Biochemistry of Pyruvate and TCA Cycle
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Questions and Answers

What is the primary role of acetyl-CoA in aerobic respiration?

  • It initiates the tricarboxylic acid (TCA) cycle. (correct)
  • It serves as a precursor for fatty acid synthesis.
  • It transports electrons to the electron transport chain.
  • It produces ATP directly during glycolysis.

    • Which process generates the most ATP during aerobic respiration?

  • Glycolysis
  • Fermentation
  • Electron transport chain (correct)
  • Tricarboxylic acid (TCA) cycle

    • What is the role of NADPH produced in the pentose phosphate pathway?

  • It functions as an energy currency in the cell.
  • It synthesizes proteins directly.
  • It activates glycolysis.
  • It serves as a biochemical reductant. (correct)

    • Which statement about pyruvate conversion is correct?

    <p>Pyruvate can be transformed into acetyl-CoA.</p> Signup and view all the answers

    Which pathway is involved in nucleotide biosynthesis?

    <p>Pentose phosphate pathway (PPP)</p> Signup and view all the answers

    What is one of the primary functions of UDP-glucose?

    <p>It serves as an intermediate in glycogen production.</p> Signup and view all the answers

    During the oxidative fate of pyruvate, what is released as a byproduct?

    <p>Carbon dioxide</p> Signup and view all the answers

    How does the regeneration of NADPH from NADP contribute to cellular function?

    <p>It plays a role in controlling oxygen free radicals in red blood cells.</p> Signup and view all the answers

    What is the primary role of nutrients in ATP synthesis?

    <p>They are catabolised to participate in reactions leading to ATP synthesis.</p> Signup and view all the answers

    Why is oxygen critical for ATP production?

    <p>It is the final electron acceptor in the electron transport chain.</p> Signup and view all the answers

    What is released when a phosphoanhydride bond in ATP is broken?

    <p>7.3 kcal/mol of energy</p> Signup and view all the answers

    Which of the following best describes bioenergetics?

    <p>The chemistry and molecular physiology of energy metabolism.</p> Signup and view all the answers

    What problem arises in heart muscle cells after a heart attack?

    <p>They receive inadequate blood flow, thus limiting oxygen and nutrients.</p> Signup and view all the answers

    During each heartbeat, approximately what percentage of ATP is used by the heart?

    <p>2%</p> Signup and view all the answers

    What consequence occurs if the heart is unable to regenerate ATP?

    <p>All ATP in the heart would be hydrolyzed.</p> Signup and view all the answers

    What role do nutrients play beyond ATP synthesis?

    <p>They form the structural components of proteins.</p> Signup and view all the answers

    What is the role of pancreatic alpha-amylase in the digestion of carbohydrates?

    <p>To cleave alpha-1,4 bonds in starch and amylose in the lumen.</p> Signup and view all the answers

    Which statement about trehalose is accurate?

    <p>It is found in some fungi, algae, and insects.</p> Signup and view all the answers

    What happens to undigested carbohydrates in the digestive system?

    <p>They undergo fermentation by bacteria in the ileum.</p> Signup and view all the answers

    Which digestive enzymes are attached to the brush border of enterocytes?

    <p>Disaccharidases and glycosidases.</p> Signup and view all the answers

    What is the function of enterocytes in the small intestine?

    <p>To transport free monosaccharides into the bloodstream.</p> Signup and view all the answers

    How is salivary alpha-amylase affected in the stomach?

    <p>It is inactivated in the acidic environment.</p> Signup and view all the answers

    What is required for monosaccharides to be absorbed across the gut membrane?

    <p>Active transport mechanisms.</p> Signup and view all the answers

    What characterizes the structure of intestinal villi?

    <p>Villi are highly folded to increase absorption efficiency.</p> Signup and view all the answers

    Which type of bond does salivary alpha-amylase cleave?

    <p>Alpha-1,4 bonds in amylose and starch.</p> Signup and view all the answers

    What is the final product of carbohydrate digestion that can be absorbed by the gut?

    <p>Monosaccharides</p> Signup and view all the answers

    What characteristic defines saturated fatty acids?

