Lecture Notes: Regulation of Energy Metabolism PDF

BIOCHEMISTRY AND NUTRITION (RNB11903) Regulation of Energy Metabolism Patmani r.  SUB-TOPICS The brain and energy metabolism* Glucagon and insulin Creatine phosphate Creatinine Glycogen Gluconeogenesis Fructose Fatty acids The Krebs cycles* Fer...

BIOCHEMISTRY AND NUTRITION (RNB11903) Regulation of Energy Metabolism Patmani r.  SUB-TOPICS The brain and energy metabolism* Glucagon and insulin Creatine phosphate Creatinine Glycogen Gluconeogenesis Fructose Fatty acids The Krebs cycles* Fermentative and anaerobic metabolism* *Doctor’s lessons GLUCONEOGENESIS Summary Gluconeogenesis is a vital metabolic pathway that enables the synthesis of glucose from non-carbohydrate sources, ensuring blood glucose levels remain stable during periods of fasting or low carbohydrate intake. Understanding this process is essential for nursing , as it plays a crucial role in metabolic health, energy production, and patient management in conditions such as diabetes and starvation Glycolysis versus gluconeogenesis Glycolysis is a catabolic process of glucose hydrolysis needed for energy and biosynthetic intermediates, whereas gluconeogenesis is a glucose production process important for maintaining blood glucose levels during starvation  INTRODUCTION Gluconeogenesis is GLUCO – glucose; NEO – new; GENESIS – creation. Gluconeogenesis is a biochemical term that describes the synthesis of glucose from substances which are not carbohydrates. Gluconeogenesis is the formation of new glucose molecules in the body as opposed to glucose that is broken down from the long storage molecule glycogen. Gluconeogenesis is the opposite process of glycolysis, which is the breakdown of glucose molecules into their components. It takes place mostly in the liver, though it can also happen in smaller amounts in the kidney and small intestine.  LEARNING OUTCOMES On successful completion of the lesson, the student will be able to: Identify the function of gluconeogenesis; Describe the pathway of gluconeogenesis.  FUNCTIONS Human Bodies Produce Glucose To Maintain Healthy Blood Sugar Levels. Glucose Levels In The Blood Must Be Maintained Because It Is Used By Cells To Make The Energy Molecule Adenosine Triphosphate (ATP). Gluconeogenesis Occurs During Times When A Person Has Not Eaten In A While, Such As During A Period Of Starvation. Without Food Intake, Blood Sugar Levels Become Low. FUNCTIONS (cont.) During This Time, The Body Does Not Have An Excess Of Carbohydrates From Food That It Can Break Down Into Glucose, So It Uses Other Molecules For The Process Of Gluconeogenesis Such As Amino Acids, Lactate, Pyruvate And Glycerol Instead. Once Glucose Is Produced Through Gluconeogenesis In The Liver, It Is Then Released Into The Bloodstream, Where It Can Travel To Cells Of Other Parts Of The Body So That It May Be Used For Energy. The Process Of Gluconeogenesis Is Sometimes Referred To Endogenous Glucose Production (EGP) Because It Requires The Input Of Energy. PATHWAY 1. Gluconeogenesis begins in either the mitochondria or cytoplasm of the liver or kidney. 2. First, two pyruvate molecules are carboxylated to form oxaloacetate. One ATP (energy) molecule is needed for this. 3. Oxaloacetate is reduced to malate by NADH so that it can be transported out of the mitochondria. 4. Malate is oxidized back to oxaloacetate once it is out of the mitochondria. 5. Oxaloacetate forms phosphoenolpyruvate using the enzyme phosphoenolpyruvate carboxykinase ( pepck). PATHWAY (cont.) 5. Phosphoenolpyruvate Is Changed To Fructose-1,6-biphosphate, And Then To Fructose-6-phosphate. ATP Is Also Used During This Process, Which Is Essentially Glycolysis In Reverse. 6. Fructose-6-phosphate Becomes Glucose-6-phosphate With The Enzyme Phosphoglucoisomerase. 7. Glucose Is Formed From Glucose-6-phosphate In The Cell’s Endoplasmic Reticulum Via The Enzyme Glucose-6-phosphatase. To Form Glucose, A Phosphate Group Is Removed, And Glucose-6- phosphate And ATP Becomes Glucose And ADP. PATHWAY (cont.) PATHWAY (cont.) SUMMARY During A prolonged fast or vigorous exercise, glycogen stores become depleted, and glucose must be synthesized de novo (new) in order to maintain blood glucose levels. Gluconeogenesis is the pathway by which glucose is formed from non-hexose precursors such as glycerol, lactate, pyruvate, and glucogenic amino acids. SUMMARY (cont.) Gluconeogenesis Is Essentially The Reversal Of Glycolysis. However, To Bypass The Three Highly Exergonic (And Essentially Irreversible) Steps Of Glycolysis, Gluconeogenesis Utilizes Four Unique Enzymes. The Enzymes Unique To Gluconeogenesis Are Pyruvate Carboxylase, Pep Carboxykinase, Fructose 1,6-bisphosphatase, And Glucose 6-phosphatase. Because These Enzymes Are Not Present In All Cell Types, Gluconeogenesis Can Only Occur In Specific Tissues. In Humans, Gluconeogenesis Takes Place Primarily In The Liver And To A Lesser Extent, The Renal Cortex.  