Pharm 211 Unit 6 Carbohydrates PDF

UNIT 6 Carbohydrates MGSBiagtanRPhMSPharm©2020 154 Saint Louis University – Department of Pharmacy This section highlights carbohydrates that are widely distributed in plants and animals; they have important structural and metabolic roles. Glucose is t...

UNIT 6 Carbohydrates MGSBiagtanRPhMSPharm©2020 154 Saint Louis University – Department of Pharmacy This section highlights carbohydrates that are widely distributed in plants and animals; they have important structural and metabolic roles. Glucose is the most important carbohydrate in mammalian biochemistry because nearly all carbohydrate in food is converted to glucose for metabolism. Knowledge of normal metabolism is essential for an understanding of abnormalities that underlie disease. In this module, we also explore the relationship of carbohydrate metabolism to energy production in cells, the conversion of glucose and other hexoses into a variety of different sugars needed for biosynthesis and production of NADH and NADPH as sources of reductive power in cells. At the end of this lesson, you should be able to: 1. Discuss the roles of carbohydrates in health. disease and formulation of pharmaceutical products; 2. Classify carbohydrates into their respective groups; 3. Identify and differentiate the models and representations of carbohydrates; 4. Discuss the metabolism of carbohydrates in the body and the mode of action of hormones in carbohydrate metabolism. A carbohydrate is a polyhydroxy aldehyde, a polyhydroxy ketone, or a compound that yields polyhydroxy aldehydes or polyhydroxy ketones upon hydrolysis. The carbohydrate fructose is a polyhydroxy ketone and the carbohydrate glucose is a polyhydroxy aldehyde. MGSBiagtanRPhMSPharm©2020 155 Saint Louis University – Department of Pharmacy As a primary metabolite, here are the most important functions of carbohydrates in the body. 1. Carbohydrate oxidation provides energy. 2. Carbohydrate storage, in the form of glycogen, provides a short-term energy reserve. 3. Carbohydrates supply carbon atoms for the synthesis of other biochemical substances (proteins, lipids, and nucleic acids). 4. Carbohydrates form part of the structural framework of DNA and RNA molecules. 5. Carbohydrates linked to lipids are structural components of cell membranes. 6. Carbohydrates linked to proteins function in a variety of cell–cell and cell–molecule recognition processes. Knowing that carbohydrates are essential in the human body, let us discuss the detailed biochemical importance as well as the pharmaceutical relevance of such carbohydrates. Let us start from monosaccharides, followed by disaccharides and last the polysaccharides. I. Biochemically Important Monosaccharides 1. D-Glyceraldehyde and Dihydroxyacetone the simplest of the monosaccharides, trioses that are important intermediates in the process of glycolysis D-Glyceraldehyde is a chiral molecule but dihydroxyacetone is not. 2. D-Glucose most abundant in nature and the most important from a human nutritional standpoint AKA grape sugar, Blood sugar and Dextrose Grape sugar since ripe fruits, particularly ripe grapes (20%–30% glucose by mass), are a good source of glucose Blood sugar since blood contains dissolved glucose ( 70–100 mg/dL) Blood sugar concentration of about 130 mg/ dL occurs in the first hour after eating, and then the concentration decreases over the next 2–3 hours back to the normal range. Cells use glucose as a primary source of energy Two hormones, insulin and glucagon, have important roles in keeping glucose blood concentrations within the normal range, which is required for normal body function MGSBiagtanRPhMSPharm©2020 156 Saint Louis University – Department of Pharmacy 3. D-Galactose seldom encountered as a free monosaccharide synthesized from glucose in the mammary glands for use in lactose (milk sugar), a disaccharide consisting of a glucose unit and a galactose unit sometimes called brain sugar because it is a component of glycoproteins found in brain and nerve tissue present in the chemical markers that distinguish various types of blood—A, B, AB, and O Structure: D-galactose and D-glucose differ only in the configuration of the —OH group and —H group on carbon. d-Galactose and D-glucose are epimers (diastereomers that differ only in the configuration at one chiral center) 4. D-Fructose biochemically the most important ketohexose AKA levulose (rotate plane-polarized light to the left) and fruit sugar the sweetest-tasting of all sugars found in many fruits and is present in honey in equal amounts with glucose used as a dietary sugar, not because it has fewer calories per gram than other sugars but because less is needed for the same amount of sweetness used as sweetener in the form of high fructose corn syrup (HFCS) Structure: from the third to the sixth carbon, the structure of D-fructose is identical to that of D-glucose-differences at carbons 1 and 2 are related to the presence of a ketone group in fructose and of an aldehyde group in glucose. 