    <p>They have no double bonds.</p> Signup and view all the answers

    Which type of fatty acid has a kink due to cis double bonds?

    <p>Monounsaturated fatty acids</p> Signup and view all the answers

    What is the structural feature of eicosanoids?

    <p>They are typically 20-carbon long polyunsaturated fatty acids.</p> Signup and view all the answers

    What is the predominant form of fatty acids found in plasma?

    <p>Fatty acid esters</p> Signup and view all the answers

    How are fatty acids transported in circulation due to their insoluble nature?

    <p>Associated with albumin</p> Signup and view all the answers

    What does the omega nomenclature indicate about fatty acids?

    <p>The position of the last double bond from the omega end.</p> Signup and view all the answers

    What is the pKa value of the terminal carboxyl group in fatty acids?

    <p>4.8</p> Signup and view all the answers

    How are long fatty acids defined in terms of carbon count?

    <p>14-20 carbons</p> Signup and view all the answers

    Which lipid is characterized by a bulky sterol structure?

    <p>Cholesterol</p> Signup and view all the answers

    What distinguishes polyunsaturated fatty acids from monounsaturated fatty acids?

    <p>They contain two or more double bonds.</p> Signup and view all the answers

    What is the primary role of hexokinase in glycolysis?

    <p>To phosphorylate glucose to glucose-6-phosphate</p> Signup and view all the answers

    Which substance is produced at the end of anaerobic glycolysis?

    <p>Lactate</p> Signup and view all the answers

    What happens to lactate produced in muscles during anaerobic glycolysis?

    <p>It is exported to the liver for gluconeogenesis</p> Signup and view all the answers

    What is the net gain of ATP in glycolysis?

    <p>2 ATP</p> Signup and view all the answers

    Which enzyme is responsible for the conversion of pyruvate to lactate?

    <p>Lactate dehydrogenase-A</p> Signup and view all the answers

    Which transporter is responsible for exporting lactate from the cell?

    <p>MCT</p> Signup and view all the answers

    What occurs during the energy investment phase of glycolysis?

    <p>ATP is consumed</p> Signup and view all the answers

    In the absence of oxygen, what is the fate of glucose in cells primarily relying on anaerobic glycolysis?

    <p>Converted to lactic acid</p> Signup and view all the answers

    Which intermediate is formed from glucose during glycolysis before it is converted to fructose-1,6-bisphosphate?

    <p>Glucose-6-phosphate</p> Signup and view all the answers

    Which of the following describes a characteristic of the reaction converting glucose to glucose-6-phosphate?

    <p>It is irreversible</p> Signup and view all the answers

    What is the role of hexokinase in the energy investment phase of glycolysis?

    <p>To phosphorylate glucose to glucose-6-phosphate</p> Signup and view all the answers

    What is the final product of anaerobic glycolysis?

    <p>Lactate</p> Signup and view all the answers

    How does lactate produced in glycolysis affect cellular metabolism in the absence of oxygen?

    <p>It is exported out of the cell via MCT</p> Signup and view all the answers

    Which statement accurately describes the fate of lactate in the body?

    <p>Lactate can be converted back to pyruvate and enter the TCA cycle</p> Signup and view all the answers

    What happens to glucose during the glycolytic pathway before it is irreversibly converted to glucose-6-phosphate?

    <p>It is phosphorylated directly by ATP</p> Signup and view all the answers

    During anaerobic glycolysis, what substrate is used to produce NADH molecules?

    <p>Glyceraldehyde-3-phosphate</p> Signup and view all the answers

    Which glycolytic intermediate is specifically formed through the isomerization of glucose-6-phosphate?

    <p>Fructose-6-phosphate</p> Signup and view all the answers

    In anaerobic conditions, what is the primary enzyme responsible for converting pyruvate to lactate?

    <p>Lactic dehydrogenase-A (LDH-A)</p> Signup and view all the answers

    What is the net gain of ATP molecules produced in one round of glycolysis?

    <p>2 ATP</p> Signup and view all the answers

    What characteristic distinguishes omega-6 fatty acids from omega-3 fatty acids?

