Metabolism “Life is all about shaping new molecules from old.” -Robert Thornton, Chemistry of Life (CD-ROM)

Outline I. Metabolism basics Reaction types, enzymes, electron acceptors, cellular location II. Breakdown of glucose (Carbs) Glycolysis, Kreb’s cycle, electron transport chain II. Breakdown of fat Lipolysis, Fatty acid oxidation III. Breakdown of protein Proteolysis, Deamination IV. Energy from protein V. Synthesizing macronutrients Gluconeogenesis, Lipogenesis VI. Feasting vs. Fasting

Metabolism—encompasses all of the chemical changes that occur in living organisms. Metabolic pathway—describes a series of chemical reactions that either break down or build molecules

Types of Metabolic pathways Catabolic—describes the break down of a large molecule into smaller units Anabolic—describes the building of more complex molecules from smaller ones

Metabolism Figure 7.1 Copyright 2004 Pearson education, Inc. published by Benjamin Cummings

Adenosine Triphosphate (ATP) ATP is an organic compound used by cells as a source of energy – Energy is stored in the phosphate bonds – When the bonds are broken, they release energy – This energy is used to do work of the cell

Adenosine Triphosphate (ATP) Figure 7.2 Copyright 2004 Pearson education, Inc. published by Benjamin Cummings

Condensation & Hydrolysis Condensation is an anabolic process – Water is released as a by-product – A—OH + H—B  A—B + H 2 0 Hydrolysis is usually a catabolic process – A large molecule is broken apart with the addition of water – A—B + H 2 0  A—OH + H—B

Phosphorylation Phosphorylation is the addition of phosphate group to a compound When the 2 high-energy phosphate bonds in ATP are hydrolyzed – energy is released – phosphate is transferred to other molecules When glucose is phosphorylated, it can be oxidized for energy or stored as glycogen

Oxidation-Reduction Reactions Molecules exchange electrons (hydrogen) Exchange reactions occur together Molecule giving up an electron is “oxidized” – Its electron is removed by oxygen Molecule receiving an electron is “reduced” – In gaining an electron, it becomes more negatively charged

Enzymes Enzymes are the protein “machines” that take molecules apart and reassemble them – Isomerases – Dehydrogenases – Hydrogenases – Transferases, etc. About ~50% of all proteins are enzymes Enzymes work by lowering the activation energy of a reaction

Coenzymes Vitamins are organic coenzymes Lack of vitamins can prevent certain chemical reactions from occurring and can result in disease: CoenzymeFunction Vitamin DCalcium metabolism, bone formation Vitamin ANight vision NiacinCarries electrons in cellular respiration

Cofactors Some enzymes require cofactors to function Cofactors are typically minerals Cofactors bind to enzymes, thus rendering them active. CofactorEnzyme ZincAlcohol dehydrogenase IronCytochromes SodiumATPases

Where does metabolism take place? Marieb, EN and Mallat, J. Human Anatomy. 2nd ed. Menlo Park, Calif.: Benjamin Cummings, c1997

Different macromolecules have different metabolic pathways…

Energy from Carbohydrates When glucose is transported to the liver, it is – Phosphorylated and metabolized for energy or stored as glycogen – Released into circulation for other cells to use as fuel or stored as glycogen (muscle tissue) – Converted to fatty acids, if glucose exceeds caloric needs, and stored as triglycerides in adipose tissue Fructose and galactose are converted to glucose in the liver and follow the same fate

I. Cellular Respiration I. Cellular Respiration The breakdown of a glucose molecule Made of three different metabolic pathways: PathwayLocationATP produced per glucose molecule GlycolysisCytosol2 ATP Citric Acid Cycle (aka Kreb’s cycle) Mitochondrial matrix2 GTP Chemiosmosis (aka ETC) Inner mitochondrial membrane ATP

Who are the key energy players? Re-introducing…. ATP! Adenosine triphosphate ATP! Adenosine triphosphate

…and the electron acceptors NAD NAD: Nicotinamide adenosine diphosphate Derivative of the B vitamin Niacin Accepts 1-2 high energy electrons to form NADH or NADH + H + FAD FAD: Flavin adenine diphosphate Derivative of the B vitamin riboflavin Accepts 2 high energy electrons to form FADH 2

Glycolysis Glucose  Pyruvate Occurs in the cytosol Is an anaerobic process Energy yield  2 ATP + 2 NADH

Glycolysis

In the Absence of Oxygen… Figure 7.7a Copyright 2004 Pearson education, Inc. published by Benjamin Cummings

In the Absence of Oxygen… Figure 7.7b Copyright 2004 Pearson education, Inc. published by Benjamin Cummings

In the Presence of Oxygen… Figure 7.8 Copyright 2004 Pearson education, Inc. published by Benjamin Cummings

Pyruvate  Acetyl CoA Aerobic reaction Occurs in mitochondria Converts pyruvate to Acetyl CoA 2 pyruvate molecules from glycolysis yields 2 NADH and 2 Acetyl CoA molecules

Kreb’s Cycle (Citric Acid Cycle) Completes the metabolic breakdown of glucose to ATP, CO 2 Energy yield 2 GTP + 8 NADH + 2FADH 2

Krebs Cycle Copyright 2004 Pearson education, Inc. published by Benjamin Cummings

Electron Transport Chain Composed of proteins and cytochromes lined in the inner mitochondrial membrane Electrons are transferred through the chain, releasing energy to pump H+ into the intermembrane space and eventually producing ATP Energy yield about ATPs

Electron transport chain Insel, Turner and Ross. Nutrition, c2002

Summary of Glucose oxidation Net energy gain from one glucose molecule= ATP

Take a breather.