5. D-Ribose component of a variety of complex molecules, including ribonucleic acids (RNAs) and energy-rich compounds such as adenosine triphosphate (ATP) and DNA molecules Structure: a pentose.-if carbon 3 and its accompanying —H and — OH groups were eliminated from the structure of D-glucose, the remaining structure would be that of D-ribose MGSBiagtanRPhMSPharm©2020 157 Saint Louis University – Department of Pharmacy II. Biochemically Important Disaccharides 1. Maltose AKA malt sugar Malt (germinated barley that has been baked and ground) contains maltose; hence the name malt sugar produced whenever the polysaccharide starch breaks down when seeds germinate in plants and in human beings during starch digestion made up of two D-glucose units, one of which must be a-D-glucose a reducing sugar because the glucose unit on the right has a hemiacetal carbon atom (C-1) three forms of the maltose molecule: alpha-maltose, beta-maltose (solid state, the b form is dominant) and the open-chain form the most important reaction is hydrolysis to produce two molecules of glucose catalysed by the enzyme maltase Formation of Disaccharides a monosaccharide that has cyclic forms (hemiacetal forms) can react with an alcohol to form a glycoside (acetal). disaccharide formation, one of the monosaccharide reactants functions as a hemiacetal, and the other functions as an alcohol. the bond that links the two monosaccharides of a disaccharide (glycoside) together is called a glycosidic linkage- the bond in a disaccharide resulting from the reaction between the hemiacetal carbon atom —OH group of one monosaccharide and an —OH group on the other monosaccharide. It is always a carbon–oxygen–carbon bond in a disaccharide. MGSBiagtanRPhMSPharm©2020 158 Saint Louis University – Department of Pharmacy Formation of Maltose: The glycosidic linkage between the two glucose units is called an 𝝰(1 —> 4) linkage. The two —OH groups that form the linkage are attached, respectively, to carbon 1 of the first glucose unit (in an 𝝰 ︎ configuration) and to carbon 4 of the second. Alpha and Beta Linkage: It is important to distinguish between the structural notation used for an 𝝰 (1 —> 4) glycosidic linkage and that used for ︎β ︎(1 —> 4) glycosidic linkage. 2. Cellobiose produced as an intermediate in the hydrolysis of the polysaccharide cellulose like maltose, cellobiose contains two D-glucose monosaccharide units-it differs from maltose in that one of the D-glucose units—the one functioning as a hemiacetal—must have a β configuration instead of the a configuration for maltose that results in change in configuration results in a β (1 —> 4) glycosidic linkage a reducing sugar, has three isomeric forms in aqueous solution and upon hydrolysis produces two D- glucose molecules Both the human body and yeast lack the enzyme cellobiase needed to break the glucose–glucose ︎ β (1 —> 4) linkage of cellobiose. Thus cellobiose cannot be digested by humans or fermented by yeast 3. Lactose made up of 𝝰 ︎-D-galactose unit and 𝝰 D-glucose unit joined by a (1 —> 4) glycosidic linkage a reducing sugar (the glucose ring can open to give an aldehyde) Epimerization of glucose yields galactose, and then the β(1 —> 4) linkage forms between a galactose and a glucose unit The alpha form of lactose is sweeter to the taste and more soluble in water than the b form. The β form can be found in ice cream that has been stored for a long time; it crystallizes and gives the ice cream a gritty texture. MGSBiagtanRPhMSPharm©2020 159 Saint Louis University – Department of Pharmacy  AKA milk sugar: major sugar found in milk enzymes in mammalian mammary glands take glucose from the bloodstream and synthesize lactose in a four-step process important ingredient in commercially produced infant formulas that are designed to simulate mother’s milk souring of milk is caused by the conversion of lactose to lactic acid by bacteria in the milk pasteurization of milk is a quick-heating process that kills most of the bacteria and retards the souring process. lactose can be hydrolyzed by acid or by the enzyme lactase, forming an equimolar mixture of galactose and glucose in the human body, the galactose so produced is then converted to glucose by other enzymes. the genetic condition lactose intolerance, an inability of the human digestive system to hydrolyze lactose Lactulose a synthetic dissccharide containing galactose and fructose. it is neither digested nor absorbed in the intestine. useful for the treatment of hepatic encephalopathy, a disorder characterized by elevated plasma ammonium levels it converts ammonia (NH3) in the lumen to ammonium ion (NH4+). This results in a reduction in the plasma NH3, since NH4+ ions are not easily absorbed. 