    <p>Presence of a double bond at the sixth carbon from the methyl end</p> Signup and view all the answers

    Which statement accurately describes triacylglycerols?

    <p>They form a significant part of the body's energy reserves in adipose tissue</p> Signup and view all the answers

    Which component of anaerobic glycolysis allows for the recycling of NAD+?

    <p>The reduction of pyruvate by LDH-A</p> Signup and view all the answers

    What is the primary role of chylomicrons in the body?

    <p>Transmit exogenous dietary lipids after absorption from the intestines</p> Signup and view all the answers

    Which essential fatty acid must humans obtain from their diet due to an inability to synthesize it?

    <p>Linoleic acid</p> Signup and view all the answers

    What feature specifically defines micelles in the context of lipid digestion?

    <p>They possess a hydrophilic outer layer formed by bile salts surrounding lipids</p> Signup and view all the answers

    What is a significant role of long-chain fatty acids in structural lipids?

    <p>They maintain the integrity and fluidity of cell membranes</p> Signup and view all the answers

    What differentiates Very Low Density Lipoproteins (VLDL) from other lipoproteins?

    <p>They carry triacylglycerols from the liver to the bloodstream</p> Signup and view all the answers

    Why can triglycerides not form micelles by themselves?

    <p>They are only slightly soluble in water and require other molecules for aggregation</p> Signup and view all the answers

    What is a primary consequence of MCAD deficiency in the context of fasting?

    <p>Decreased ATP and NADH production</p> Signup and view all the answers

    What is the most common effect of alcohol-induced acute pancreatitis on lipid digestion?

    <p>Decreased secretion of pancreatic amylase</p> Signup and view all the answers

    In the context of Des Todd's efforts to lose weight, what is a likely impact of a low fat diet?

    <p>Reduction in de novo lipogenesis from carbohydrates</p> Signup and view all the answers

    How does ketogenesis change in a person with MCAD deficiency during fasting?

    <p>Decreased due to lack of glucose</p> Signup and view all the answers

    What dietary recommendation is most appropriate for managing Alan Marshall's condition effectively?

    <p>Low-fat diet to reduce steatorrhea</p> Signup and view all the answers

    What mechanism primarily triggers gluconeogenesis in the liver during fasting in a healthy individual?

    <p>Increased production of acetyl-CoA</p> Signup and view all the answers

    What is a key indicator of metabolic disease in Mica's case?

    <p>Hypoglycemia during fasting</p> Signup and view all the answers

    What effect does prolonged fasting have on an individual with MCAD deficiency?

    <p>Higher risk of hypoglycemia</p> Signup and view all the answers

    Why is the efficiency of exercise important for Des Todd's weight loss strategy?

    <p>Mobilizes free fatty acids and glycerol</p> Signup and view all the answers

    What underlying issue causes Mica's inability to maintain normal blood glucose levels?

    <p>Inadequate gluconeogenesis from non-carbohydrates</p> Signup and view all the answers

    What connects the digestive processes occurring in the stomach and the small intestine for amino acid metabolism?

    <p>Activation of zymogens into enzymes</p> Signup and view all the answers

    Which enzyme is specifically involved in activating trypsinogen in the small intestine?

    <p>Enteropeptidase</p> Signup and view all the answers

    What mechanism do enterocytes utilize to absorb amino acids from the intestinal lumen?

    <p>Na+-dependent carrier transport</p> Signup and view all the answers

    What role does the Na-K ATPase pump play in amino acid absorption?

    <p>It maintains the concentration gradient for Na+ and amino acids</p> Signup and view all the answers

    What is a potential consequence of polypeptides passing into the bloodstream of premature infants?

    <p>Development of food allergies</p> Signup and view all the answers

    Which of the following correctly describes the role of trypsin once activated?

    <p>It activates other zymogens into functional enzymes</p> Signup and view all the answers

    What occurs to gastric contents as they empty into the intestine regarding pH?

    <p>pH rises due to bicarbonate secretion</p> Signup and view all the answers

    What is the final substance that predominantly crosses into blood circulation from the intestine?