Glucose metabolism drawn as a block diagram the green glycolysis pathway from glucose to pyruvate making a little ATP, the blue pentose phosphate pathway generating reducing equivalents and various sugars, the orange TCA cycle generating many reducing equivalents and several metabolic building blocks, and finally the grey electron transport chain generating ATP. In this session we study the purple gluconeogenesis pathway for generating glucose and the yellow glycogenesis pathway for generating glycogen. Block diagram of glucose metabolism. Each colored block represents a sequence of enzymatic reactions grouped together to simplify metabolism as major functional units.  SAQ Q1 Gluconeogenesis takes place in Gluconeogenesis takes place in the liver and cortex of kidneys. It usually takes place when the carbohydrates in the diet are insufficient to meet the demand of glucose in the body. Q2 What is the function of ATP in gluconeogenesis? The energy source for the many steps of this biological reaction is ATP molecules. In several steps, it promotes the production of glucose from non-sugar substrates. Q3 Define Glucagon. Glucagon is a hormone that is secreted by the α-cells of pancreatic islets when the body’s blood glucose level begins to drop. By two mechanisms, glucagon regulates the transition of fructose 1, 6-bisphosphate to fructose 6-phosphate or promotes the process of gluconeogenesis. Q4 What enzymes are used in gluconeogenesis? The gluconeogenesis pathway has four irreversible steps catalysed by the enzymes phosphoenolpyruvate carboxykinase, pyruvate carboxylase, glucose 6-phosphatase, and fructose 1,6-bisphosphatase, which is generally found in the liver, kidney, intestine, or muscle. Practice questions on gluconeogenesis: 1. What are the key biochemical features of the regulated steps of gluconeogenesis? 2. What is the primary function of gluconeogenesis in the liver? 3. How is reciprocal regulation of glycolysis and gluconeogenesis ensured? 4. What would you expect in a patient who has a deficiency in glucose-6-phosphatase? 5. Why does gluconeogenesis play such a critical role in maintaining blood glucose level homeostasis?  FRUCTOSE Fructose is also known as “fruit sugar” because it primarily occurs naturally in many fruits. It also occurs naturally in other plant foods such as honey, sugar beets, sugar cane and vegetables. Fructose is the sweetest naturally occurring carbohydrate and is 1.2–1.8 times sweeter than sucrose (table sugar). INTRODUCTION Fructose Is An Abundant Sugar In The Diet. This Dietary Monosaccharide Is Present Naturally In Fruits And Vegetables, Either As Free Fructose Or As Part Of The Disaccharide Sucrose And As Its Polymer Inulin. Sucrose (Table Sugar) Is A Disaccharide Which When Hydrolyzed Yields Fructose And Glucose.  On successful completion of the lesson, the student will be able to: Describe the metabolism of fructose: LEARNING Fructolysis Metabolism Of Fructose To OUTCOMES Dihydroxyacetone phosphate (DHAP) And Glyceraldehyde Synthesis Of Glycogen From DHAP And Glyceraldehyde 3-phosphate Synthesis Of Triglyceride From DHAP And Glyceraldehyde 3-phosphate Dietary Sources of Fructose: The major dietary source of fructose is the disaccharide sucrose (cane sugar), and highfructose corn syrups (HFCS) used in the manufactured foods and beverages. Sucrose is hydrolysed in the intestine to one mol. of glucose and one mol. of fructose by the enzyme Sucrase. Fructose is absorbed by facilitated transport and taken by portal blood to liver, where it is mostly converted to glucose. It is also found in free form in honey and many fruits. Metabolic Pathways of Fructose: In the body, entry of fructose into the cells is not controlled by the hormone insulin. This is in contrast to glucose which is regulated for its entry into majority of the tissues. Fructose is almost entirely metabolized in the liver in humans  A specific enzyme fructokinase is present in Liver. Fructokinase has been identified also in kidney and intestine. Fructose is mostly phosphorylated by fructokinase to fructose 1-phosphate. This enzyme phosphorylates fructose only and will not phosphorylate glucose. This appears to be the major pathway for phosphorylation of fructose. Its activity is not affected by insulin. This explains why fructose disappears from the blood of diabetic patients at a normal rate. Metabolism of Fructose to Dihydroxyacetone Phosphate (DHAP) and Glyceraldehyde Overview: Fructose is phosphorylated by fructokinase to form fructose-1-phosphate. Aldolase B then breaks down fructose-1- phosphate into dihydroxyacetone phosphate and glyceraldehyde. Reaction: Fructose → Fructose-1-phosphate → Dihydroxyacetone Phosphate (DHAP) + Glyceraldehyde Example: Rapid metabolism of fructose after a high-fructose meal yields DHAP and glyceraldehyde, which can enter the glycolysis pathway. 