4. Sucrose AKA table sugar most abundant of all disaccharides and occurs through- out the plant kingdom produced commercially from the juice of sugar cane and sugar beets sugar cane contains up to 20% by mass sucrose, and sugar beets contain up to 17% by mass sucrose two monosaccharide units present in a D-sucrose molecule are ︎ 𝝰-D-glucose and b-D-fructose a non-reducing sugar since it has no hemi-acetal is present in the molecule, because the glycosidic linkage involves the reducing ends of both monosaccharides. Sucrose, in the solid state and in solution, exists in only one form—there are no 𝝰 and β isomers, and an open-chain form is not possible Structure: The glycosidic linkage is not 𝝰 (1 —> 4) linkage, as was the case for maltose, cellobiose, and lactose. It is instead an 𝝰, β(1 —> 2) glycosidic linkage. The —OH group on carbon 2 of D-fructose (the hemiacetal carbon) reacts with the —OH group on carbon 1 of D-glucose (the hemiacetal carbon). MGSBiagtanRPhMSPharm©2020 160 Saint Louis University – Department of Pharmacy  Sucrase, the enzyme needed to break the 𝝰, β(1 —> 2) linkage in sucrose, is present in the human body. Hence sucrose is an easily digested substance. Sucrose hydrolysis (digestion) produces an equimolar mixture of glucose and fructose called invert sugar III. Biochemically Important Polysaccharides A polysaccharide is a polymer that contains many monosaccharide units bonded to each other by glycosidic linkages. Polysaccharides are often also called glycans. Glycan is an alternate name for a polysaccharide. Important parameters that distinguish various polysaccharides (or glycans) from each other are: 1. The identity of the monosaccharide repeating unit(s) in the polymer chain: A. Homopolysaccharides on hydrolysis yield only a single type of monosaccharide. They are named based on the nature of the monosaccharide. Thus, glucans are polymers of glucose whereas fructosans are polymers of fructose. examples are starch, glycogen, chitin, cellulose B. Heteropolysaccharides on hydrolysis yield a mixture of a few monosaccharides or their derivatives. B.1. Mucopolysaccharides: AKA glycosaminoglycans (GAG) made up of repeating units of sugar derivatives, namely amino sugars and uronic acids with acetylated amino group, sulphate group and carboxyl group presence of sulfate and carboxyl groups contributes to acidity of the molecules, making them acid mucopolysaccharides/acidic polysaccharide Mucopolysaccharides are essential components of tissue structure. The extracellular spaces of tissue (particularly connective tissue-cartilage, skin, blood vessels, tendons) consist of collagen and elastin fibers embedded in a matrix or ground substance predominantly composed of GAG Some of the mucopolysaccharides are found in combination with proteins to form mucoproteins or mucoids or proteoglycans. Mucoproteins may contain up to 95% carbohydrate and 5% protein 2. The function of the polysaccharide in the human/animal body or plants: 2.1. Storage Polysaccharide: a polysaccharide that is a storage form for monosaccharides and is used as an energy source in cells. In cells, monosaccharides are stored in the form of polysaccharides rather than as individual monosaccharides in order to lower the osmotic pressure within cells. Incorporating many monosaccharide molecules into a single polysaccharide molecule results in a dramatic reduction in molecular numbers. The most important storage polysaccharides are starch (in plant cells) and glycogen (in animal and human cells). 2.2. Structural Polysaccharide: a polysaccharide that serves as a structural element in plant cell walls and animal exoskeletons. Two of the most important structural polysaccharides are cellulose and chitin. Both are homopolysaccharides 3. The length of the polymer chain: Polysaccharide chain length can vary from less than a hundred monomer units to up to a million monomer units. MGSBiagtanRPhMSPharm©2020 161 Saint Louis University – Department of Pharmacy 4. The type of glycosidic linkage between monomer units: As with disaccharides, several different types of glycosidic linkages are encountered in polysaccharide structures. 