    <p>Free amino acids</p> Signup and view all the answers

    Which of the following is true regarding pepsin?

    <p>It initiates protein digestion in the stomach</p> Signup and view all the answers

    What characterizes the primary source of amino acids in the human body?

    <p>Exogenous protein from dietary intake</p> Signup and view all the answers

    Which glucose transporter is specifically found on the brush border membrane of enterocytes and utilizes active transport?

    <p>SGLT</p> Signup and view all the answers

    Which of the following statements is true regarding GLUT2?

    <p>Bidirectional transporter located in the liver</p> Signup and view all the answers

    What is the primary function of GLUT4 in adipose tissue?

    <p>Stimulated by insulin to increase glucose uptake</p> Signup and view all the answers

    In which tissue would you find GLUT1 and what is its main characteristic?

    <p>Neurons; it operates independently of insulin</p> Signup and view all the answers

    What is the role of insulin in relation to GLUT4 expression?

    <p>It induces GLUT4 expression facilitating glucose uptake when blood glucose is high.</p> Signup and view all the answers

    After entering adipocytes, which metabolic pathways can glucose go through?

    <p>Converted to fatty acids or glycerol-3-phosphate</p> Signup and view all the answers

    Which glucose transporter does not require insulin for its function?

    <p>GLUT3</p> Signup and view all the answers

    Where is GLUT5 primarily located and what does it transport?

    <p>Brush border membrane; fructose</p> Signup and view all the answers

    Which statement correctly describes the glucose storage forms in the body?

    <p>Muscles store glucose mainly as glycogen for their own use.</p> Signup and view all the answers

    Study Notes

    Oxidative Fate of Pyruvate

    • Pyruvate from glycolysis is converted to acetyl-CoA, which enters the TCA cycle.
    • This conversion releases carbon dioxide, representing the last carbon bond from the original glucose molecule.
    • Electrons are transferred from pyruvate to NAD+ leading to NADH formation, which is a key carrier for electrons in the electron transport chain.
    • Aerobic respiration results in significantly more ATP production compared to anaerobic respiration.

    Tricarboxylic Acid (TCA) Cycle Overview

    • The TCA cycle is a central metabolic pathway that oxidizes acetyl-CoA derived from glucose, fatty acids, and amino acids to generate ATP.
    • The cycle is essential for energy production and biosynthesis of various molecules.

    Pentose Phosphate Pathway (PPP)

    • Generates NADPH, a crucial reducing agent for various metabolic reactions, including protecting red blood cells from oxidative damage.
    • Produces ribose-5-phosphate, a component of nucleotides.

    UDP-Glucose Pathway

    • Involves uridine diphosphate glucose (UDP-glucose).
    • Key functions:
      • Intermediate in glycogen production.
      • Used in molecular constructions, such as adding sugars to proteins during post-translational modifications.

    Digestion Pathway

    • Salivary α-amylase partially breaks down starch in the mouth.
    • Amylase activity stops in the acidic environment of the stomach due to pH changes.
    • Pancreatic α-amylase further digests starch in the small intestine's lumen.
    • Other hydrolase enzymes on intestinal mucosal cells complete the breakdown of carbohydrates into monosaccharides.
    • Monosaccharides are then absorbed into the bloodstream through the intestinal epithelial cells and transported to the liver via the portal circulation.
    • Undigested carbohydrates pass to the ileum and may be fermented by bacteria.

    Intestinal Villi

    • Villi are finger-like projections in the small intestine that increase surface area for nutrient absorption.
    • Villi contain enterocytes, which are absorptive cells with a brush border that facilitates digestion.
    • The brush border contains disaccharidase complexes and glycosidases, responsible for breaking down disaccharides into monosaccharides.

    Disaccharides

    • Lactose and sucrose are digested into monosaccharides by glycosidases in the small intestine.
    • Monosaccharides can be absorbed by intestinal epithelial cells and enter the blood.

