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Metabolism Total of all chemical changes that occur in body. Includes: Anabolism: energy-requiring process where small molecules joined to form larger molecules E.g. Glucose + Glucose Catabolism: energy-releasing process where large molecules broken down to smaller Energy in carbohydrates, lipids, proteins is used to produce ATP through oxidation-reduction reactions

Metabolism i

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Page 1: Metabolism i

Metabolism• Total of all chemical changes that occur in body.

Includes:– Anabolism: energy-requiring process where small

molecules joined to form larger molecules• E.g. Glucose + Glucose

– Catabolism: energy-releasing process where large molecules broken down to smaller

• Energy in carbohydrates, lipids, proteins is used to produce ATP through oxidation-reduction reactions

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BreakdownProteins to Amino Acids, Starch to Glucose

SynthesisAmino Acids to Proteins, Glucose to Starch

Metabolism is the sum of Catabolism and AnabolismOpposite chemical processes. Catabolism releases energy (exergonic), and Anabolism takes up energy (endergonic)

Catabolism and Anabolism

We can consider these bioenergetics in terms of the physical laws of thermodynamics

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Energy and Metabolism

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4

Metabolic Pathways

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Interconversion of Nutrient Molecules

• Glycogenesis– Excess glucose used to form glycogen

• Lipogenesis– When glycogen stores filled, glucose and amino acids used

to synthesize lipids

• Glycogenolysis– Breakdown of glycogen to glucose

• Gluconeogenesis– Formation of glucose from amino acids and glycerol

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As vias catabólicas convergem para uns poucos produtos finais

As vias anabólicas divergem para a síntese de muitas biomoléculas

Common intermediate

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Breakdown of macromolecules tobuilding blocks -- generally hydrolytic

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Metabolic Pathways• The enzymatic reactions of

metabolism form a network of interconnected chemical reactions, or pathways.

• The molecules of the pathway are called intermediates because the products of one reaction become the substrates of the next.

• Enzymes control the flow of energy through a pathway.

Intermediary Metabolism

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• A metabolic pathway has many steps– That begin with a specific molecule and end with a

product– That are each catalyzed by a specific enzyme

Enzyme 1 Enzyme 2 Enzyme 3

A B C D

Reaction 1 Reaction 2 Reaction 3

Startingmolecule

Product

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Oxidation-Reduction Reactions• Oxidation occurs via the loss of hydrogen or the

gain of oxygen • Whenever one substance is oxidized, another

substance is reduced• Oxidized substances lose energy• Reduced substances gain energy• Coenzymes act as hydrogen (or electron)

acceptors• Two important coenzymes are nicotinamide

adenine dinucleotide (NAD+) and flavin adenine dinucleotide (FAD)

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Comparação dos estados de oxidação dos átomos de carbono

nas biomoléculas

(quanto mais oxidado mais estável é a molécula, logo menos energia pode ser extraída da quebra das

ligações)

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Fotossíntese Respiração

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Four general stages in the biochemical energy production process in the human body.

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ATPAdenosine Triphosphate

ATP powers most energy requiring process in living systems.

ComponentsEnergy stored in the triphosphate group

– Cells use ATP’s to drive endergonic reactions– ATP ADP (releases energy)

– Cells are continually producing new ATP’s– ADP ATP (requires energy)

ATP - the energy “currency” of cells

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The interconversion of ATP and ADP is the principal medium for energy exchange in biological processes.

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Flavin Adenine Dinucleotide, FAD (a) and Nicotinamide Adenine Dinucleotide, NAD (b)

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Carbohydrate Metabolism

• Since all carbohydrates are transformed into glucose, it is essentially glucose metabolism

• Oxidation of glucose is shown by the overall reaction: C6H12O6 + 6O2 � 6H2O + 6CO2 + 36 ATP + heat

• Glucose is catabolized in three pathways– Glycolysis– Krebs cycle– The electron transport chain and oxidative

phosphorylation

∆∆∆∆G = -686kcal/mol of glucose

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Carbohydrate Catabolism

transferring a phosphate directly to ADP from another molecule

use of ATP synthase and energy derived from a proton (H+) gradient to make ATP

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Glycolysis• A three-phase pathway in which:

– Glucose is oxidized into pyruvic acid (PA)• It loses 2 pairs of hydrogens

– NAD+ is reduced to NADH + H+

• It accepts 2 pairs of hydrogens lost by glucose – ATP is synthesized by substrate-level

phosphorylation

• Pyruvic acid: end-product of glycolysis– Moves on to the Krebs cycle in an aerobic

pathway (i.e. sufficient oxygen available to cell)– Is reduced to lactic acid in an anaerobic

environment (insufficient O2 available to cell)– pyruvic acid lactic acid

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Glycolysis

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Energy investement phase

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Glycolysis: Phase 1 and 2• Phase 1: Sugar activation

– Two ATP molecules activate glucose into fructose-1,6-diphosphate

• The 1 and 6 indicate which carbon atom to which they are attached.