5. The degree of branching of the polymer chain: The ability to form branched-chain structures distinguishes polysaccharides from the other two major types of biochemical polymers and nucleic acids, which occur only as linear (unbranched) polymers. A. Storage Polysaccharides 1. Starch AKA glucosan, glucan or amylum homopolysaccharide containing only glucose monosaccharide units the energy-storage polysaccharide in plants if excess glucose enters a plant cell, it is converted to starch and stored for later use when the cell cannot get enough glucose from outside the cell, it hydrolyzes starch to release glucose two different polyglucose polysaccharides can be isolated from most starches Amylose, a straight-chain glucose polymer, usually accounts for 15%–20% of the starch glucose units are connected by alpha (1—> 4) glycosidic linkages the number of glucose units present in an amylose chain depends on the source of the starch; 300–500 monomer units are usually present. Amylopectin, a branched glucose polymer, accounts for the remaining 80%–85% of the starch alpha (1 —> 6) linkages occur about once every 25–30 glucose units because of the branching, amylopectin has a larger average molecular mass than the linear amylose. up to 100,000 glucose units may be present in an amylopectin polymer chain 2. Glycogen polysaccharide containing only glucose units the glucose storage polysaccharide in humans and animals the function is thus similar to that of starch in plants, and it is sometimes referred to as animal starch liver cells and muscle cells are the storage sites for glycogen in humans all glycosidic linkages are of the a type, and both (1 —> 4) and (1 —> 6) linkages are present about three times more highly branched than amylopectin, and it is much larger, with up to 1,000,000 glucose units present When excess glucose is present in the blood (normally from eating too much starch), the liver and muscle tissue convert the excess glucose to glycogen, which is then stored in these tissues. Whenever the glucose blood level drops (from exercise, fasting, or normal activities), some stored glycogen is hydrolyzed back to glucose. These two opposing processes are called glycogenesis and glycogenolysis, the formation and decomposition of glycogen, respectively. Glycogen is an ideal storage form for glucose. The large size of these macromolecules prevents them from diffusing out of cells. Also, conversion of glucose to glycogen reduces osmotic pressure. Cells would burst because of increased osmotic pressure if all of the glucose in glycogen were present in cells in free form. High concentrations of glycogen in a cell sometimes precipitate or crystallize into glycogen granules. MGSBiagtanRPhMSPharm©2020 162 Saint Louis University – Department of Pharmacy B. Structural Polysaccharides 1. Cellulose the structural component of plant cell walls, is the most abundant naturally occurring polysaccharide. “woody” portions of plants—stems, stalks, and trunks— have particularly high concentrations of this fibrous, water- insoluble substance glycosidic linkages in cellulose are therefore b(1—> 4) 5000 glucose units, which gives macromolecules with molecular masses of about 900,000 amu cotton is almost pure cellulose (95%), and wood is about 50% cellulose it is not a source of nutrition for human beings since humans lack the cellulase capable of catalyzing the hydrolysis of beta (1 —> 4) linkages in cellulose intestinal tracts of animals such as horses, cows, and sheep contain bacteria that produce cellulase, an enzyme that can hydrolyze cellulose beta (1 —> 4) linkages and produce free glucose from cellulose intestinal tracts of termites contain the same microorganisms, which enable termites to use wood as their source of food microorganisms in the soil can also metabolize cellulose, which makes possible the biodegradation of dead plants despite its non-digestibility, cellulose is still an important component of a balanced diet. serves as dietary fiber that provides the digestive tract with “bulk” that helps move food through the intestinal tract and facilitates the excretion of solid wastes. readily absorbs water, leading to softer stools and frequent bowel action-links have been found between the length of time stools spend in the colon and possible colon problems some dietary fibers bind lipids such as cholesterol and carry them out of the body with the feces. this lowers blood lipid concentrations and, possibly, the risk of heart and artery disease. About 25–35 grams of dietary fiber daily is a desirable intake. 2. Chitin gives rigidity to the exoskeletons of crabs, lobsters, shrimp, insects, and other arthropods also occurs in the cell walls of fungi linear polymer (no branching) with all beta(1 —> 4) glycosidic linkages an N-acetyl amino derivative of D-glucose C. Mucopolysaccharides 1. Hyaluronic Acid found in the ground substance of synovial fluid of joints and vitreous humor of eyes also present as a ground substance in connective tissues, and forms a gel around the ovum serves as a lubricant and shock absorbent in joints Composition: alternate units of D-glucuronic acid and N-acetyl D-glucosamine held together by beta (1—> 3) glycosidic bond Hyaluronic acid contains about 250–25,000 disaccharide units (held by 1 4 bonds) with