Energy Metabolism - Introduction

Introduction

• Energy yielding macronutrients (CHO, proteins, and lipids) provide energy for the body, especially CHO and lipids.

• By the end of these lectures, students should be able to:

  • Discuss how the body extracts energy from glucose, amino acids, and fatty acids.

  • Understand how various tissues use different nutrients based on the body’s energy needs.

  • Discuss how the body regulates metabolism and utilizes different macronutrients in various states of energy availability.

• The lectures will focus on the chemical reactions that help cells obtain and use energy from nutrients.

Energy Metabolism

• Energy metabolism involves the chemical reactions that enable cells to store and use energy from nutrients.

• Many reactions in the body are involved in the breakdown, synthesis, and transformation of energy-yielding nutrients, allowing the body to store and use energy.

• Cells can also metabolize alcohol.

• Metabolic pathways work together in a complex way to maintain a steady supply of energy in the form of adenosine triphosphate (ATP), a high-energy molecule used to fuel cellular activities.

Metabolic Pathways

• Metabolic pathways in the body occur simultaneously and are highly coordinated, enabling the body to use different combinations of nutrients in response to various physiological states.

• Ensuring that raw materials and energy are available to all cells at all times.

• A metabolic pathway consists of a series of interrelated, enzyme-catalyzed chemical reactions, some of which are simple while others are more complex.

Metabolic Pathway

• Chemical reactions transform molecules, sometimes breaking them down (catabolism) and other times forming new ones (anabolism).

• Example: Bread starch is broken down into glucose units, which are then catabolized to release energy for activities like muscle contractions.

• Glucose molecules can be assembled into glycogen for storage.

Metabolic Pathways

• A metabolic pathway is a series of reactions that begins with a specific molecule and ends with a product.

• Pathways can be anabolic (building up) or catabolic (breaking down).

• Each step in the pathway is catalyzed by a specific enzyme.

• Metabolic pathways are never inactive; their activity continues in response to internal and external cues.

Glycolysis - Example of a Metabolic Pathway

• Glycolysis is presented as an example of a metabolic pathway.

• It involves a preparatory phase with:

  • phosphorylation of glucose

  • conversion to glyceraldehyde 3-phosphate

• It also includes a payoff phase with:

  • oxidative conversion of glyceraldehyde 3-phosphate to pyruvate

  • coupled formation of ATP and NADH

• Key steps and enzymes include:

  • Hexokinase

  • Phosphohexose isomerase

  • Phosphofructokinase-1

  • Aldolase

  • Triose phosphate isomerase

  • Glyceraldehyde 3-phosphate dehydrogenase

  • Phosphoglycerate kinase

  • Phosphoglycerate mutase

  • Enolase

  • Pyruvate kinase

• The process involves several intermediate molecules, including:

  • Glucose 6-phosphate

  • Fructose 6-phosphate

  • Fructose 1,6-bisphosphate

  • Glyceraldehyde 3-phosphate

  • Dihydroxyacetone phosphate

  • 1,3-Bisphosphoglycerate

  • 3-Phosphoglycerate

  • 2-Phosphoglycerate

  • Phosphoenolpyruvate

  • Pyruvate

TCA Cycle (Metabolic Pathway)

• The TCA cycle, also known as the Krebs cycle or citric acid cycle, is a metabolic pathway.

• Key molecules in the cycle include:

  • Citrate

  • Isocitrate

  • α-Ketoglutarate

  • Succinyl CoA

  • Succinate

  • Fumarate

  • Malate

  • Oxaloacetate

• Important enzymes in the cycle include:

  • Citrate synthase

  • Aconitase

  • Isocitrate dehydrogenase

  • α-Ketoglutarate dehydrogenase complex

  • Succinyl CoA synthetase

  • Succinate dehydrogenase

  • Fumarase

  • Malate dehydrogenase

• The cycle involves the production of NADH + H^+, FADH2, and CO2.