    Anaerobic Glycolysis

    • Glucose enters the cell through glucose transporters (GLUTs).
    • Glucose is phosphorylated to glucose-6-phosphate, which is an irreversible reaction.
    • This phosphorylation is a "committed" step, meaning that glucose is committed to further metabolism.

    Glycolysis: Energy Investment Phase

    • ATP donates a phosphate group to glucose, catalyzed by hexokinase.
    • Glucose is converted to glucose-6-phosphate.
    • This reaction is irreversible.
    • Isomerization occurs, transforming glucose-6-phosphate into fructose-6-phosphate.
    • Another phosphate group is added to fructose-6-phosphate, converting it to fructose-1,6-bisphosphate, catalyzed by phosphofructokinase-1 (PFK-1), a critical control point in glycolysis.

    Glycolysis: Energy Generation Phase

    • Fructose-1,6-bisphosphate is cleaved into two triose phosphates.
    • Each triose phosphate produces 2 ATP molecules and 1 NADH molecule.
    • Therefore, the overall net gain for glycolysis is 2 ATP and 2 NADH molecules.
    • Pyruvate is the end product of glycolysis.

    Anaerobic Glycolysis

    • In the absence of oxygen, pyruvate is reduced to lactate by lactate dehydrogenase-A (LDH-A).
    • Lactate is transported out of the cell via monocarboxylate transporters (MCT).
    • No net generation of NADH occurs, and oxygen is not required.

    Fate of Lactate

    • Lactate is primarily released from red blood cells, as they only carry out anaerobic glycolysis due to the absence of mitochondria.
    • Lactate can be used by heart muscle, resting skeletal muscle, and other tissues.
    • Lactate can be converted back to pyruvate, which can then enter the TCA cycle.
    • The Cori cycle describes the process of lactate returning to the liver from muscles and red blood cells, where it is converted back to glucose via gluconeogenesis and then taken up by red blood cells again.

    Lipid Metabolism

    • Lipids are a diverse group of compounds that are insoluble or slightly soluble in water.
    • Examples include bile salts, eicosanoids, steroid hormones, triacylglycerol, phospholipids, sphingolipids, fat-soluble vitamins, and cholesterol.

    Classes of Lipids

    • Lipids share some structural similarities but also differ in their structures and functions.
    • Cholesterol has a distinct four-fused hydrocarbon ring structure and is the precursor for bile salts, steroid hormones, and vitamin D.
    • Fatty acids have a long hydrocarbon chain with a terminal carboxyl group, which is common to eicosanoids, phospholipids/sphingolipids, and triacylglycerol.

    Examples of Lipids

    • Arachidonic acids are 20-carbon long polyunsaturated fatty acids.

    Structure of Fatty Acids

    • The hydrocarbon chain of fatty acids is primarily hydrophobic.
    • The terminal carboxyl group (COOH) has a pKa of 4.8. At physiological pH, the carboxyl group ionizes to COO-, leading to amphipathic properties.
    • Free fatty acids are highly insoluble and are transported in the blood bound to albumin.
    • More than 90% of circulating fatty acids are in the form of esters (e.g., triacylglycerol, cholesterol esters, phospholipids) contained within lipoprotein particles..

    Fatty Acid Classification

    • Saturated fatty acids have no double bonds in their hydrocarbon chain.
    • Unsaturated fatty acids have double bonds in their hydrocarbon chain.
    • Monounsaturated fatty acids have one double bond, while polyunsaturated fatty acids have more than one double bond.
    • Cis double bonds cause a fatty acid to kink.
    • Humans primarily utilize saturated and monounsaturated fatty acids.

    Fatty Acid Nomenclature

    • Short fatty acids: 2-4 carbons
    • Medium fatty acids: 6-12 carbons
    • Long fatty acids: 14-20 carbons
    • Very long fatty acids: ≥22 carbons
    • Shorthand Notation:
      • Carbons are numbered from the carboxyl end (α) to the omega/methyl end (ω).
      • The first number indicates the total number of carbons.
      • The second number indicates the number of double bonds.
      • Double bond positions are indicated in parentheses. (e.g., 18:1(Δ9) = oleic acid)

    Omega Nomenclature

    • The position of the last double bond is counted starting from the omega end (ω).
    • E.g., ω-3 fatty acids have their last double bond at the third carbon position from the ω end.
    • Omega nomenclature is used to classify fatty acids based on the position of the last double bond, particularly its relative position to the methyl end.

