Chapter 19 & 20

Metabolic pathway & Energy production

Chemistry 20

Metabolism

Chemical reactions in cells that break down or build molecules. It produces energy and provide substances to cell growth.

Catabolic reactions:

Anabolic reactions:

Complex molecules Simple molecules + Energy

Simple molecules + Energy (in cell) Complex molecules

Metabolism in cell

CarbohydratesPolysaccharides

Proteins

Lipids

GlucoseFructose

Galactose

Amino acids

Glycerol

Fatty acids

Step 1: Digestion and hydrolysis

Glucose Pyruvate Acetyl CoACitricAcidcycle

CO2 & H2O

UreaNH4

+

Step 2: Degradationand some oxidation

Step 3: Oxidation to CO2,H2O and energy

e

e

Mitochondria

Cell Structure

Membrane

Nucleus

Cytoplasm

(Cytosol)

Mitochondria

Nucleus: consists the genes that control DNA replication and protein synthesis of the cell.

Cytoplasm: consists all the materials between nucleus and cell membrane.

Cytosol: fluid part of the cytoplasm (electrolytes and enzymes).

Mitochondria: energy producing factories.

Cell Structure

Enzymes in matrix catalyze the oxidation of carbohydrates, fats , and amino acids.

Produce CO2, H2O, and energy.

ATP and Energy

- Adenosine triphosphate (ATP) is produced from the oxidation of food.

- Has a high energy.

- Can be hydrolyzed and produce energy.

-N-glycosidic bondHH

HO

-O-P-O-P-O-P-O-CH2

HO OH

N

N

N

N

NH2

phosphoric anhydrides

phosphoricester

-D-ribofuranose

adenine

O-O- O-

H

O O O

Ribose

3 Phosphates

ATP and Energy

-O-P-O-P-O-AMPO

O--O

OH2O

ATP ADP

-O-P-O-AMP-O

OH2PO4

-+ + + 7.3 kcal/mol

Pi

(adenosine triphosphate) (adenosine diphosphate) (inorganic phosphate)

- We use this energy for muscle contraction, synthesis an enzyme, send nerve signal, and transport of substances across the cell membrane.

- 1-2 million ATP molecules may be hydrolysis in one second (1 gram in our cells).

- When we eat food, catabolic reactions provide energy to recreate ATP.

ADP + Pi + 7.3 kcal/mol ATP

Step 1: Digestion

Carbohydrates Lipids (fat) Proteins

Convert large molecules to smaller ones

that can be absorbed by the body.

Digestion: Carbohydrates

+

+

Polysaccharides

Dextrins

Maltose Glucose

Mouth

Salivaryamylase

Stomach pH = 2 (acidic)

Maltose +Maltase

Glucose Glucose

Lactose +Lactase

Galactose Glucose

Sucrose +Sucrase

Fructose Glucose

Small intestinepH = 8

Dextrins

Bloodstream Liver (convert all to glucose)

α-amylase (pancreas)

Digestion: Lipids (fat)

Intestinal wall

Monoacylglycerols + 2 Fatty acids → Triacylglycerols

Small intestine

Bloodstream

Glycerol + 3 Fatty acids

H2C

HC

H2C

Fatty acid

Fatty acid

Fatty acid

+ 2H2O

H2C

HC

H2C

OH

Fatty acid

OH

+ 2 Fatty acids

lipase(pancreas)

Triacylglycerol Monoacylglycerol

Protein

Lipoproteins

Chylomicrons

Lymphatic system

Cells Enzymes hydrolyzes

liver Glucose

Digestion: Proteins

Intestinal wall

Small intestine

Bloodstream

Cells

Stomach

Pepsinogen Pepsin

Proteins Polypeptides

HCl

Polypeptides Amino acids

TypsinChymotrypsin

denaturation + hydrolysis

hydrolysis

Some important coenzymes

2 H atoms 2H+ + 2e-

oxidation Coenzyme + Substrate Coenzyme(+2H) + Substrate(-2H)

Reduced Oxidized

NAD+

FAD

Coenzyme A

Coenzymes

NAD+

Nicotinamide adenine dinucleotide

HH

H

O

HO OH

N

CNH2

-O-P-O-CH2

O

O

AMP H

O

a -N-glycosidic bond

+

The plus sign on NAD+

represents the positivecharge on this nitrogen

Nicotinamide;derivedfrom niacin

ADP

(vitamin)

Ribose

- Is a oxidizing agent.