3.Synthesis of Glycogen from DHAP and Glyceraldehyde 3-Phosphate Process: Both dihydroxyacetone phosphate and glyceraldehyde can be converted into glyceraldehyde 3-phosphate (G3P). Glyceraldehyde 3-phosphate is a glycolytic intermediate that can be used for glycogen synthesis. Key Steps: Conversion: Dihydroxyacetone phosphate is isomerized to glyceraldehyde 3- phosphate. Glycogen Synthesis: Glyceraldehyde 3-phosphate is utilized in the glycogen synthesis pathway, catalyzed by glycogen synthase. Example: After a meal, excess glucose from the diet can be converted to glyceraldehyde 3-phosphate, leading to glycogen storage for energy use during fasting.  Fate of D-glyceraldehyde: D-glyceraldehyde can enter glycolytic pathway when converted to either to Glyceraldehyde-3-P or to some other metabolites of glycolytic pathway. Glyceraldehyde is phosphorylated by the enzyme triokinase to glyceraldehyde 3- phosphate which, along with DHAP, enters glycolysis or gluconeogenesis. 4. Synthesis of Triglycerides from DHAP and Glyceraldehyde 3- Phosphate Process: Dihydroxyacetone phosphate and glyceraldehyde 3-phosphate serve as precursors for triglyceride synthesis, especially in adipose tissue and the liver. Conversion: Glyceraldehyde 3-phosphate is converted to lysophosphatidic acid, which is then transformed into triglycerides. Key Steps: Dihydroxyacetone Phosphate → Glyceraldehyde 3-Phosphate → Triglycerides Example: When energy intake exceeds energy expenditure, the body converts surplus carbohydrates into triglycerides for long-term energy storage. Note: The fructose is more rapidly metabolized (via glycolysis) by the liver than glucose. This is due to the fact that the rate limiting reaction in glycolysis catalysed by phosphofructokinase is by passed. Increased dietary intake of fructose significantly elevates the production of acetyl CoA and lipogenesis (fatty acid, triacylglycerol and very low density lipoprotein synthesis). Ingestion of large quantities of fructose or sucrose is linked with many health complications. Fig: Overview of Fructose Metabolism Summary Fructose metabolism involves several key processes that contribute to energy production and storage. Understanding these pathways is crucial in managing conditions like obesity and diabetes, where fructose intake and metabolism may play a significant role. Important Note: Excessive consumption of fructose, particularly from added sugars, can lead to metabolic disturbances and is linked to insulin resistance and fatty liver disease. Re cap  Fructolysis The initial catabolism of fructose is referred to as fructolysis, In analogy with glycolysis, the catabolism of glucose. In fructolysis, the enzyme fructokinase initially produces fructose 1-phosphate, Which is split by aldolase b to produce the trioses dihydroxyacetone phosphate (DHAP) and glyceraldehyde. Unlike glycolysis, in fructolysis the Triose Glyceraldehyde lacks a phosphate group. A third enzyme, triokinase, is therefore required To Phosphorylate Glyceraldehyde, producing GLYCERALDEHYDE 3-PHOSPHATE. The resulting trioses are identical to those obtained in glycolysis and can enter the gluconeogenic pathway for glucose or glycogen synthesis or be further catabolized through the lower glycolytic pathway to pyruvate. Metabolic conversion of fructose to glycogen in the liver  SUMMARY Fructose is A monosaccharide, the simplest form of carbohydrate. As the name implies, mono (one) saccharides (sugar) contain only one sugar group; thus, they cannot be broken down any further. Unlike glucose, fructose does not stimulate a substantial insulin release. Fructose is transported into cells via a different transporter than glucose.  SUMMARY (cont.) While glucose can be utilized (metabolized) by just about every cell in the human body, fructose cannot. Fructose needs to be processed and stored in the liver as a back-up energy source called glycogen. Once the liver's storage capacity is filled, then excess fructose is converted by the liver into various products; one main product is triglycerides. Triglycerides are further converted by the liver into very low-density lipoproteins (VLDL), which are released for storage in fat cells and muscle.  Importance of Fructose Metabolism for Humans 1.Energy Production: Fructose metabolism provides an alternative source of energy, particularly during periods of low glucose availability. This is crucial for maintaining energy balance and metabolic flexibility. 2.Liver Function: The liver plays a central role in processing fructose, which is important for detoxifying sugars and preventing metabolic overload. Efficient fructose metabolism helps prevent fatty liver disease and other liver-related conditions. 3.Metabolic Intermediates: The breakdown of fructose produces key intermediates like DHAP and glyceraldehyde-3-phosphate, which are essential for various metabolic pathways, including glycolysis and gluconeogenesis. These intermediates are vital for producing glucose and ATP, the body’s primary energy currency. Importance of Fructose Metabolism for Humans 4. Glycogen Storage: The ability to convert fructose-derived intermediates into glycogen is crucial for maintaining blood glucose levels during fasting. Glycogen acts as a readily available energy reserve that can be mobilized quickly when needed. 