• Phase 2: Sugar cleavage (splitting) – Fructose-1,6-bisphosphate (6 C’s) is split

into two 3-carbon compounds:• Glyceraldehyde 3-phosphate (GAP)

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Glycolysis: Phase 3• Phase 3: Oxidation and ATP formation

– The 3-carbon sugars are oxidized (reducing NAD+); i.e., 2 H’s + NAD NADH2

– Inorganic phosphate groups (Pi) are attached to each oxidized fragment

– The terminal phosphates are cleaved and captured by ADP to form four ATP molecules

– The final products are:• Two pyruvic acid molecules• Two NADH + H+ molecules (reduced NAD+)• A net gain of two ATP molecules

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ATP Production and Glycolysis

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GlycolysisGlycolysis• First stage of glucose catabolism.

• No oxygen needed.

• All organisms uses this process.

• It occurs in the cytoplasm where the necessary enzymes are located.

• 6C Glucose is converted into two 3C pyruvate.

• Small amount of energy, 2ATP, is produced.

Pathway of glycolysis is strictly regulated according to the cell’s needs for energy.

The rate limiting step of the pathway is reaction 3, the phosphorylation of F 6-P, which is catalyzed by phospho-fructokinase.

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Anaerobic Metabolism

Fermentation in animal cells…

Lactic Acid Fermentation

• Breakdown of glucose in absence of oxygen

– Produces 2 molecules of lactic acid and 2 molecules of ATP

• Phases– Glycolysis– Lactic acid formation

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Anaerobic Metabolism

Fermentation in plants, yeast…Again…only 2 ATP per glucose

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Aerobic Metabolism

If enough O2 is present…

To Krebs Cycle and ETC

~ 36 more ATP per glucose!

Glycolysis = 2 ATP

Krebs Cycle and ETC = 34 ATP

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Glycolysis

For glycolysis to continue, NADH must be recycled to NAD+ by either:

1. aerobic respiration – occurs when oxygen is available as the final electron acceptor

2. fermentation – occurs when oxygen is not available; an organic molecule is the final electron acceptor

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Ciclo de Cori

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Sintese de "glucose nova" a partir de metabolitos comuns

• Os seres humanos consumem 160 g de glucose por dia • 75% dessa é consumida no cérebro • Os fluidos corporais contêm apenas 20 g de glucose • As reservas de glicogénio rendem 180-200 g de glucose

• Portanto o corpo deve ser capaz de sintetizar a sua própria glucose

Gluconeogénese

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Gluconeogénese

• Ocorre principalmente no figado e nos rins.

• Não é uma mera reversão da glicólise por duas razões:

O balanço energético tem que mudar de modo a tornar a gluconeogenese favorável (�G da glicolise = -74 kJ/mol)

A regulação de uma das vias deve ser activada e a da via reversa deve ser inibida – isto requer algo de novo !

• Sete dos passos da glicólise estão conservados e três passos são substituidos:Passos 1, 3, e 10 (que são os passos regulados!)

• As reacções novas devem seguir um novo caminho de reacção espontâneo (∆G negativo na direcção da sintese de açucar), e devem ser regulados de maneira diferente.

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Regulação da Gluconeogenese

Controlo reciproco com a glicólise• Quando a glicolise está em funcionamento, a gluconeogenese não

está a realizar-se • Quando o estado energético da célula é elevado, a glicolise deve ser

desligada e o piruvato (entre outros), deve ser utilizado para a sintese e armazenamento de glucose

• Quando o estado energético da célula é baixo, a glucose deve ser rápidamente degradada de modo a fornecer energia

• Os passos regulados da glicólise são os mesmos passos que são regulados na direcção oposta !

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Krebs Cycle: Preparatory Step

• Occurs in the mitochondrial matrix and is fueled by pyruvic acid and fatty acids

• Pyruvic acid from glycolysis is converted to acetyl coenzyme A (A-CoA) in three main steps:– Decarboxylation

• 1 carbon is removed from pyruvic acid; 3C → 2C molecule• The lost carbon forms carbon dioxide; exhaled

– Oxidation• 2 Hydrogen atoms are removed from pyruvic acid (‘oxidation’)

and picked up by NAD• NAD+ is reduced to NADH + H+ (see next slide)

– Formation of acetyl CoA – the resulting acetic acid is combined with coenzyme A, a sulfur-containing coenzyme, to form acetyl CoA (ACoA)

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Each transition of pyruvate to acetyl coenzyme A yields one NADH and one CO2.

The acetyl coenzyme A then enters the Krebs cycle.