    Generation of ATP

    • The process of creating ATP, the primary energy currency of the cell, involved multiple metabolic pathways.

    Overview of ATP and Bioenergetics

    • Nutrients are metabolized to provide energy and building blocks for ATP synthesis.
    • Oxygen is crucial for ATP production as it acts as a final electron acceptor in the electron transport chain.
    • Without sufficient oxygen, cells cannot produce ATP efficiently and their functioning is impaired.

    ATP Structure

    • ATP consists of an adenine base, ribose sugar, and three phosphate groups.
    • The phosphoanhydride bonds, linking the phosphate groups, are high-energy bonds.
    • The breakage of one phosphoanhydride bond releases about 7.3 kcal/mol of energy.

    Bioenergetics

    • Bioenergetics is the study of energy transformations in living organisms, including cellular energy metabolism.
    • It involves the conversion of energy from one form to another, primarily in the context of ATP generation and utilization.

    Fatty Acids

    • Arachidonic acid is an omega-6 fatty acid and a precursor of prostaglandins
    • Linoleic acid is an omega-6, essential fatty acid that maintains membrane fluidity (of skin).
    • 𝛼-linolenic acid is an omega-3 essential fatty acid required for growth and development
    • Humans lack the enzymes needed to synthesize essential fatty acids and must obtain them via diet.
    • Fatty acids with chain lengths of 4 to 10 carbons are found in significant quantities in milk
    • Structural lipids and triacylglycerols contain primarily fatty acids of at least 16 carbons

    Triacylglycerols and Transported Fats

    • Triacylglycerols are only slightly soluble in water and cannot form micelles by themselves
    • Triacylglycerols coalesce within white adipose tissue to form large oil droplets that are nearly anhydrous
    • Cytosolic lipid droplets in adipose tissue are the major energy reserve of the body
    • Three fatty acids are esterified at their carboxyl ends to a glycerol backbone to form triacylglycerol
    • Micelles are aggregates of surfactant phospholipid molecules dispersed in a liquid, forming a colloidal suspension
    • A single droplet of hydrophobic lipid droplets enclosed with a shell of bile salts forms a micelle
    • The hydrophilic side of bile salts faces the outside of the sphere in micelles
    • Chylomicrons are lipoprotein particles that consist of triacylglycerol, phospholipids, cholesterol, and proteins
    • Chylomicrons transport exogenous dietary lipids.
    • Very Low Density Lipoproteins (VLDL) are produced in the liver and transport triacylglycerols and dietary carbohydrates from lipogenesis from the liver to blood circulation
    • VLDL transports endogenously synthesized lipids

    Glucose Transporters

    • Glucose transporters in the small intestine are located on the luminal side across the cytosol of enterocytes to the capillary
    • SGLT (Sodium-glucose linked transporters) use active transport
    • SGLT are located on the brush border membrane and co-transport glucose/galactose with sodium ions down a sodium concentration gradient generated by the Na-K ATPase pump in the basolateral membrane
    • GLUT (Glucose transporter) uses facilitated transport
    • GLUT5 is located on the brush border membrane, transporting fructose from the lumen to the cytosol and on the basolateral side, transporting cytosolic fructose out to capillaries
    • GLUT2 is located on the basolateral membrane and transports fructose, galactose, and glucose into the enterohepatic vein
    • The liver stores excess glucose and releases it into the peripheral circulation for metabolic need by peripheral cells

    Glucose Transport in Other Body Tissues

    • GLUT1 is found in blood cells, the Blood Brain Barrier, and Foetal Cells
    • GLUT2 is found in the liver, kidneys, pancreas, and intestine
    • GLUT3 is found in neurons and the placenta
    • GLUT4 is found in muscles and adipocytes
    • GLUT1, GLUT2, and GLUT3 are insulin insensitive
    • GLUT4 is insulin sensitive
    • Almost all cells utilize glucose as fuel molecules via GLUT1 and GLUT3

