MOLECULES IN METABOLISM

Metabolic Chemistry Related to Overweight Reactions and molecules in the digestive process

THE FATE OF FOOD Food is digested to produce molecules that are used to support life In the context of body weight the fate of three classes of food are central o Carbohydrates (sugars) o Lipids (fats) o Amino acids (from proteins) The metabolisms of all three overlap

METABOLIC CHEMISTRY Catabolism and Anabolism Molecular constituents of food are broken down into smaller molecules (catabolism) o for reassembly into larger molecules (anabolism) such as fats or proteins o for oxidation to CO 2 and H 2 O and energy A balance is required to maintain a stable organism - homeostasis

ENERGY STORAGE Energy produced in metabolism is stored in an energy- rich molecule ATP Adenosine triphosphate ATP – the battery of life Biological processes requiring energy use ATP The accessible energy in ATP lies in the triphosphate link Removing one phosphate gives adenosine diphosphate (ADP) plus energy.

ADENOSINE TRIPHOSPHATE, ATP adenosine energy-storage bond triphosphate

ENERGY STORAGE IN ATP Adenosine diphosphate (ADP) Adenosine triphosphate (ATP) H 3 PO 4 H2OH2O H2OH2O energy released energy stored The human body produces and consumes its own mass in ATP each day

ENERGY PRODUCTION IN THE CELL Energy is produced by oxidation of molecular fuels - small molecules derived from carbohydrates, lipids, proteins The oxidation uses oxidised forms of coenzymes ultimately producing CO 2, H 2 O and stored energy Energy is stored directly as ATP or as reduced forms of coenzymes that ultimately reduce oxygen to H 2 O Reduction of oxygen to H 2 O yields more ATP and oxidised form of coenzymes

MOLECULES IN METABOLISM Organic molecules from metabolised nutrients often enter metabolic pathway reactions bound to a coenzyme. Coenzyme A is an important coenzyme Phosphate is often bound to organic molecules Oxidation/reduction (electron transport) reactions use NADH NAD +

COENZYME A Usually written as HS-CoA HS-CoA activates organic molecules for metabolic reactions by binding through HS-group to give reactive “–CoA” species Acetyl-CoA is an important example

NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD) nicotinamide adenine phosphate Important in oxidation/reduction reactions 1

NAD + AS AN OXIDISING AGENT NAD + is the main coenzyme for oxidation reactions of metabolic fuels for energy NAD + oxidises other molecules forming NADH and H + NADH is oxidised back to NAD + indirectly by oxygen to give H 2 O (the electron transport chain) For each molecule of NADH reoxidised 2.5 molecules of ATP are produced from ADP So energy from oxidising metabolic fuels is stored as ATP

ACETYL CoA – THE CROSSROADS acetyl-CoA fatty acids fats carbohydrates glycogen glucose CO 2 + energy proteins amino acids pyruvate citric acid cycle glycolysis fatty acid oxidation fatty acid synthesis Glucose in excess of metabolic needs results in fat deposition oxidation

SOURCES OF ACETYL CoA Three metabolic reactions of food components produce are linked o Glycolysis of glucose o Oxidation of fatty acids o Amino acid deamination Each can act as a source of Acetyl-CoA Acetyl-CoA is oxidised in the citric acid (Krebs) cycle producing energy

THE CITRIC ACID CYCLE All air-breathing organisms use the citric acid cycle to generate energy Several metabolic pathways deliver acetyl-CoA and other intermediates for the cycle: o Glycolysis of glucose via pyuvate to acetyl-CoA o Fatty acid oxidation via acetyl-CoA o Amino acid deamination via α-ketoacids

CO 2 CH 2 C=O CO 2 - oxaloacetate CH 3 C=O SCoA acetyl CoA CH 2 HO-C - CO 2 - CH 2 CO 2 - citrate HO-CH - CO 2 - H - C CH 2 CO 2 - isocitrate C=O CH 2 CO 2 - CH 2  -ketoglutarate C=O CH 2 CO 2 - CH 2 SCoA succinyl CoA CO 2 - CH 2 CO 2 - CH 2 succinate CO 2 - CH CO 2 - CH fumarate CO 2 - HOCH CO 2 - CH 2 malate THE CITRIC ACID CYCLE Two carbon atoms enter as acetyl-CoA and are ejected as to CO 2

ENERGY FROM GLUCOSE OXIDATION Three processes are involved o Glycolysis of glucose to two pyruvate molecules o Pyruvate oxidation to acetyl-CoA o Oxidation of acetyl-CoA to CO 2 in the citric acid cycle Energy stored from oxidation of one molecule of glucose = 36 ATP after all reduced coenzymes are reoxidised