Stages of Energy Catabolism

• Stage 1: Proteins, glycogen, and triglycerides are broken down into their fundamental components (amino acids, glucose, fatty acids and glycerol).

  • Proteins undergo proteolysis to amino acids.

  • Glycogen undergoes glycogenolysis to glucose.

  • Triglycerides undergo lipolysis to fatty acids and glycerol.

• Stage 2: Amino acids, glucose, and fatty acids enter specific pathways and are converted to intermediate products such as pyruvate and acetyl-CoA.

  • Amino acids undergo transamination and deamination.

  • Glucose undergoes glycolysis to pyruvate.

  • Pyruvate is converted to Acetyl-CoA

  • Fatty acids undergo β-oxidation to Acetyl-CoA

• Stage 3: Intermediate products enter the citric acid cycle and are oxidized to carbon dioxide, releasing energy. Electrons and hydrogen ions are transferred to coenzymes NAD^+ and FAD, forming NADH + H^+ and FADH_2.

• Stage 4: Reduced coenzymes NADH + H^+ and FADH_2 enter the electron transport chain and participate in oxidative phosphorylation, generating ATP and water.

Metabolic Reactions

• Anabolic reactions: small molecules are put together to build larger ones, requiring energy (ATP); these reactions are endergonic.

  • Examples: Glucose units combine to make glycogen chains, amino acids link to make proteins, and glycerol and fatty acids assemble to form triglycerides.

• Catabolic reactions: large molecules are broken down into smaller ones, releasing energy; these reactions are exergonic.

  • Example: Glycolysis (glucose catabolism) involves splitting glucose molecules for energy.

• Catabolic reactions are the reverse of anabolic reactions.

Energy Source

• Cells use chemical energy held in the bonds of carbohydrates, proteins, fats, and alcohol.

• Originally, this energy comes from light energy from the sun, which green plants use to make CHO through photosynthesis.

• First law of thermodynamics (conservation of energy): energy cannot be created or destroyed but can be converted from one form to another.

Food Energy to Cellular Energy

• Energy from food (CHO, protein, fats) is transferred to a form that cells can use.

• How energy is extracted from food:

  • Digestion, absorption, and transport.

  • Breakdown of small molecules to a few key metabolites, which liberates energy.

  • Transfer of energy to a form that the body can use: complete breakdown of metabolites to CO2 and H2O, liberating large amounts of energy.

Cell as Metabolic Processing Center

• Cells are the work center of metabolism.

• Cell organelles include:

• Mitochondria: produce ATP through cellular respiration, specifically aerobic respiration. The TCA cycle takes place in the mitochondria.

Site of Reactions - Cells

• Metabolic work occurs continuously within all body cells, with the type and extent varying depending on the cell type.

• Liver cells are the most versatile and metabolically active.

  • Liver cells make and store glycogen and break down glucose for energy when needed.

  • They also make glucose from some amino acids and glycerol.

  • The liver manufactures bile and breaks down fatty acids for energy when needed.

  • It removes excess amino acids from circulation, deaminates them, or converts them to other amino acids.

  • The liver removes ammonia from the blood and converts it to urea for excretion by the kidneys.

Helpers in Reactions – Enzymes and Co-enzymes

• Many enzymes are inactive unless combined with cofactors, which are usually derived from a vitamin or a mineral.

• Vitamin-derived cofactors are called coenzymes.

• All B vitamins form coenzymes used in metabolic reactions.

Helpers in Reactions – Enzymes and Co-enzymes

• Metabolic reactions almost always require enzymes to facilitate their action.

• Enzymes are catalytic proteins that speed up chemical reactions in metabolic pathways.

• Some B-vitamins serve as coenzymes to the enzymes that release energy from glucose, glycerol, fatty acids, and amino acids.

Key Energy Players

• Certain compounds have recurring roles in metabolic activities.

• Adenosine triphosphate (ATP) is the fundamental energy molecule used to power cellular functions and is the universal energy currency.