- Participates in reactions that produce (C=O) such as oxidation of alcohols to aldehydes and ketones.

NAD+

CH3-CH2-OH + NAD+ CH3-C-H + NADH + H+

NAD+ + 2H+ + 2e- NADH + H+

NAd

CNH2

OH

H+ 2e-

NAd

CNH2

OH H

+ +

NAD+

(oxidized form)NADH

(reduced form)

:+

O

FAD

Flavin adenine dinucleotide

O=P-O-AMP

O-

CH2

C

O

C

C

CH2

N

H OH

OHH

H

N

N

NH3C

H3C O

HO

OH Ribitol

Flavin

Riboflavin

ADP

(Vitamin B2)

(sugar alcohol)

FAD

- Is a oxidizing agent.

- Participates in reaction that produce (C=C) such as dehydrogenation of alkanes.

R-C-C-R + FAD R-C=C-H + FADH2

H H

H H H H

AdN

N

N

NHH3C

H3C O

O

+ 2H+ + 2e-H3C

H3C O

OH

HAdN

N

N

NH

FAD FADH2

Coenzyme A (CoA)

Aminoethanethiol

( vitamin B5)

Coenzyme A

HS-CoA

Coenzyme A (CoA)

CH3-C- + HS-CoA CH3-C-S-CoA

O O

Acetyl group Coenzyme A Acetyl CoA

- It activates acyl groups, particularly the acetyl group.

Metabolism in cell

CarbohydratesPolysaccharides

Proteins

Lipids

GlucoseFructose

Galactose

Amino acids

Glycerol

Fatty acids

Step 1: Digestion and hydrolysis

Glucose Pyruvate Acetyl CoACitricAcidcycle

CO2 & H2O

UreaNH4

+

Step 2: Degradationand some oxidation

Step 3: Oxidation to CO2,H2O and energy

e

e

Mitochondria

Step 2: Glycolysis

- We obtain most of our energy from glucose.

- Glucose is produced when we digest the carbohydrates in our food.

- We do not need oxygen in glycolysis (anaerobic process).

C6H12O6 + 2 NAD+ 2CH3-C-COO- + 2 NADH + 4H+

O

PyruvateGlucose

2 ADP + 2Pi 2 ATP

Inside of cell

Pathways for pyruvate

Aerobic conditions: if we have enough oxygen.

Anaerobic conditions: if we do not have enough oxygen.

- Pyruvate can produce more energy.

Aerobic conditions

- Pyruvate is oxidized and a C atom remove (CO2).

- Acetyl is attached to coenzyme A (CoA).

- Coenzyme NAD+ is required for oxidation.

CH3-C-C-O- + HS-CoA + NAD+ CH3-C-S-CoA + CO2 + NADH

O O

pyruvate Coenzyme A Acetyl CoA

O

Important intermediate productin metabolism.

Anaerobic conditions

- When we exercise, the O2 stored in our muscle cells is used.

- Pyruvate is reduced to lactate.

- Accumulation of lactate causes the muscles to tire and sore.

- Then we breathe rapidly to repay the O2.

- Most lactate is transported to liver to convert back into pyruvate.

CH3-C-C-O- CH3-C-C-O-

O O

pyruvate Lactate

O HO

H

Reduced

NADH + H+ NAD+

Glycogen

- If we get excess glucose (from our diet), glucose convert to glycogen.

- It is stored in muscle and liver.

- We can use it later to convert into glucose and then energy.

- When glycogen stores are full, glucose is converted to triacylglycerols and stored as body fat.