HC=O HC-OH HO-CH HC-OH CH 2 OH HC=O HC-OH HO-CH HC-OH CH 2 O-P CH 2 OH C=O HO-CH HC-OH CH 2 O-P C=O HO-CH HC-OH CH 2 O-P HC-OH HC=O CH 2 O-P C=O CH 2 OH CH 2 O-P HC-OH CH 2 O-P HC-OH CO 2 - CH 3 C=O CO 2 - CH 2 OH HC-O-P CO 2 - CH 2 C-O-P CO GLYCOLYSIS OF GLUCOSE TO PYRUVATE glucose glucose 6-phosphatefructose 6-phosphate fructose 1,6-bisphosphate bisphosphoglycerate 3-phosphoglycerate 2-phosphoglycerate phosphoenolpyruvate pyruvate Glycolysis of glucose yields 2 pyruvate + 2 ATP + 2 NADH

CONVERSION OF PYRUVATE TO ACETYL CoA CO 2 - CH 3 C=O HSCoA + NAD + CO 2 + NADH CH 3 C=O SCoA acetyl CoA

ACETYL CoA FROM OXIDATION OF FATTY ACIDS CH 3 (CH 2 ) n CH 2 C=O SCoA CH 3 CH C=O SCoA (CH 2 ) n CH 3 C=O CH 2 C=O (CH 2 ) n SCoA CH 3 HC-OH CH 2 C=O (CH 2 ) n SCoA CH 3 C=O (CH 2 ) n SCoA CH 3 C=O SCoA acetyl CoA n n - 2

pyruvate (mitochondria) acetyl CoA (mitochondria) citrate (mitochondria) citrate (cytosol) oxaloacetate (cytosoL) acetyl CoA in cytosol malate (cytosol) CO 2 glucose glycolysis pyruvate (cytosol) in cytosol oxaloacetate Fatty acid synthesis from acetyl CoA takes place in the cytosol ACETYL CoA FROM GLUCOSE FOR FATTY ACID SYNTHESIS

pyruvate (mitochondria) citrate (cytosol) malate (cytosol) CO 2 glucose glycolysis pyruvate (cytosol) CH 2 C=O CO 2 - oxaloacetate (cytosol) CH 2 HO-C-CO 2 - CH 2 CO 2 - CH 3 C=O SCoA acetyl CoA (mitochondria) CH 3 C=O CO 2 - HO-CH 2 CO 2 - CH 2 citrate (mitochondria) oxaloacetate ACETYL CoA FROM GLUCOSE FOR FATTY ACID SYNTHESIS CH 3 C=O SCoA acetyl CoA in cytosol

AMINO ACID METABOLISM Amino acids, from protein hydrolysis, can be deaminated to form α-ketoacids Some α-ketoacids can be converted to pyruvate or to other intermediates in the citric acid cycle for glucose synthesis Others are converted into acetyl-CoA, used in fatty acid synthesis

LIPID (FAT) SYNTHESIS Lipids (fats) are fatty acid esters of glycerol Fatty acids are synthesised by sequential addition of two-carbon units to acetyl-CoA Acetyl CoA is derived from several sources, eg glycolysis of glucose, from dietary carbohydrates Acetyl CoA is produced in the mitochondria but fatty acid synthesis takes place in the cytosol Lipids are synthesised from fatty acids in adipose tissue and in the liver Fatty acids for lipid synthesis can also arise from dietary fats

FATTY ACID SYNTHESIS FROM ACETYL CoA C=O SCoA malonyl CoA CH 2 CO 2 - C=O SACP malonyl ACP CH 2 CO 2 - C=O SACP CH 2 R C=O CH 2 R C=O SACP CH 2 HC-OH CH 2 R C=O SACP CH 2 HC CH 2 R C=O SACP HC CH 2 R C=O SACP CH 2 growing fatty acid chain CH 3 C=O SCoA acetyl CoA

CHEMICAL CONTROLS Hormones are chemicals messengers released by a cell or a gland in one part of the body that transmit messages that affect cells in other parts of the organism. Important hormones in human metabolism include: o Ghrelin - the hunger-stimulating hormone o Leptin - the satiety (full-feeling) hormone o Glucagon - the stored glucose releasing hormone o Insulin - stimulates the formation of stored fat from glucose Insulin and glucagon are part of a feedback system to regulate blood glucose levels Leptin production is suppressed by abdominal fat.