a molecular weight up to 4 million MGSBiagtanRPhMSPharm©2020 163 Saint Louis University – Department of Pharmacy  Hyaluronidase: enzyme that breaks Beta(1–>4 linkages) hyaluronic acid and other GAG present in high concentration in testes, seminal fluid, and in certain snake and insect venoms. Hyaluronidase of semen is assigned an important role in fertilization as this enzyme clears the gel (hyaluronic acid) around the ovum allowing a better penetration of sperm into the ovum. Hyaluronidase of bacteria helps their invasion into the animal tissues 2. Chondroitin 4-Sulfate Greek : chondros- meaning cartilage major constituent of various mammalian tissues (bone, cartilage, tendons, heart, valves, skin, cornea etc.) Composition: D-glucuronic acid and N-acetyl D-galactosamine 4-sulfate 3. Heparin an anticoagulant (prevents blood clotting) that occurs in blood, lung, liver, kidney, spleen etc helps in the release of the enzyme lipoprotein lipase which helps in clearing the turbidity of lipemic plasma Composition: N-sulfo D-glucosamine 6-sulfate and glucuronate 2-sulfate 4. Dermatan Sulfate mostly found in skin, dermatan sulfate is structurally related to chondroitin 4-sulfate the only difference is that there is an inversion in the configuration around C5 of D-glucuronic acid to form L-iduronic acid 5. Keratan Sulfate heterogeneous GAG with a variable sulfate content, besides small amounts of mannose, fructose, sialic acid Composition: D-galactosamine 6-sulfate and N-acetylglucosamine 6-sulfate MGSBiagtanRPhMSPharm©2020 164 Saint Louis University – Department of Pharmacy Structure: Here are the structures of the mucopolysaccharides. Note the components that combine to make up those sugars. Additionally, check the type of linkages present. MGSBiagtanRPhMSPharm©2020 165 Saint Louis University – Department of Pharmacy Structural Aspects of Carbohydrates We now examine the structures and representations of carbohydrates that contribute to their functions and properties. As we consider the details of their structure, we will find the rationale why it is in alpha or beta configuration. I. D and L Isomers D and L isomers are mirror images of each other spatial orientation of H and OH groups on the carbon atom (C5 for glucose) that is adjacent to the terminal primary alcohol carbon determines whether the sugar is D- or L-isomer D-series: OH group is on the right side, L series: OH group is on the left side II. Epimers If two monosaccharides differ from each other in their configuration around a single specific carbon (other than anomeric) atom, they are referred to as epimers to each other Examples: glucose and galactose are epimers with regard to carbon 4 (C4-epimers); they differ in the arrangement of OH group at C4 Glucose and mannose are epimers with regard to carbon 2 (C2-epimers) III. Stereoisomerism Stereoisomers are isomers that have the same molecular and structural formulas but differ in the orientation of atoms in space. Enantiomers- stereoisomers that are mirror images of each other Diastereomers- stereoisomers that are not mirror images of one another. MGSBiagtanRPhMSPharm©2020 166 Saint Louis University – Department of Pharmacy A. Designating Handedness Using Fischer Projection Formula a two-dimensional structural notation for showing the spatial arrangement of groups about chiral centers in molecules. a chiral center is represented as the intersection of vertical and horizontal lines- the atom at the chiral center, which is almost always carbon, is not explicitly shown B. Haworth Projection Formulas Haworth projection formula is a two-dimensional structural notation that specifies the three-dimensional structure of a cyclic form of a monosaccharide Such projections carry the name of their originator, the British chemist Walter Norman Haworth In a Haworth projection, the hemiacetal ring system is viewed “edge on” with the oxygen ring atom at the upper right (six- membered ring) or at the top (five-membered ring). The D or L form of a monosaccharide is determined by the position of the terminal CH2OH group on the highest- numbered ring carbon atom. In the D form, this group is positioned above the ring. In the L form, which is not usually encountered in biochemical systems, the terminal CH2OH group is positioned below the ring. MGSBiagtanRPhMSPharm©2020 167 Saint Louis University – Department of Pharmacy  alpha or beta configuration is determined by the position of the —OH group on carbon 1 relative to the CH2OH group that determines D or L series. In a b configuration, both of these groups point in the same direction; in an a configuration, the two groups point in opposite directions C. Chair Conformation the most stable conformation of cyclohexane that resembles a chair. Example: D-glucose Metabolism of Carbohydrates