5. Lipid Synthesis: The conversion of fructose to triglycerides supports energy storage in adipose tissue. Triglycerides are a concentrated energy source that can be utilized during prolonged fasting or periods of increased energy demand. 6. Nutritional Considerations: Understanding fructose metabolism is important in dietary contexts. High intake of fructose, especially from processed sugars, can lead to metabolic disturbances, including insulin resistance and obesity. This knowledge helps in guiding dietary recommendations and managing conditions like metabolic syndrome and diabetes. 7. Clinical Implications: An awareness of how fructose is metabolized can inform treatment strategies for conditions such as non-alcoholic fatty liver disease (NAFLD) and obesity. It can also help in understanding the impacts of high-fructose diets on overall health. CONCLUSION Fructose metabolism is vital for energy homeostasis, liver health, and the regulation of fat storage A comprehensive understanding of this process helps in the clinical management of metabolic disorders and informs dietary guidelines to promote better health outcomes. LIPIDS presentation title 47 Learning Outcomes By the end of this topic, you should be able to do the following: 1. Describe the definition and classification of lipids. 2. Explain the characteristics of lipids. 3. Explain the digestion and absorption of lipids. 48 presentation title Why We NeeD Them ? Fats serve multiple functions in foods: Give flaky texture to baked goods Make meats tender Provide flavor and aromas Contribute to satiety Fats and other lipids perform important functions in the body: Energy storage Insulation Transport of proteins in blood Cell membrane structure 49 presentation title 50 presentation title Fatty acid 51 presentation title Fatty Acids Are Found in Triglycerides and Phospholipids Fatty acids: chain of carbon and hydrogen atoms with acid group (COOH at one end) Over 20 different fatty acids Can vary by: 1. length of chain 2. whether carbons have double or single bonds between them 3. total number of double bonds 52 presentation title  TYPES Length Of Fatty Acids Fatty Acids Differ By Length, Often Categorized As Short To Very Long. Short-chain Fatty Acids (SCFA) Are Fatty Acids With Aliphatic Tails Of Five Or Fewer Carbons (E.G. Butyric Acid). Medium-chain Fatty Acids (MCFA) Are Fatty Acids With Aliphatic Tails Of 6 To 12 Carbons, Which Can Form Medium-chain Triglycerides. Long-chain Fatty Acids (LCFA) Are Fatty Acids With Aliphatic Tails Of 13 To 21 Carbons. Very Long Chain Fatty Acids (VLCFA) Are Fatty Acids With Aliphatic Tails Of 22 Or More Carbons. 54 presentation title  TYPES (cont.) Saturated & Unsaturated Fatty acids Fatty Acids Vary in Length and Structure Saturated fatty acids: all carbons bonded to hydrogen Example: stearic acid, 18 carbons, solid at room temperature Unsaturated fatty acids: one or more double bond between carbons (less saturated with hydrogen) More liquid at room temperature Monounsaturated fatty acids: one double bond Example: Oleic acid, 18 carbons (olive oil) Polyunsaturated fatty acids: more than one double bond Example: essential fatty acids linoleic and alpha-linolenic acids (soybean oil) 56 presentation title 57 presentation title  Nonessential And Essential Fatty Acids Essential Fatty Acids Must Be Obtained From Food. They Fall Into Two Categories - Omega-3 And Omega-6. The 3 And 6 Refer To The Position Of The First Carbon Double Bond And The Omega Refers To The Methyl End Of The Chain. Omega-3 And Omega-6 Fatty Acids Are Precursors To Important Compounds Called Eicosanoids.  Nonessential And Essential Fatty Acids Eicosanoids Are Powerful Hormones That Control Many Other Hormones And Important Body Functions, Such As The Central Nervous System And The Immune System. Eicosanoids Derived From Omega-6 Fatty Acids Are Known To Increase Blood Pressure, Immune Response And Inflammation. In Contrast, Eicosanoids Derived From Omega-3 Fatty Acids Are Known To Have Heart- healthy Effects. Given The Contrasting Effects Of The Omega-3 And Omega-6 Fatty Acids, A Proper Dietary Balance Between The Two Must Be Achieved To Ensure Optimal Health Benefits. 