Metabolism in cell

CarbohydratesPolysaccharides

Proteins

Lipids

GlucoseFructose

Galactose

Amino acids

Glycerol

Fatty acids

Step 1: Digestion and hydrolysis

Glucose Pyruvate Acetyl CoACitricAcidcycle

CO2 & H2O

UreaNH4

+

Step 2: Degradationand some oxidation

Step 3: Oxidation to CO2,H2O and energy

e

e

Mitochondria

Step 3: Citric Acid Cycle

- Is a central pathway in metabolism.

- Uses acetyl CoA from the degradation of carbohydrates, lipids, and proteins.

- Two CO2 are given off.

- There are four oxidation steps in the cycle provide H+ and electrons to reduce FAD and NAD+ (FADH2 and NADH).

8 reactions

Reaction 1

Formation of Citrate

CH3-C-S-CoA

O

Acetyl CoA

COO-

C=O

CH2

COO-

Oxaloacetate

COO-

CH2

CH2

COO-

CHO COO-

Citrate

+ CoA-SH

Coenzyme A

+

H2O

Reaction 2

Isomerisation to Isocitrate

COO-

CH2

CH2

COO-

CHO COO-

Citrate Isocitrate

COO-

CH2

C

COO-

CH COO-

HO H

Isomerisation

- Because the tertiary –OH cannot be oxidized. (convert to secondary –OH)

Reaction 3

First oxidative decarboxylation (CO2)

Isocitrate

COO-

CH2

C

COO-

CH COO-

HO H

- Oxidation (-OH converts to C=O).- NAD+ is reduced to NADH.- A carboxylate group (-COO-) is removed (CO2).

C-COO-H

CH-COO-

CH2-COO-

HOIsocitrate

C-COO-H

C-COO-

CH2-COO-

C-HH

C-COO-

CH2-COO-

NADH + H+NAD+

-Ketoglutarate

CO2

isocitratedehydrogenase

O O

Oxalosuccinate

COO-

CH2

C

COO-

CH COO-

O

α-Ketoglutrate

COO-

CH2

C

COO-

CH2

O

CO2

Reaction 4

Second oxidative decarboxylation (CO2)

α-Ketoglutrate

COO-

CH2

C

COO-

CH2

O CH2

C-COO-

CH2-COO-

-Ketoglutarate

O

CoA-SH

NADHNAD+

-ketoglutaratedehydrogenase

complex

CH2

C

CH2-COO-

SCoAOSuccinyl-CoA

+ CO2

Succinyl CoA

COO-

CH2

C

S-CoA

CH2

O + CO2

- Coenzyme A convert to succinyl CoA.- NAD+ is reduced to NADH.- A second carboxylate group (-COO-) is removed (CO2).

Reaction 5

Hydrolysis of Succinyl CoA

Succinyl CoA

COO-

CH2

C

S-CoA

CH2

O

- Energy from hydrolysis of succinyl CoA is used to add a phosphate group (Pi) to GDP (guanosine diphosphate).

- Phosphate group (Pi) add to ADP to produce ATP.

+ H2O + GDP + Pi

COO-

CH2

CH2

COO-

Succinate

+ GTP + CoA-SHFAD FADH2

CH2-COO-

CH2-COO-

Succinate

succinatedehydrogenase

C

CH

H

COO-

-OOC

Fumarate

ADP + Pi ATP

Reaction 6

Dehydrogenation of Succinate

- H is removed from two carbon atoms.- Double bond is produced.- FAD is reduced to FADH2.

COO-

CH2

CH2

COO-

Succinate

FAD FADH2

CH2-COO-

CH2-COO-

Succinate

succinatedehydrogenase

C

CH

H

COO-

-OOC

Fumarate

COO-

CH

CH

COO-

Fumarate

Reaction 7

Hydration

- Water adds to double bond of fumarate to produce malate.

COO-

C

CH2

COO-

HO H

Malate

H2O

COO-

CH

CH

COO-

Fumarate

Reaction 8

Dehydrogenation forms oxaloacetate

- -OH group in malate is oxidized to oxaloacetate.

- Coenzyme NAD+ is reduced to NADH + H+.