    Glucose Storage Spaces

    • There are three storage spaces for glucose:
      • Liver: as glycogen or as fatty acid and cholesterol in triacylglycerol
      • Muscle: as glycogen
      • Adipocytes: as triacylglycerol
    • The liver produces and stores glycogen for the entire body
    • Muscles use GLUT4, which is insulin sensitive, and mainly store glycogen for their own use
    • Adipocytes use GLUT4
    • Adipocytes release insulin to induce GLUT4 expression when blood glucose is high, facilitating glucose uptake
    • Glucose has two fates after entering the adipocytes:
      • Acetyl-CoA for de novo fatty acid biosynthesis
      • Conversion to glycerol-3-phosphate to form the backbone for triacylglycerol, which is the storage form of lipids
    • LPL, ACC, and DGAT are enzymes involved in the lipid uptake pathway by adipocytes
    • Galactose is converted into glucose and stored as glycogen
    • Fructose is taken up by the liver and converted to glucose, glycogen, and lactate, a fraction may be converted into fatty acids
    • Blood fructose concentrations are always low.

    Anaerobic Glycolysis

    • Glucose phosphorylation is the entry of glucose into the cell mediated by the glucose transporter, e.g., GLUT1
    • Glucose is phosphorylated to glucose-6-phosphate upon entry, this is the committed step for metabolism as it is irreversible
    • ATP is hydrolyzed to donate a phosphate group to glucose in the energy investment phase of glycolysis, facilitated by the enzyme hexokinase
    • Glucose is converted to glucose-6-phosphate in the energy investment phase of glycolysis
    • The energy investment phase of glycolysis is irreversible
    • In glycolysis, glucose-6-phosphate is isomerically rearranged to form fructose-6-phosphate, which is catalyzed by an enzyme that can catalyze both forward and backward reactions
    • In the energy investment phase of glycolysis, a second phosphate group is hydrolyzed to form fructose-1,6-bisphosphate
    • In the energy generation phase of glycolysis, F-1,6-P splits to form two triose biphosphates
    • Inorganic phosphate groups are released, producing two ATP and one NADH per triose phosphate molecule in the energy generation phase of glycolysis
    • The net generation of two ATP and two NADH occurs in glycolysis
    • Pyruvate/Pyruvic acid is the end product of glycolysis
    • In anaerobic glycolysis, pyruvate is reduced by LDH-A (lactic dehydrogenase-A) to lactate in the absence of oxygen
    • Lactate is exported from the cell via a transporter called MCT (monocarboxylate transporter)
    • There is no net generation of NADH in anaerobic glycolysis and no need for O2

    Fate of Lactate

    • Lactate is mainly released from RBCs
    • RBCs carry oxygen but not mitochondria, so they can only carry out anaerobic glycolysis
    • Lactate in blood can go to heart muscles, resting skeletal muscles, etc., and be converted to pyruvate for entering the TCA cycle
    • Lactate from anaerobic glycolysis in muscles, red blood cells, and many other cells can return to the liver to reconvert to glucose by gluconeogenesis via pyruvate, and be taken up by RBCs again (Cori cycle)

    Clinical Connections of Lipid Metabolism

    • Case 1 – Mica:

      • A 6-month-old female presenting with seizure, stomach virus, and poor appetite
      • Blood glucose level 1.5 mmol/L (reference range 3.3-6.0 mmol/L)
      • Urine ketone bodies level negative
      • Indicates a metabolic disease, a Medium-chain fatty acyl-CoA dehydrogenase (MCAD) deficiency
      • Hypoglycemic at fasting

    • Mechanism of MCAD deficiency:

      • Lack of normal food intake leads to fasting conditions
      • The body needs to use fatty acid utilization to maintain plasma glucose levels and provide ketone bodies to peripheral tissues
      • Mica cannot utilize medium chain fatty acids for 𝛽-oxidation due to MCAD deficiency
      • Decreased acetyl-CoA production triggers the activation of enzymes to kick off gluconeogenesis in the liver to make glucose, which is normally used to maintain plasma glucose levels
      • Impaired fatty acid 𝛽-oxidation leads to reduced ATP and NADH production, which are vital components in gluconeogenesis
      • Ketogenesis is also decreased due to the lack of acetyl-CoA