60 presentation title  TYPES (cont.) Nonessential and Essential Fatty Acids (cont.) Image by Allison Calabrese / CC BY 4.0 62 presentation title Unsaturated fatty acids; Trans Unsaturated fatty acids contain one or more carbon-carbon double bonds (C=C). These double bonds can exist as cis or trans isomers. Cis Configuration: In the cis configuration, the hydrogen atoms adjacent to the double bond are on the same side of the chain. This arrangement causes the fatty acid chain to bend, which limits its flexibility. The more cis double bonds present, the more rigid the structure becomes due to this bending effect. Trans A Trans Configuration, By Contrast, Means That The Adjacent Two Hydrogen Atoms Lie On Opposite Sides Of The Chain. As A Result, They Do Not Cause The Chain To Bend Much And Their Shape Is Similar To Straight Saturated Fatty Acids Uses of Fat, Phospholipids & Cholesterol An energy-dense source of fuel: 9 calories per gram Glucagon also stimulates release of fat from fat cells to fuel heart, liver, and muscleIs needed for absorption of fat-soluble vitamins A, D, E, K, and carotenoids Insulates body to maintain body temperature Cushions bones, organs, nerves 64 presentation title 65 presentation title  Triglycerides Contain Three Fatty Acid Chains Triglyceride: three fatty acids connected to glycerol “backbone ”Most common lipid found in foods and body ▪ Referred to as fats ✓Saturated fats have mostly saturated fatty acids ✓Unsaturated fats have mostly unsaturated fatty acids 66 presentation title 2. Phospholipids Contain Phosphate Phospholipids: have glycerol backbone but two fatty acids and a phosphorus group Phosphorus containing head is hydrophilic Fatty acid tail is hydrophobic Cell membranes made of phospholipid bilayer Major phospholipid in cell membrane = lecithin Lecithin used as emulsifier in foods such as salad dressings to keep oils and water mixed together 67 presentation title 68 presentation title 69 presentation title 70 presentation title Sterols Have a Unique Ring Structure Sterols are comprised mainly of four connecting rings of carbon and hydrogen Example: cholesterol Important role in cell membrane structure Precursor of important compounds in body Not required in diet since body makes all cholesterol needed 71 presentation title 72 presentation title 73 presentation title  What Happens to the Fat You Eat? Lipoproteins transport fat through the lymph and blood. Remember: Lymph node is a network of valves that help maintain the internal fluid environment. Chylomicrons: carry digested fat through lymph into bloodstream Very low-density lipoproteins (VLDL): deliver fat made in liver to cells Low-density lipoproteins (LDL, “BAD” cholesterol): deposit cholesterol on walls of arteries High-density lipoproteins (HDL, “GOOD” cholesterol): remove cholesterol from body and deliver to liver for excretion 74 presentation title Lipoproteins are particles made of protein and fats (lipids). They carry cholesterol through your bloodstream to your cells. The two main groups of lipoproteins are called HDL (high- density lipoprotein) or "good" cholesterol and LDL (low-density lipoprotein) or "bad" cholesterol. Lipoprotein (a) is a type of LDL. presentation title 75  What are the types of lipoproteins? There are five main types of lipoproteins: High-density lipoprotein (HDL) is the “good cholesterol.” It carries cholesterol back to your liver to be flushed out of your body. High levels of HDL reduce your risk of cardiovascular (heart) disease. Low-density lipoprotein (LDL) is the “bad cholesterol.” It increases your risk of coronary artery disease, heart attacks and stroke. LDL carries cholesterol that accumulates as plaque inside blood vessels. Plaque buildup can make blood vessels too narrow for blood to flow freely. This condition is atherosclerosis. Very low-density lipoproteins (VLDL) are another type of “bad cholesterol.” VLDLs carry triglycerides — and to a lesser degree, cholesterol — to your tissues. Intermediate-density lipoproteins (IDL) are created when VLDLs give up their fatty acids. They’re then either removed by your liver or converted into LDL. Chylomicrons are very large particles that also transport triglycerides. 76 presentation title  THE METABOLISM OF FATTY ACIDS AS A FUEL SOURCE The Metabolism Of Fatty Acids Involves The Uptake Of Free Fatty Acids By Cells Via Fatty Acid-binding Proteins Which Transport The Fatty Acids Intracellularly From The Plasma Membrane. The Free Fatty Acids Are Then Activated Via Acyl-COA And Transported To: 1) The Mitochondria Or Peroxisomes To Be Converted Into ATP And Heat As A Form Of Energy; 2) Facilitate Gene Expression Via Binding To Transcription Factors; Or 3) The Endoplasmic Reticulum For Esterification Into Various Classes Of Lipids That Can Be Used As Energy Storage.  THE METABOLISM OF FATTY ACIDS AS A FUEL SOURCE (cont.) When Used As An Energy Source, Fatty Acids Are Released From Triacylglycerol And Processed Into Two-carbon Molecules Identical To Those Formed During The Breakdown Of Glucose. Moreover, The Two-carbon Molecules Generated From The Breakdown Of Both Fatty Acids And Glucose Are Used To Generate Energy Via The Same Pathways. Glucose Can Also Be Converted Into Fatty Acids Under Conditions Of Excess Glucose Or Energy Within A Cell. RE CAP 79 presentation title WATCH THIS VIDEO https://youtu.be/5BBYBRWzsLA?t=28 80 presentation title  ▪The Krebs cycles The Citric Acid Cycle Or TCA Cycle,  LEARNING OUTCOMES On Successful Completion Of The Lesson, The Student Will Be Able To: Explain the Krebs cycle Describe The important of Krebs cycle  INTRODUCTION; THE KREBS CYCLE The Krebs Cycle, ▪ Also Known As The Citric Acid Cycle Or TCA Cycle, Kreb cycle is a series of biochemical reactions in a closed loop. The cycle starts with acetyl-CoA which is derived from carbohydrates, fats, and proteins. It enters the cycle and gets converted into citrate, a six-carbon molecule. The TCA cycle is involved in both anabolic and catabolic processes and is a tightly regulated cycle. The end products after each turn of the cycle are one GTP or ATP molecule, three NADH molecules, and one FADH2 molecule. These are required to transfer electrons to the mitochondrial respiratory chain, also known as the electron transport chain (ETC).  