHD). Other electron donors (e.g., fatty acids and glycerol 3-phosphate)also direct electrons into Q (via FAD). Complex II is a parallel electron transport pathway to complex 1, but unlike complex 1, no protons are transported to the inter membrane space in this pathway. Therefore, the pathway through complex II contributes less energy to the overall electron transport chain process.

Complex III

In complex III (cytochrome bc₁ complex or CoQH₂-cytochrome c reductase)the Q-cycle contributes to the proton gradient by an asymmetric absorption/release of protons. Two electrons are removed from QH₂ at the Q_O site and sequentially transferred to two molecules of cytochrome c, a water-soluble electron carrier located within the inter membrane space. The two other electrons sequentially pass across the protein to the Q_i site where the quinone part of ubiquinone is reduced to quinol. A proton gradient is formed by one quinol {\displaystyle {\ce {2H+2e-}}}oxidations at the Q_o site to form one quinone {\displaystyle {\ce {2H+2e-}}}at the Q_i site. (In total, four protons are translocated: two protons reduce quinone to quinol and two protons are released from two ubiquinol molecules.)

When electron transfer is reduced, by a high membrane potential or respiratory inhibitors such as antimycin A, Complex III may leak electrons to molecular oxygen which results in superoxide formation. This complex is inhibited by dimercaprol (British Antilewisite, BAL), Napthoquinone and Antimycin.

Complex IV

In complex IV (cytochrome c oxidase), sometimes called cytochrome AA3, four electrons are removed from four molecules of cytochrome c and transferred to molecular oxygen (O₂), producing two molecules of water. The complex contains coordinated copper ions and several heme groups. At the same time, eight protons are removed from the mitochondrial matrix (although only four are translocated across the membrane), contributing to the proton gradient. The exact details of proton pumping in complex IV are still under study. Cyanide is an inhibitor of complex 4.

Electron Donors

In the current biosphere, the most common electron donors are organic molecules. Organisms that use organic molecules as an electron source are called organotrophs. Chemo organotrophs (animals, fungi, protists) and photolithographs (plants and algae) constitute the vast majority of all familiar life forms. Some prokaryotes can use inorganic matter as an electron source. Such an organism is called a (chemo) lithotrophs ("rock-eater"). Inorganic electron donors include hydrogen, carbon monoxide, ammonia, nitrite, sulfur, sulfide, manganese oxide, and ferrous iron. Lithotrophs have been found growing in rock formations thousands of meters below the surface of Earth. Because of their volume of distribution, lithotrophs may actually outnumber organotrophs and phototrophs in our biosphere.

Electron Acceptors

Just as there are a number of different electron donors (organic matter in organotrophs, inorganic matter in lithotrophs), there are a number of different electron acceptors, both organic and inorganic. If oxygen is available, it is most often used as the terminal electron acceptor in aerobic bacteria and facultative anaerobes. Mostly in anaerobic environments different electron acceptors are used, including nitrate, nitrite, ferric iron, sulfate, carbon dioxide, and small organic molecules such as fumarate.

Krebs’ Cycle

 

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Krebs’ Cycle

Definition

The citric acid cycle (CAC) also known as the Tricarboxylic acid cycle (TCA cycle) or the Krebs cycle is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins.   

Introduction

The TCA cycle is used by organisms that respire (as opposed to organisms that ferment) to generate energy, either by anaerobic respiration or aerobic respiration. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions. Even though it is called as a 'cycle', at least three segments of the citric acid cycle have been observed.

The name of this metabolic pathway is derived from the citric acid (a Tricarboxylic acid, often called citrate, as the ionized form predominates at biological pH that is consumed and then regenerated by this sequence of reactions to complete the cycle. The cycle consumes acetate (in the form of acetyl-CoA) and water, reduces NAD⁺ to NADH, releasing carbon dioxide. The NADH generated by the citric acid cycle is fed into the oxidative Phosphorylation (electron transport) pathway. The net result of these two closely linked pathways is the oxidation of nutrients to produce usable chemical energy in the form of ATP.

In eukaryotic cells, the citric acid cycle occurs in the matrix of the mitochondrion. The overall yield of energy-containing compounds from the TCA cycle is three NADH, one FADH₂, and one GTP and a total 38ATP.

Over view- One of the primary sources of acetyl-CoA is from the breakdown of sugar by Glycolysis which yield pyruvate that in turn is decarboxylated by the pyruvate dehydrogenase complex generating acetyl-CoA according to the following reaction scheme:

CH₃C (=O)C(=O)O⁻pyruvate + HSCoA + NAD⁺ → CH₃C(=O)SCoAacetyl-CoA + NADH + CO₂

The product of this reaction, acetyl-CoA, is the starting point for the citric acid cycle. Acetyl-CoA may also be obtained from the oxidation of fatty acids. Above is a schematic outline of the cycle –

Regulation- Its regulating factors are given below-

1. Allosterical regulation by metabolites-The regulation of the citric acid cycle is largely determined by substrate availability and inhibitory influences exerted by its own intermediates and products.