• Two other molecules, NADH and FADH_2, are important carriers that carry high-energy electrons for the synthesis of ATP.

NADH and FADH2 - Body’s Energy Shuttle

• Breaking down energy-yielding nutrients releases high-energy electrons; further reactions transfer energy from these electrons to form ATP.

• To reach the site of ATP production, high-energy electrons are carried by special molecular carriers.

• One major electron acceptor is nicotinamide adenine dinucleotide (NAD), a derivative of the B vitamin niacin.

• The metabolic pathways have several energy transfer points where NAD accepts 2 high-energy electrons and two hydrogen ions (2 H^+) to form NADH + H^+.

NADH and FADH2 - Body’s Energy Shuttle

• Another major electron acceptor is flavin adenine dinucleotide (FAD), a derivative of the B vitamin riboflavin.

• FAD accepts two high-energy electrons as well as two protons (2H^+) and forms FADH_2.

NADH and FADH2 - Body’s Energy Shuttle

• There's a lot of energy stored in the bonds between the carbon and hydrogen atoms in glucose.

• During cellular respiration, redox reactions transfer this bond energy in the form of electrons from glucose to electron carriers.

• An electron carrier is a molecule that transports electrons during cellular respiration.

• By using electron carriers, energy harvested from glucose can be temporarily stored until the cell can convert the energy into ATP.

NADH and FADH2 - Body’s Energy Shuttle

• Many coenzymes exist in two forms: oxidized (NAD^+ , FAD) and reduced (NADH + H^+, FADH_2).

• When energy-rich molecules get re-oxidized, their electrons and hydrogen ions are transferred to NAD^+ and FAD.

• The coenzyme NAD^+ can accept 2 electrons (2e^-) and 2 hydrogen ions (H^+) forming NADH + H^+.

• Similarly, FADH_2 is formed when 2 electrons and 2 H are transferred to FAD.

• The energy carried by these reduced coenzymes is used to power the synthesis of the body’s most important energy source – adenosine triphosphate or ATP.

Coenzymes and Energy Transfer Reactions

• Oxidation (loss of electrons) and reduction (gain of electrons) reactions involve the gain and loss of electrons.

• These reactions often occur simultaneously and are referred to as coupled reactions.

• When one molecule is oxidized (loses electrons and hydrogen ions), another is being reduced (gains electrons and hydrogen ions).

• Coupled redox reactions allow energy to be transferred from one molecule to another.

Regulation of Energy Metabolism by ATP Levels

• Energy metabolism comprises anabolic pathways (molecules that store energy) and catabolic pathways (storage energy molecules are broken down to release energy).

• The combination of pathways depends on the cellular need for energy.

• When there are adequate ATP levels, catabolic reactions decrease, and anabolic pathways increase, and vice versa.

• This ensures that cells have ATP and various substrates available at all times.

Energy Metabolism Regulated by Hormones

• Primary hormones involved in the regulation of catabolic and anabolic pathways are insulin, glucagon, cortisol, and epinephrine.

Adenosine Triphosphate (ATP)

• What it is.

• Its importance.

• Its synthesis.

Role of ATP in Energy Metabolism

• Cells cannot use nutrients directly for energy.

• Energy stored in the chemical bonds of nutrients has to be converted into a usable form – adenosine triphosphate or ATP.

• About half of the energy contained in energy-yielding nutrients is captured as ATP; the rest is lost as heat.

• ATP provides energy for protein synthesis, muscle contraction, active transport, nerve transmission, and other energy-requiring reactions in the body.

ATP - Body’s Energy Currency

• To power its needs, the body converts energy in foods to a readily usable form – ATP.

• ATP kick-starts many energy-releasing processes and powers energy-consuming processes.

• Producing ATP is the fundamental goal of metabolism’s energy-producing pathways.