The Krebs Cycle Where Does Kreb Cycle Takes Place? In eukaryotes: The citric acid cycle takes place in the matrix of the mitochondria Pyruvate is produced in the cytosol of the cell. Pyruvate is converted to acetyl CoA and is transported to the mitochondrial matrix, the innermost part of the mitochondria. Kreb Cycle Steps The Krebs cycle is a series of chemical reactions that occur in the mitochondria of cells. The steps of the Kreb cycle are as follows: Step 1: The cycle starts with the entry of a two-carbon acetyl group derived from acetyl-CoA combined with a four-carbon compound oxaloacetate. Six-carbon molecule known as citrate is formed. The reaction is catalyzed by the enzyme citrate synthase. Step 2: Isocitrate, the isomer of Citrate is formed. It is a hydration reaction and is catalyzed by the enzyme aconitase. Step 3: Isocitrate undergoes an oxidative decarboxylation reaction, realizing a molecule of carbon dioxide (CO2) and producing NADH. This step is catalyzed by the enzyme isocitrate dehydrogenase. Step 4: Isocitrate is oxidized to alpha-ketoglutarate. Carbon dioxide and NADH are produced in this step, which is catalyzed by the enzyme alpha-ketoglutarate dehydrogenase complex. Step 5: Alpha-ketoglutarate is oxidized. Carbon dioxide and NADH are produced. Guanosine diphosphate (GDP) is phosphorylated to form guanosine triphosphate (GTP), which gets converted into ATP. The reaction is catalyzed by the enzyme alpha-ketoglutarate dehydrogenase complex. Step 6: Alpha-ketoglutarate is converted to succinyl-CoA, and one molecule of NADH is produced. The reaction is catalyzed by the alpha-ketoglutarate dehydrogenase complex. Step 7: Succinyl-CoA reacts with a molecule of guanosine diphosphate (GDP), and forms one molecule of guanosine triphosphate (GTP) and succinate. The reaction is catalyzed by the enzyme succinyl-CoA synthetase. Step 8: Succinate is oxidized to fumarate, and FADH2 (Flavin adenine dinucleotide) is produced. The reaction is catalyzed by the enzyme succinate dehydrogenase, which is also a part of the electron transport chain. Step 9: Fumarate is hydrated to malate. The reaction is catalyzed by the enzyme fumarase. Step 10: Malate is oxidized to oxaloacetate, and one molecule of NADH is produced. The reaction is catalyzed by the enzyme malate dehydrogenase.  Krebs Cycle Summary Steps of the Krebs Cycle – The various steps involved are: 1. Acetyl-CoA Formation ▪ Acetyl-CoA combines with oxaloacetate to form citrate. 2. Isomerization ▪ Citrate is converted to isocitrate. 3. Decarboxylation ▪ Isocitrate undergoes oxidative decarboxylation to form α-ketoglutarate, releasing CO2 and producing NADH. 4. Second Decarboxylation ▪ α-ketoglutarate is decarboxylated to form succinyl-CoA, releasing CO2 and producing NADH. 5. Succinyl-CoA Formation ▪ Succinyl-CoA is produced from α-ketoglutarate, generating GTP/ATP and NADH. 6. Succinate Formation ▪ Succinyl-CoA is converted to succinate, producing FADH2. 7. Fumarate Formation ▪ Succinate is oxidized to form fumarate, generating FADH2. 8. Malate Formation ▪ Fumarate is hydrated to form malate. 9. Regeneration of Oxaloacetate ▪ Malate is oxidized to regenerate oxaloacetate, producing NADH. 10. End Product – 4CO2, 6 NADH, 2 FADH2, and 2 ATPs. Krebs Cycle Function The various important functions of Krebs Cycle are: Generation of high-energy molecules like ATP through oxidative phosphorylation. Production of electron carriers NADH and FADH2, which transfer electrons to the electron transport chain. Oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins to release energy. Synthesis of intermediates like citrate, α-ketoglutarate, succinyl-CoA, and oxaloacetate for various metabolic pathways. Removal of carbon dioxide as a waste product through decarboxylation reactions.  Importance of Krebs Cycle Energy Production: Energy-rich molecule in the form of ATP is produced in the Kreb cycle Krebs cycle is the final pathway of oxidation of glucose, fat, and amino acids. Generation of NADH and FADH2: These molecules act as electron carriers in subsequent steps of cellular respiration. Biosynthesis of Intermediates: The Krebs cycle produces intermediate compounds important for various biosynthetic pathways in the cell. For example, oxaloacetate can be used for gluconeogenesis, and alpha-ketoglutarate can be utilized for amino acid synthesis. The genetic defects of Krebs’s cycle enzymes are linked with neural damage. Succinyl-CoA produced in the Krebs cycle is associated with the synthesis of hemoglobin and myoglobin. The Kreb cycle is regulated by the supply of NAD+ and utilization of ATP in the physical and chemical work.. Vitamins like Riboflavin, niacin, thiamin, and pantothenic acid are part of various enzyme cofactors (FAD, NAD) and coenzyme A.  