2. Citrate- It inhibits phosphofructokinase. This prevents a constant high rate of flux when there is an accumulation of citrate and a decrease in substrate for the enzyme.

3. Regulation by calcium- Calcium regulates various enzymes used in the citric acid cycle.

4. Transcriptional regulation-There is an important link between intermediates of the citric acid cycle and the regulation of hypoxia-inducible factors (HIF). HIF plays a role in the regulation of oxygen homeostasis, and is a transcription factor that targets glucose utilization in the cell.

Energy Yield

The theoretical maximum yield of ATP through oxidation of one molecule of glucose in Glycolysis, citric acid cycle, and oxidative Phosphorylation is 38 (assuming 3 molar equivalents of ATP per equivalent NADH and 2 ATP per FADH₂). Two equivalents of NADH and four equivalents of ATP are generated in Glycolysis, which takes place in the cytoplasm. Transport of two of these equivalents of NADH into the mitochondria consumes two equivalents of ATP, thus reducing the net production of ATP to 36. Furthermore, inefficiencies in oxidative Phosphorylation due to leakage of protons across the mitochondrial membrane and slippage of the ATP synthase/proton pump commonly reduces the ATP yield from NADH and FADH₂ to less than the theoretical maximum yield. The observed yields are, therefore, closer to ~2.5 ATP per NADH and ~1.5 ATP per FADH₂, further reducing the total net production of ATP to approximately 30. An assessment of the total ATP yield with newly revised proton-to-ATP ratios provides an estimate of 29.85 ATP per glucose molecule.

Metabolism in Starvation

 Metabolism in Starvation

Definition-Starvation is a severe deficiency in caloric energy intake, below the level needed to maintain an organism's life.

Introduction- It is the most extreme form of malnutrition. In humans, prolonged starvation can cause permanent organ damage and eventually, death. The term inanition refers to the symptoms and effects of starvation. Total starvation includes total lack of water, food and salts. The length of time, a person can survive, depends upon the fat stores. The longest period of survival never exceeds 9 to 10 weeks; Starvation induces a number of metabolic changes, some occurring within a few days. There is a progressive fall in B.M.R. body temperature, pulse rate and blood pressure. Ketosis develops and some retention of salt and water occurs. Metabolism of carbohydrate, fats and protein undergoes sever changes.

Causes- Starvation is an imbalance between energy intake and energy expenditure. The body expends more energy than it takes in. This imbalance can arise from one or more medical conditions or circumstantial situations, which can include:

1. Medical causes-

1. Anorexia nervosa
2. Bulimia nervosa
3. Eating disorder, not otherwise specified
4. Celiac disease
5. Coma
6. Major depressive disorder
7. Diabetes mellitus
8. Digestive disorders
9. Constant vomiting and Diarrhea

2. Non Medical causes-

1. Child, elder, or dependant abuse
2. Famine for any reason, such as  weather changes, political strife and war
3. Hunger striking
4. Excessive fasting
5. Poverty

Stages-

The symptoms of starvation show up in three stages. Phase one and two can show up in anyone that skips meals, reduces intake of foodor goes through a fasting period. Phase three is more severe, can be fatal, and results from long-term starvation.

Stage one-stage of carbohydrate depletion- Initially the body begins to maintain blood sugar levels by producing and breaking glycogen in the liver and also breaking down stored fat and protein. The liver can provide glycogen for the first few hours. After that, the body begins to break down fat and protein. Fatty acids are used by the body as an energy source for muscles, but lower the amount of glucose that gets to the brain. Another chemical that comes from fatty acids is glycerol. It can be used like glucose for energy, but eventually runs out.

Stage two-Stage of fat depletion-This phase two can last for up to weeks at a time. In this phase, the body mainly uses stored fat for energy. The breakdown occurs in the liver and turns fat into ketones. After fasting has gone on for one week, the brain will use these ketones and any leftover glucose. Using ketones lowers the need for glucose, and the body slows the breakdown of proteins.

Stage three- stage of breakdown of body proteins- By this point, the fat stores are gone and the body begins to turn to stored protein for energy. This means it needs to break down muscle tissues which are full of protein; the muscles break down very quickly. Protein is essential for our cells to work properly, and when it runs out, the cells can no longer function properly. The cause of death due to starvation is usually an infection, or the result of tissue breakdown. The body is unable to gain enough energy to fight off bacteria and viruses. The signs at the end stages include: hair color loss, skin flaking, swelling in the extremities, and a bloated belly. Even though they may feel hunger, people in the end-stage of starvation are usually unable to eat enough food.