Carbohydrates are major source of energy for the living cells. As such, carbohydrates are the first cellular constituents, synthesized by green plants during photosynthesis from carbon dioxide and water, on absorption of light. Thus, light is the ultimate source of energy for all biological processes. The monosaccharide glucose is the central molecule in carbohydrate metabolism since all the major pathways of carbohydrate metabolism are connected with it. Glucose is utilized as a source of energy, it is synthesized from non-carbohydrate precursors and stored as glycogen to release glucose as and when the need arises. Here are the major pathways of carbohydrate metabolism: 1. Glycolysis (Embden-Meyerhof pathway): The oxidation of glucose to pyruvate and lactate. 2. Citric acid cycle (Krebs cycle or tricarboxylic acid cycle): The oxidation of acetyl CoA to CO2. Krebs cycle is the final common oxidative pathway for carbohydrates, fats or amino acids, through acetyl CoA. 3. Gluconeogenesis: The synthesis of glucose from non-carbohydrate precursors (e.g. amino acids, glycerol etc.) that occurs in the cytosol. 4. Glycogenesis: The formation of glycogen from glucose. 5. Glycogenolysis: The breakdown of glycogen to glucose. MGSBiagtanRPhMSPharm©2020 168 Saint Louis University – Department of Pharmacy  A. Digestion starts in the mouth: salivary alpha-amylase continues in the small intestines: pancreatic amylase absorption thru active transport sent to the liver for glycolysis ➡ Kreb cycle B. Glycolysis AKA Embden-Meyerhof pathway uses glucose to convert to three-carbon pyruvate molecules produce ATP; anaerobic process enzymes are present in the cytosomal fraction of the cell essential for brain which is dependent on glucose for energy Three distinct phases: A. Energy investment phase or priming stage B. Splitting phase C. Energy generation phase. Starting materials: D-glucose + 2 ADP + 2Pi End Products: 2 pyruvate + 4 ATP + 2 NADH + 2H REACTION ENYZME PRODUCT/S 1.Phosphorylation Hexokinase G6PO4 2. Isomerization Phosphoglucoisomerase F6PO4 3. Phosphorylation Phosphofructokinase F1,6-biPO4 glyceraldehyde PO4 4. Cleavage Aldolase DHA P04 5. Isomerization Triosephosphate isomerase two glyceraldehyde-3-PO4 glyceraldehyde phosphate 3 two 1,3- 6. Oxidation & Phosphorylation dehydrogenase Bisphosphoglycerate 7. Phosphorylation of ADP phosphoglycerokinase two 3-Phosphoglycerate 8. Isomerization phosphoglyceromutase two 2-Phosphoglycerate 9. Dehydration enolase two Phosphoenolpyruvate 10. Phosphorylation of ADP pyruvate kinase two pyruvate MGSBiagtanRPhMSPharm©2020 169 Saint Louis University – Department of Pharmacy C. Glycogenesis formation of glycogen from glucose takes place in the cytosol and requires ATP and UTP, besides glucose synthesis of glycogen from glucose-1-phosphate additional source of glucose aside from gluconeogenesis key enzyme: glycogen synthase D. Glycogenolysis degradation of stored glycogen in liver and muscle key enemy: glycogen phosphorylase glycogen stored in the liver and muscles, is converted first to glucose-1- phosphate and then into glucose-6-phosphate glucagon is released from the pancreas in response to low blood glucose and epinephrine is released in response to a threat or stress glucagon and epinephrine stimulate glycogen phosphorylase to begin glycogenolysis and inhibit glycogen synthetase (to stop glycogenesis) E. Gluconeogenesis The synthesis of glucose from non- carbohydrate compounds is known major substrates/precursors are lactate, pyruvate, glucogenic amino acids, propionate and glycerol Importance: In fasting even more than a day, gluconeogenesis must occur to meet the basal requirements of the body for glucose and to maintain the intermediates of citric acid cycle. This is essential for the survival of humans and other animals F. Citric Acid Cycle the most important metabolic pathway for the energy supply to the body about 65-70% of the ATP is synthesized in Krebs cycle the final common oxidative pathway for carbohydrates, fats and amino acids it does not only supplies energy but also provides many intermediates required for the synthesis of amino acids, glucose, heme etc. MGSBiagtanRPhMSPharm©2020 170 Saint Louis University – Department of Pharmacy  the most important central pathway connecting almost all the individual metabolic pathways (either directly or indirectly). uses acetyl CoA in the synthesis of ATP occurs in the mitochondrial matrix aerobic conditions only important in the process of cellular respiration amphibolic reaction involve oxidation and reduction: NAD and FAD NAD: 3x and FAD: once Starting materials: Acetyl CoA + 3 NAD + FAD + GDP + P + 2 H2O End Products: each cycle: 2CO2 + 3NADH + 2H + FADH2 + CoA + GTP MGSBiagtanRPhMSPharm©2020 171 Saint Louis University – Department of Pharmacy