Importance: The NADH and FADH₂ produced are critical for the electron transport chain, leading to further ATP production. During oxidative phosphorylation, electrons derived from NADH and FADH2 combine with O2, and the energy released from these oxidation/ reduction reactions is used to drive the synthesis of ATP from ADP.  Summary Conclusion – Krebs Cycle or Citric Acid Cycle The Krebs Cycle, also known as the Citric Acid Cycle or TCA cycle (tricarboxylic acid cycle), serves as a central metabolic pathway, releasing energy stored in the form of ATP. This citric cycle occurs within the mitochondria. Beginning with acetyl-CoA derived from carbohydrates, fats, and proteins, it ultimately generates energy-rich molecules like ATP, NADH, and FADH2. The Krebs Cycle is an integral part of cellular respiration, contributing to the oxidation of glucose, fatty acids, and amino acids. Its importance lies in energy production, the synthesis of intermediates for various metabolic pathways, and its association with neural function and hemoglobin synthesis. The Krebs Cycle is essential for energy production in cells. It generates key molecules (NADH and FADH₂) for the electron transport chain. Understanding the cycle helps to appreciate how metabolic processes affect patient health and energy levels.  Importance of the Krebs Cycle for Humans The Krebs Cycle, or Citric Acid Cycle, is vital for human metabolism and overall health for several reasons: Energy Production: The Krebs Cycle is a key component of cellular respiration, producing adenosine triphosphate (ATP), the primary energy currency of the cell. ATP is essential for various cellular processes, including muscle contraction, nerve impulse transmission, and biosynthesis. Metabolic Intermediates: The cycle generates important metabolic intermediates that are precursors for the synthesis of amino acids, nucleotides, and other biomolecules. This is crucial for growth, repair, and maintenance of tissues. Electron Carriers: The production of reduced NAD (NADH) and reduced FAD (FADH₂) during the cycle is critical for the electron transport chain. These electron carriers facilitate the generation of additional ATP through oxidative phosphorylation, significantly increasing the energy yield from nutrients.  Importance of the Krebs Cycle for Humans Carbon Dioxide Production: The Krebs Cycle helps in the removal of carbon dioxide (CO₂), a waste product of metabolism. Efficient elimination of CO₂ is crucial for maintaining acid-base balance in the body and preventing respiratory acidosis. Integration of Metabolism: The cycle integrates carbohydrate, fat, and protein metabolism. It allows the body to utilize different macronutrients for energy, ensuring flexibility in energy production based on dietary intake and energy needs. Regulation of Metabolism: The Krebs Cycle is tightly regulated by various enzymes and cofactors. This regulation ensures that energy production matches the cell’s demands, helping to maintain metabolic homeostasis.  Several diseases and metabolic disorders are associated with dysfunctions in the Krebs Cycle. Here are some key conditions: 1. Mitochondrial Diseases Description: These are a group of disorders caused by dysfunctional mitochondria, which can affect the Krebs Cycle and energy production. Examples: Mitochondrial myopathy, Leber’s hereditary optic neuropathy (LHON). 2. Cancer Description: Some cancer cells exhibit altered metabolism, known as the Warburg effect, where they rely on anaerobic metabolism even in the presence of oxygen. This can involve changes in Krebs Cycle activity. Impact: This metabolic shift supports rapid cell proliferation and survival in low-oxygen environments.  Several diseases and metabolic disorders are associated with dysfunctions in the Krebs Cycle. 4. Obesity Description: Obesity is linked to metabolic syndrome, which can disrupt normal energy metabolism, including the Krebs Cycle. Impact: Dysfunctional energy metabolism can lead to increased fatty acid accumulation and insulin resistance. 5. Ischemia Description: Reduced blood flow to tissues (ischemia) can limit oxygen availability, affecting the Krebs Cycle’s ability to produce ATP. Impact: This can lead to tissue damage and conditions like myocardial infarction (heart attack) or stroke.  Several diseases and metabolic disorders are associated with dysfunctions in the Krebs Cycle. 6. Neurodegenerative Diseases Description: Conditions such as Alzheimer's disease and Parkinson's disease are associated with mitochondrial dysfunction, which can impair the Krebs Cycle. Impact: This can lead to decreased energy production and increased oxidative stress in neurons. 