Effects- The following effects are seen-

General condition- During the first two days there is a craving for food, particularly at meal times. But later on this craving subsides, weakness increases and a strong dislike to go for any physical or mental effort develops. At about this time the subject falls into a state of semi consciousness. The pulse rate and the body temperature remain almost normal till before death. The sleep increases and respiration becomes slower. Temperature falls before death. The amount of urine as well as its urea content falls. Stool is formed and may be passed during or at the close of the starvation period.

Body weight- The body weight is steadily lost. The daily loss in a person during the first ten days amounts to between 1-15% of the original body weight. At the onset of the fast changes are seen in the fat depots and subcutaneous tissue. The extracellular fluid in large quantity is also lost. Dissolution of the muscular tissue and protoplasmic structure occurs later. The muscle fibers are much reduced in size and many of the fibers are degenerated. Various tissues lose weight as under-

Tissue	Loss of weight
muscles	35%
brain	30%
heart	30%
Kidneys	20%
liver	55%
spleen	70%
Endocrines	2-6%

 

The organs and the tissues of the body are not affected alike. The more vital organs lose the least weight, whereas the less vital ones lose the most.

Metabolism- During starvation, the body has to depend upon its own tissue materials. Of the three food stuffs-glycogen, fat and protein the liver glycogen store is first mobilized. The protein, mobilized from stored protein in the tissue, is transformed into glucose (Gluconeogenesis).

This initial stage will last for not more than two days. In the next stage 80%-90% of energy requirements are met from fats and the remainder (10-20%) from the proteins. Since adipose tissue represents the largest amount of stored food, the second stage will last for the longest period over two weeks.

In the third stage, when the fat-store is almost exhausted, energy requirements are derived from the breakdown of the body proteins. The cell substance will break up with a consequent dislocation of cell metabolism and cell life. This state of affairs, it continued, it will lead to death. The third stage lasts for less than one week

The determination of total RQ and of non-protein R.Q will indicate the extent to which these three molecules are burning at the three stages. The R.Q. is highest at the first stage and diminishes later on.

Metabolic Changes- A brief description of the different metabolic changes is given below-

Carbohydrate metabolism- Carbohydrate store becomes almost depleted in the first two days. The blood sugar is maintained at a steady level even up to the end. This steady level is believed to be due to Gluconeogenesis in the liver.

Fat metabolism- Fat which remains in adipose tissue (element variable) is used first. It goes into the liver where it is completely oxidized and an increased amount of acetyl coenzyme A is produced, resulting formation of ketone bodies whereas due to absence of carbohydrates, fat oxidation usually remains incomplete producing ketosis and acidosis. Thus alkali reserve diminished and various ill-effects of ketosis are produced. Ketones from the liver pass into the blood and ketone bodies appear in the urine. The acidosis is compensated by bicarbonate of blood, increased pulmonary ventilation and increased elimination of CO₂, from the alveoli, creased ammonia formation in the kidney and excretion of ammo salts in the urine.

Protein metabolism- Tissue protein is broken down and amino acids formed after hydrolysis constitute the amino acid pool. The amino acids from this pool are utilized for the maintenance of the structural and functional efficiency of the vital organs. The amino acids also undergo deamination in the liver and the non-nitrogenous part helps in the maintenance of the blood sugar level. The amount of nitrogen excretion during the first few days is directly proportional to the amount of protein intake before starvation. The average daily excretion in the first week is about 10 gm. During the second and third weeks the values are very low. But just before death when proteins are rapidly breaking down the urinary nitrogen rises (premortal rise).

The end products of endogenous protein metabolism, i.e. Creatinine, creatine, neutral sulphur compounds and uric acid are the main nitrogenous products. Creatine excretion gradually falls as the weight of muscles diminishes. On the fifth day of starvation a man excretes 11.4 gm of nitrogen and the energy output is about 2,000 calories. 6-25 gm of protein when broken down eliminates 1 gm of nitrogen. The urinary nitrogen indicates 6.25x11.4=71-5 gm of protein catabolism. Thus the energy liberated at that amount of protein catabolism is 71.5x4.1 Cal=300 calories. The rest of the calories are derived from 190 gm of fat.

Mineral metabolism- Phosphorus and sulphur excretion in urine at first rises and then falls. The excretion of calcium is elevated and that of chloride, sodium, potassium and magnesium is reduced during starvation. Changes in blood and urine during starvation

Blood changes-

(1) Acidosis with diminished alkali reserve.

(2) Low blood sugar,

(3) Increased blood fats.

(4) Presence of ketone bodies.

(5) Raised potassium (Showing breakdown of tissue cells).

Urine changes-

(1) Volume becomes less.

(2) Nitrogen content steadily falls.

(3) Presence of abnormal constituents like creatine, ketones, etc

(4) Ammonia excretion increases as also the ammonia coefficient.

(5) Rise of acidity.

(6) Fall of potassium that causes chlorine retention (Index of breakdown of tissues).