COO-

C

CH2

COO-

HO H

Malate

COO-

C=O

CH2

COO-

Oxaloacetate

C-COO-

CH2-COO-

Oxaloacetate

NAD+ NADH

malatedehydrogenase

CH-COO-HO

CH2-COO-

L-Malate

O+ H+

Summary

Pyruvate

-KetoglutarateSuccinyl-CoA

Fumarate

Oxaloacetate

Fatty AcidsProteins

Acetyl-CoA

Carbohydrates

Malate

intermediatesof the citric acid cycle

The catabolism of proteins, carbohydrates, and fatty acids

all feed into the citric acid cycle at one or more points:

Summary

FAD

FADH2

NAD+

NADH

NAD+

NADHCO2

NAD+

NADHCO2

Acetyl-CoA

GDPGTP

Citric acidcycle

(8 steps)

CoA

+ H+

+ H+

H+ +

CoA

CH3C-SCoAO

+ GDP +Pi + 3NAD++ FAD + 2H2O

2CO2 + GTPCoA + 3NADH + FADH2 + 3H++

12 ATP produced from each acetyl-CoA

Electron Transport

H+ and electrons from NADH and FADH2 are carried by an electron carrieruntil they combine with oxygen to form H2O.

FMN (Flavin Mononucleotide)

Fe-S clusters

Coenzyme Q (CoQ)

Cytochrome (cyt)

Electron carriers

FMN (Flavin Mononucleotide)

O=P-O-AMP

O-

CH2

C

O

C

C

CH2

N

H OH

OHH

H

N

N

NH3C

H3C O

HO

OH Ribitol

Flavin

Riboflavin

(Vitamin B2)

(sugar alcohol)

-

2H+ + 2e-

O=P-O-AMP

O-

CH2

C

O

C

C

CH2

N

H OH

OHH

H

N

N

NH3C

H3C O

HO

OH Ribitol

Flavin

Riboflavin

-

H

H

FMN + 2H+ + 2e- → FMNH2

Reduced

Fe-S Clusters

Fe3+

SS

SS

Cys

Cys

Cys

Cys

Fe2+

SS

SS

Cys

Cys

Cys

Cys

+ 1 e-

Fe3+ + 1e- Fe2+

Reduced

Coenzyme Q (CoQ)

OH

OH

2H+ + 2e-

Reduced Coenzyme Q (QH2)Coenzyme Q

Q + 2H+ + 2e- → QH2

Reduced

Cytochromes (cyt)

- They contain an iron ion (Fe3+) in a heme group.

- They accept an electron and reduce to (Fe2+).

- They pass the electron to the next cytochrome and they are oxidized back to Fe3+.

Fe3+ + 1e- Fe2+

ReducedOxidized

cyt b, cyt c1, cyt c, cyt a, cyt a3

Electron Transfer

Mitochondria

Electron Transfer

Complex I

NADH + H+ + FMN → NAD+ + FMNH2

FMNH2 + Q → QH2 + FMN

NADH + H+ + Q → QH2 + NAD+

Complex II

FADH2 + Q → FAD + QH2

Electron Transfer

Complex III

QH2 + 2 cyt b (Fe3+) → Q + 2 cyt b (Fe2+) + 2H+

Complex IV

4H+ + 4e- + O2 → 2H2O

Oxidative Phosphorylation

Transport of electrons produce energy to convert ADP to ATP.

ADP + Pi + energy → ATP

Chemiosmotic model

- H+ make inner mitochondria acidic.- Produces different proton gradient. - H+ pass through ATP synthase (a protein complex).

ATP synthase

Total ATP

Glycolysis: 6 ATP

Pyruvate: 6 ATP

Citric acid cycle: 24 ATP

36 ATPOxidation of glucose

C6H12O6 + 6O2 + 36 ADP + 36 Pi → 6CO2 + 6H2O + 36 ATP

Metabolism in cell

CarbohydratesPolysaccharides

Proteins

Lipids

GlucoseFructose

Galactose

Amino acids

Glycerol

Fatty acids

Step 1: Digestion and hydrolysis

Glucose Pyruvate Acetyl CoACitricAcidcycle

CO2 & H2O

UreaNH4

+

Step 2: Degradationand some oxidation

Step 3: Oxidation to CO2,H2O and energy

e

e

Mitochondria

Oxidation of fatty acids

CH3-(CH2)14-CH2-CH2-C-OH

O α

oxidation

- Oxidation happens in step 2 and 3.