7. Inherited Metabolic Disorders Examples: Citrate Transporter Deficiency: Affects citrate transport in mitochondria, disrupting energy metabolism. Alpha-Ketoglutarate Dehydrogenase Deficiency: Leads to developmental delays and neurological issues. SAQ Why is the Kreb Cycle called Kreb? The Krebs cycle is named after its discoverer, Hans Krebs. It is also known as the citric acid cycle or the tricarboxylic acid cycle. What is the Kreb Cycle in Simple Terms? Kreb cycle is a series of reactions occurring in the mitochondrial matrix, through which almost all living cells produce energy in aerobic respiration. It uses oxygen and gives out water and carbon dioxide as products. What is the Main Function of the TCA Cycle? The main function of kreb cycle is to produce energy in the form of ATP. Kreb cycle produces intermediate compounds such as amino and fatty acids that are important in other biosynthetic reactions.  Can the Krebs Cycle Occur in Other Organisms Besides Animals? Yes, the Krebs cycle is a fundamental metabolic pathway found in various organisms, including animals, plants, fungi, and many bacteria. It is a central characteristic of cellular energy metabolism and is conserved across different forms of life. What are the End Products of the Krebs Cycle? The end products of one turn of the Krebs cycle are three molecules of NADH, one molecule of FADH2, one molecule of GTP (convertible to ATP), and two molecules of carbon dioxide (CO2) released as waste.  SAQ What are the 7 Types of Krebs Cycle? The Krebs cycle involves a series of biochemical reactions, including 1. citrate synthase, 2. aconitase, 3. isocitrate dehydrogenase, 4. alpha-ketoglutarate dehydrogenase, 5. succinyl-CoA synthetase, 6. succinate dehydrogenase, 7. fumarase, and 8. malate dehydrogenase. Why is Krebs Cycle Important? The Krebs Cycle is vital for energy production, generating ATP through oxidative phosphorylation, synthesizing intermediates for various metabolic pathways, and contributing to cellular respiration and neural function.  Fermentative and aerobic metabolism*  LEARNING OUTCOMES On Successful Completion Of The Lesson, The Student Will Be Able To: Explain the Fermentative and aerobic metabolism Describe The important of Fermentative and anaerobic metabolism Aerobic Metabolism: Definition: A metabolic process that requires oxygen to produce energy (ATP) from glucose and other substrates. Location: Takes place in the mitochondria of cells. Process: Glycolysis: Occurs in the cytoplasm where glucose is broken down into pyruvate. Krebs Cycle (Citric Acid Cycle): Pyruvate is converted into acetyl-CoA and further processed, producing NADH and FADH2. Electron Transport Chain (ETC): NADH and FADH2 transfer electrons, leading to ATP synthesis via oxidative phosphorylation. Oxygen acts as the final electron acceptor, forming water. Energy Yield: Produces approximately 36-38 ATP molecules per glucose molecule. Fermentative Metabolism (Anaerobic Metabolism): Definition: A metabolic process that occurs in the absence of oxygen, enabling cells to generate energy. Location: Occurs in the cytoplasm. Process: Glycolysis: Similar to aerobic metabolism, glucose is converted to pyruvate. Fermentation: Pyruvate is converted into lactic acid (in humans) or ethanol and carbon dioxide (in some organisms), regenerating NAD+ for glycolysis to continue. Energy Yield: Produces only 2 ATP molecules per glucose molecule. Aerobic Metabolism: Efficiency: Provides a high yield of ATP, crucial for energy- intensive activities, especially in muscle and brain tissues. Sustainability: Supports prolonged activities and overall metabolic health, allowing for endurance and recovery. Role in Exercise: Essential for aerobic exercise performance, enabling sustained energy output and efficient recovery after physical exertion. Fermentative Metabolism (Anaerobic): Adaptability: Allows for energy production during periods of low oxygen availability, such as intense exercise or in anaerobic conditions. Rapid Energy Source: Provides quick ATP production for short bursts of high-intensity activities, essential in situations like sprinting or heavy lifting. Impact on Muscle Function: Lactic acid accumulation can lead to muscle fatigue but also serves as a temporary energy source. Lactic acid can be converted back to glucose in the liver via the Cori cycle, aiding recovery and energy replenishment. Clinical Relevance: Understanding anaerobic metabolism is important in managing conditions related to oxygen deprivation, such as respiratory disorders or during shock, as well as in sports medicine. Aerobic vs anaerobic respiration Summary Understanding both fermentative and anaerobic metabolism is essential as these metabolic pathways are fundamental to energy production in humans. Recognizing their implications in patient care can enhance treatment strategies, particularly in managing conditions involving metabolic stress, exercise physiology, and recovery from illness or surgery.