Adenosine Triphosphate (ATP)

• ATP comprises three basic units: a ribose sugar, a base called adenine, and a chain of three phosphate groups.

• The energy in the bonds between each phosphate group is greater than the energy in most other chemical bonds.

• When energy is needed, hydrolysis reactions readily break down these high-energy bonds, splitting off one or two phosphate groups and releasing their energy.

• Breaking the bond releases energy and inorganic phosphate (Pi), forming adenosine diphosphate (ADP).

• The released energy powers metabolic reactions, and the ADP formed is then regenerated to ATP.

ATP

• ATP and ADP are inter-convertible.

• Cells constantly regenerate and use ATP.

• Energy is needed to add a phosphate group to ADP to make ATP, and this energy comes from catabolic reactions occurring in the cells.

Synthesis of ATP

• ATP is important for cells, and since it cannot be stored to any extent, cells must continuously make it.

• ATP is used as quickly as it is made.

• Two ways in which ATP is synthesized:

  • Substrate-level phosphorylation.

  • Oxidative phosphorylation.

Synthesis of ATP - Substrate Level Phosphorylation

• A phosphate group from a substrate (other phosphorylated intermediates) is added directly to ADP to form ATP.

• Does not necessarily need O2, hence important when tissues have little O2 available.

• All cells are capable of this process.

• Produces less ATP compared to oxidative phosphorylation.

Synthesis of ATP – Oxidative Phosphorylation

• Oxidative phosphorylation is the final step in cellular respiration (process of generating energy from food).

Synthesis of ATP – Oxidative Phosphorylation

• Oxidative phosphorylation is the final step in cellular respiration.

• It occurs in the mitochondria, the energy center of the cells, which is divided into inner and outer compartments.

  • The inner compartment is the mitochondrial matrix.

  • The space between the inner and outer compartments is the inter-membrane space.

• Oxidative phosphorylation is linked to a process known as the electron transport chain, located in the inner mitochondrial membrane.

• The electron transport chain is a cluster of proteins that transfer electrons from one member of the transport chain to another through a series of redox reactions in the inner mitochondrial membrane to form a gradient of protons that drives the creation of adenosine triphosphate (ATP).

Oxidative Phosphorylation and Electron Transport Chain

• Energy from the catabolism of CHO, protein, and lipids cannot be transferred directly to ADP.

• Electrons (e-) and hydrogen ions (H+) are transferred to oxidized co-enzymes (electron carriers) NAD^+ & FAD.

• Upon acceptance of the electrons and hydrogen ions, the electron carriers are reduced to NADH + H^+ and FADH_2.

• When reduced NADH + H^+ and FADH_2 are re-oxidized back to NAD^+ and FAD in the electron transport chain, energy is released.

• This process is accomplished by a series of chemical reactions that link the oxidation of NADH + H^+ and FADH_2 to the synthesis of ATP.

• These reactions are coupled; the energy needed to phosphorylate ADP is provided by the oxidation of NADH + H^+ and FADH_2.

• In this way, the energy contained in the reduced coenzymes (electron carriers) is used to form ATP.

Oxidative Phosphorylation

• A series of protein complexes makes up the ETC and are embedded in the inner mitochondrial membrane.

• When NADH + H^+ and FADH_2 enter the ETC, their electrons & hydrogen ions are removed by enzymes, regenerating NAD & FAD in the process.

• The released electrons & hydrogen ions take separate routes.

• The electrons pass along the protein complexes.

Synthesis of ATP – Oxidative Phosphorylation

• The energy generated by the movement of electrons causes the hydrogen ions to be pumped out of the mitochondrial matrix and into the inter-membrane space.

• Hence, a net negative charge (from the electrons) builds up in the matrix space, while a net positive charge builds up in the inter-membrane space.

• This differential electrical charge establishes an electrochemical gradient.

Synthesis of ATP – Oxidative Phosphorylation

• The outside of the membrane is positive, while the inside is negative.