II. Breakdown of FAT Enzymes break down triglycerides into their component parts, glycerol and fatty acids

Then what? Glycerol is converted to pyruvate or glucose by the liver Fatty acid contains nearly all the energy Fatty acids must be activated—linked to coenzyme A before it can enter catabolic pathways. This activation happens in the cytosol and costs 1 ATP (ATP  AMP +2P i )

Carnitine Shuttle Fatty acid oxidation takes place in the mitochondria Fatty acids rely upon carnitine to ferry them from the cytosol into the mitochondria Carnitine deficiency can slow production of ATP (heart/skeletal muscle can lose endurance)

Beta oxidation In the mitochondria, beta oxidation disassembles the fatty acids and converts it into molecules of acetyl CoA Enzymes clip a 2-carbon link from the end of the chain. As the chain is shortened, 1 FADH 2 and 1 NADH form, and the 2-carbon link becomes acetyl CoA The acetyl CoA enters Kreb’s cycle and eventually the electron transport chain (just like glucose) Fatty acids usually produce substantially more ATP than glucose

To burn fat, you need carbohydrates!!! Acetyl CoA from beta-oxidation can not start the citric acid cycle without a steady supply of oxaloacetate Starvation and very-low carb diets can deplete oxaloacetate This reroutes the acetyl CoA to form ketone bodies

Ketoacidosis Ketogenesis (production of ketone bodies) occurs when abundance of acetyl CoA overwhelms available supply of oxaloacetate Ketones are a type of emergency energy to the body’s tissues Liver makes ketone bodies (3 types) from acetyl coA, travels through bloodstream to other tissues The ketone Acetoacetate can be converted back into acetyl coA, but with low levels of OAA, Kreb’s cycle is very inefficient

Formation of ketone bodies

Ketoacidosis Kidneys excrete excess ketone bodies in urine and lungs exhale them Ketosis occurs when removal process can’t keep up Blood levels of ketones rises, altering the pH Can result in brain damage and eventually, death

What everyone wants to know… How do we store Fat? Fatty acids are stored as triglycerides High fat diets High fat diets: most go to straight to fat stores High protein diets High protein diets: body converts most of excess protein to fat High carb diets High carb diets: does not convert protein to fat; however, it shifts your body’s fuel preferences to burn more carbs than fat

III. Breakdown of proteins Proteins are only used for energy in the absence of fat or carbs Carbon skeletons: are formed by the deamination of amino acids and can enter the metabolic pathways at several points depending on their structure (# carbons)

Energy from Protein During starvation, the body turns to its own tissues for energy Figure 7.19

Breakdown of proteins Glucogenic Amino Acids: become pyruvate or a Kreb’s cycle intermediate Ketogenic Amino Acids: become acetyl CoA The carbon skeleton’s point of entry determines the amount of ATP produced

Energy from Protein Figure 7.20

Energy from Protein Ammonia from protein catabolism – Used as nitrogen source for synthesis of nonessential amino acids – High levels are toxic – Liver converts ammonia to less toxic urea Urea is transported to kidneys via bloodstream NH 3 Ammonia NH 3 Ammonia Kidney Liver Urea is excreted in urine by kidneys CO 2 C Urea O NH 2 H2NH2N +

Energy from Protein The body prefers using carbohydrates and fat for energy Protein is reserved for metabolic functions that cannot be performed by others – building and repairing body tissues Protein are used for fuel primarily during low total energy or carbohydrate intake

Energy from Protein Dietary proteins are digested into amino acids or small peptides Amino acids are transported to the liver – made into proteins – released into the blood for uptake by other cells for building and repair functions Excess dietary protein – used for energy or converted to fatty acids for storage as triglycerides

Stored Energy Stored energy can be used during times of sleep, fasting, or exercise Extra energy is stored as – Carbohydrate in limited amounts as liver and muscle glycogen – Fat (triglycerides) in unlimited amounts The body has no mechanism for storing amino acids or nitrogen

Synthesizing Macronutrients Gluconeogenesis: making glucose from nonglucose substrates – Primarily from amino acids – Small amount from glycerol (triglyceride) – Maintains blood glucose during sleep, fasting, illness, and exercise Protein catabolism for glucose production can draw on vital tissue proteins (skeletal and heart muscles and organ proteins)

Synthesizing Macronutrients Lipogenesis or de novo synthesis: making fat from nonfat substances such as carbohydrates, amino acids, and alcohol – Occurs when consuming excess calories – Acetyl CoA units assemble into fatty acid chains – Fatty acids combine with glycerol to form triglycerides – Mostly occurs in liver cells

Feasting

Fasting

From FOOD energy to CELL energy! Stage I Digestion, absorption, and transport Stage II Breakdown of small molecules to metabolites Stage III Transfer of energy to a usable form for cells