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Citric Acid CycleMelvin Calvin (UCB)

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Krebs Cycle• An eight-step cycle in which each acetic acid is

decarboxylated and oxidized, generating: – Three molecules of NADH + H+ (ox/red)– One molecule of FADH2 (ox/red)– Two molecules of CO2 (decarboxylation)– One molecule of ATP (substrate level

phosphorylation• For each molecule of glucose entering glycolysis,

two molecules of acetyl CoA enter the Krebs cycle

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Krebs Cycle

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Krebs Cycle

After glycolysis, pyruvate oxidation, and the Krebs cycle, glucose has been oxidized to:

- 6 CO2

- 4 ATP- 10 NADH- 2 FADH2

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OxidativeOxidative PhosphorylationPhosphorylation

Complex I

Complex III Complex IV

Complex V

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Electron carriers take these high energy electrons to the Electron Transport ChainElectrons are run down an “electron slide”…

The energy released from this “slide” is used to make ATP…

The electrons and H+ are accepted by oxygen and become water

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Electron Transport Chain

• Food (glucose) is oxidized and the released hydrogens:– Are transported by coenzymes NADH and FADH2

– Enter a chain of proteins bound to metal atoms (cofactors)

– Combine with molecular oxygen to form water– Release energy

• The energy released is harnessed to attach inorganic phosphate groups (Pi) to ADP, making ATP by oxidative phosphorylation– “phosphorylation” - to add phosphate to a substance

» ADP + P ATP

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Mechanism of Oxidative Phosphorylation

• The hydrogens delivered to the chain are split into protons (H+) and electrons– The protons are pumped across the inner mitochondrial

membrane to the intermembrane space– This creates a pH and concentration gradient (of H+)

– The electrons are shuttled from one acceptor to the next• Electrons are delivered to oxygen, forming oxygen ions• Oxygen ions attract H+ that were pumped into the

intermembrane space to form water• H+ that were pumped to the intermembrane space:

– Diffuse down their gradients back to the matrix via ATP synthase (from greater to lesser concentration)

– Release energy to make ATP

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Six of the eight electron carriers (enzymes) are found at fixed sites within the inner mitochondrial membrane. The other two electron carriers are mobile, moving between fixed sites.

Complex INADH ubiquinoneoxireductase

Complex IIIUbiquinol-

cytochrome coxireductase

Complex IVCytochrome c

oxidase

Complex IISuccinate ubiquinoneoxireductase

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Proton Pumps: every two electrons passed through the ETC produces 10 H+ ions from the mitochondrial matrix to the intermembrane space.

NADH FMN/Fe-S Q Cytb/Cytc1 Cytc Cyta/Cyta3 O2

Succinate/ FAD

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ATP is accompanied by the flow of protons from the intermembrane space back into the mitochondrial matrix. The proton flow results from an electrochemical gradient across the inner mitochondrial membrane.

The Chemiosmotic Theory Proposed by Peter Mitchell in the 1960’s (Nobel Prize 1978)

H+ flow forms a circuit (similar to an electrical circuit)

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ATP Synthase• The enzyme

consists of three parts: a rotor, a knob, and a rod

• Current created by H+ causes the rotor and rod to rotate

• This rotation activates catalytic sites in the knob where ADP and Piare combined to make ATP

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http://vcell.ndsu.nodak.edu/animations/etc/movie.htm

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Energy Yield of Respiration

theoretical energy yields- 38 ATP per glucose for bacteria- 36 ATP per glucose for eukaryotes

actual energy yield- 30 ATP per glucose for eukaryotes- reduced yield is due to “leaky” inner

membrane and use of the proton gradient for purposes other than ATP synthesis

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Cytosolic NADH must enter themitochondria to fuel oxidative phosphorylation , but NADH and NAD cannot diffuse across the inner mitochondrial membrane phosphorylation, NAD+

By passes Complex I: How many ATP molecules are produced per NADH molecule used?

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Complete Oxidation of glucose

• Complete oxidation of glucose involves the following pathways and net reactions:

• Glycolysis: glucose + 2ADP + 2Pi + 2NAD+ � 2pyruvate + 2 ATP + 2NADH + 2 H+ + 2H2O

2 pyruvate + 2CoA + 2 NAD+ � 2acetylCoA + 2CO2 + 2 NADH

• TCA cycle: 2acetylCoA + 6 NAD+ + 2FAD + 2GDP + 2Pi + 4H2O � 4CO2 + 6 NADH + 4H+ + 2FADH2 + 2GTP + 2CoA

• Overall oxidation: glucose + 2ADP + 2GDP + 4 Pi +8NAD+ + 2FAD + 2H2O � 6CO2 + 2ATP + 2GTP +8NADH + 6H+ + 2FADH2