    • Case 2 – Alan Marshall:

      • A 44-year-old male with a history of alcohol abuse and alcohol-induced acute pancreatitis
      • Presents with typical symptoms: abdominal pain, nausea, and vomiting
      • Alcohol insults are responsible for a third of acute pancreatitis cases in the US

    • Mechanism:

      • Ethanol induced pancreatic necrosis
      • Damaged pancreatic acini affect normal pancreatic amylase secretion into the small intestine
      • The lack of enzymes affects the normal rate of hydrolysis, such as triacylglycerol hydrolysis
      • This affects the normal rate of lipid absorption in the small intestine
      • Induces steatorrhea (fat-rich stools)

    • Management:

      • Take commercially available pancreatic enzymes
      • Eat a low-fat diet
      • Consume short-chain rather than long-chain fatty acids

    • Case 3 – Des Todd:

      • An 18-year-old male with prolonged sedentary behavior during the summer, resulting in a BMI of 27
      • He is out of shape due to overeating and lack of exercise
      • Attempts to lose weight by following a low-fat diet and exercising to burn fat

    • Efficiency of a low-fat diet:

      • Fat storage does not solely come from dietary intake, excess carbohydrates provide carbon for de novo lipogenesis
      • Excess protein carbon skeletons from amino acids also provide carbon for de novo lipogenesis

    • Efficiency of exercise:

      • Burning fat involves catabolizing stored body fat for energy consumption
      • Stored body fat is primarily triacylglycerol
      • Lipolysis mobilizes triacylglycerol into free fatty acids and glycerol
      • 𝛽-oxidation converts fatty acids into acetyl CoA, which enters the TCA cycle and ETC for ATP production
      • Ketone bodies can provide a quick alternative fuel source to body cells

    Metabolism of Exogenous Amino Acids

    • Amino acids are the building blocks of proteins

    • Amino acids are obtained from two sources:

      • Exogenous supply from the diet
      • Endogenous supply from constant protein turnovers

    • Amino acids have a general structure

    • Exogenous supply of amino acids:

      • This is the main source of amino acid intake
      • Proteins in food are broken down into free amino acids before entering the blood via the enterocytes

    • Digestion of proteins begins in the stomach:

      • Activation of pepsin from pepsinogen by the chief cells in the stomach
      • Self-cleavage occurs when pH drops due to the secretion of HCl

    • The process continues to completion in the small intestine:

      • The pancreas secretes numerous zymogens that are eventually activated into enzymes, e.g. trypsin, chymotrypsin, elastase, and carboxypeptidases
      • Trypsinogen is cleaved to trypsin by enteropeptidase secreted by the brush border cells of the small intestine
      • Once trypsin is activated, it cleaves other zymogens as they enter the gastrointestinal lumen from the pancreas
      • The gastric contents of the food are emptied into the intestine, pH rises by the action of bicarbonate, allowing endopeptidases to cleave the proteins into free amino acids
      • Exopeptidases are secreted by enterocytes. They are present inside enterocytes and on the brush borders and act on small peptides

    • Absorption of amino acids:

      • Amino acids are absorbed from the intestinal lumen
      • Enterocytes take in free amino acids, dipeptides, and tripeptides from the intestinal lumen
      • The Na+-dependent carrier transports both Na+ and amino acids into enterocytes
      • Na+ is pumped out for K+ by Na-K ATPase pump

    • On the serosal side, amino acids are carried by facilitated transport down its concentration gradient, an example of secondary active transport

    • Only free amino acids cross into the blood circulation

    • Traces of polypeptides can pass into the blood

      • These polypeptides may be transported through intestinal epithelial cells by pinocytosis or by slipping between the cells lining the gut wall
      • Polypeptides can cause allergies in premature infants due to the proteins in their food

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