• The positive hydrogen ions are allowed to flow back across the membrane through the specialized channels manned by the enzyme ATP synthase, which uses the energy created by the energetically favorable transport to synthesize ADP and phosphate into ATP.

Oxidative Phosphorylation & ETC

• As NADH + H^+ and FADH_2 are passed along the protein complexes of the electron transport chain, electrons (e-) and hydrogen ions (H^+) are released.

• Energy released from the movement of electrons is used to pump hydrogen ions (H^+) out of the mitochondrial matrix and into the intermembrane space.

• At the completion of the electron transport chain, cytochromes combine electrons, hydrogen ions, and oxygen to form water. Because oxygen is needed, this is an aerobic process.

• The accumulation of hydrogen ions (H^+) in the intermembrane space creates a force. This force enables the hydrogen ions (H^+) to reenter the mitochondrial matrix by passing through a channel.

• The movement of hydrogen ions (H^+) through the channel causes the enzyme ATP synthase to catalyze the reaction that adds a phosphate group to ADP, converting it to ATP.

Synthesis of ATP

• NADH + H^+ and FADH2 enter the ETC at different locations along the protein complexes; hence, the amount of ATP generated differs – 2.5 ATPs for each NADH & 1.5 ATPs for each FADH2 molecule.

• Some books may state 3 ATP for each NADH & 2 ATPs for each FADH_2.

Synthesis of ATP - ETC

• At the completion of the ETC, cytochromes (iron-containing protein complexes) reunite the electrons and hydrogen ions to form hydrogen.

• The hydrogen then combines with oxygen (O2) to form water (H2O).

• The oxygen we inhale is essential for the completion of these reactions, and CO_2 produced is exhaled.

Recap of Main Points

• Chemical energy needed by the cells for cellular metabolism is held in the bonds of energy-yielding nutrients.

• However, these are not usable for cells, so they must be converted to the usable form, ATP.

• Breaking down nutrients releases high-energy electrons; further reactions transfer energy from these electrons to ATP.

• To reach the site of ATP production, high-energy electrons are carried by special molecular carriers.

• By using electron carriers, energy harvested from nutrients can be temporarily stored until the cell can convert the energy into ATP.

• Electron carriers are nicotinamide adenine dinucleotide (NAD)—a derivative of the B vitamin niacin—and flavin adenine dinucleotide (FAD), a derivative of the B vitamin riboflavin.

Recap of Main Points

• The metabolic pathways have several energy transfer points where NAD and FAD accept 2 high-energy electrons and two hydrogen ions (2 H^+) from the breakdown of nutrients to form NADH + H^+ and FADH_2.

• When reduced NADH + H^+ and FADH2 are re-oxidized back to NAD^+ and FAD in the ETC, energy is released, and the process is accomplished by a series of chemical reactions that link the oxidation of NADH + H^+ and FADH2 to the synthesis of ATP.

• The process whereby NADH + H^+ and FADH_2 are oxidized and ADP is phosphorylated is called oxidative phosphorylation.

Recap of Main Points

• Oxidative phosphorylation is one way of making ATP and accounts for 90% ATP; the other is substrate-level phosphorylation.

• Now that we know how electron carriers NADH + H^+ & FADH_2 are linked to ATP synthesis.

• In the remaining lectures on energy metabolism, we will look at where the electron carriers NADH + H^+ & FADH_2 come from.

• We will look at glucose, amino acid and fatty acid catabolism and the TCA cycle.

Reference

• Main reference used for these notes: Chapter 7 Energy Metabolism pp:289-319. McGuire & Beerman. Nutritional Sciences: from Fundamentals to Foods. Wadsworth Cengage Learning, USA.

• Insel P, Turner, RE, Ross, D. (2004). Nutrition. Chapter 3. Jones & Bartlett Publishers Inc, US.

• Whitney, E.N., Sharon, R., (2011). Understanding Nutrition, Wadsworth Publishing, Belmont, USA.