- Each beta oxidation produces acetyl CoA and a shorter fatty acid.

- Oxidation continues until fatty acid is completely break down to acytel CoA.

Oxidation of fatty acids

Fatty acid activation

- Before oxidation, they activate in cytosol.

R-CH2-C-OH

O

+ ATP + HS-CoA R-CH2-C-S-CoA

O

+ H2O + AMP + 2Pi

Fatty acyl CoAFatty acid

-Oxidation: 4 reactions

Reaction 1: Oxidation (dehydrogenation)

R-CH2-C-C-C-S-CoA

O

Fatty acyl CoA

H H

H H

+ FAD R-CH2-C=C-C-S-CoA + FADH2

OH

H

Reaction 2: Hydration

R-CH2-C=C-C-S-CoA + H2O

OH

H

R-CH2-C-C-C-S-CoA

O

H H

HHO

Reaction 3: Oxidation (dehydrogenation)

Reaction 4: Cleavage of Acetyl CoA

R-CH2-C-C-C-S-CoA + NAD+

O

H H

HHO

R-CH2-C-CH2-C-S-CoA + NADH+ H+

OO

R-CH2-C-CH2-C-S-CoA + CoA-SH

OO

R-CH2-C-S-CoA

O

CH3-C-S-CoA

O

+

Acetyl CoAFatty acyl CoA

Oxidation of fatty acids

One cycle of -oxidation

R-CH2-CH2-C-S-CoA + NAD+ + FAD + H2O + CoA-SH

O

R-C-S-CoA

O

CH3-C-S-CoA + NADH + H+ + FADH2

O

+

Acetyl CoAFatty acyl CoA

# of Acetyl CoA =# of fatty acid carbon

2= 1 + oxidation cycles

Ketone bodies

- If carbohydrates are not available to produce energy.

- Body breaks down body fat to fatty acids and then Acetyl CoA.

- Acetyl CoA combine together to produce ketone bodies.

- They are produced in liver.

- They are transported to cells (heart, brain, or muscle).

CH3-C-S-CoA

O

Acetyl CoA

CH3-C-S-CoA

OCH3-C-CH2-C-O-

O O CH3-C-CH3 + CO2 + energy

O

Acetoacetate

Acetone

-Hydroxybutyrate

CH3-CH-CH2-C-O-

OH O

Ketosis (disease)

- When ketone bodies accumulate and they cannot be metabolized.

- Found in diabetes and in high diet in fat and low in carbohydrates.

- They can lower the blood pH (acidosis).

- Blood cannot carry oxygen and cause breathing difficulties.

Fatty acid synthesis

- When glycogen store is full (no more energy need).

- Excess acetyl CoA convert to 16-C fatty acid (palmitic acid) in cytosol.

- New fatty acids are attached to glycerol to make triacylglycerols. (are stored as body fat)

Metabolism in cell

CarbohydratesPolysaccharides

Proteins

Lipids

GlucoseFructose

Galactose

Amino acids

Glycerol

Fatty acids

Step 1: Digestion and hydrolysis

Glucose Pyruvate Acetyl CoACitricAcidcycle

CO2 & H2O

UreaNH4

+

Step 2: Degradationand some oxidation

Step 3: Oxidation to CO2,H2O and energy

e

e

Mitochondria

Degradation of amino acids

- They are degraded in liver.

Transamination:

- They react with α-keto acids and produce a new amino acid and a new α-keto acid.

-OOC-C-CH2-CH2-COO-

O

alanine

CH3-CH-COO-

NH3

+

+

α-ketoglutarate

-OOC-CH-CH2-CH2-COO-

O

pyruvate

CH3-C-COO-

NH3

+

+

glutamate

Degradation of amino acids

Oxidative Deamination

-OOC-CH-CH2-CH2-COO-

NH3

+

glutamate

+ H2O + NAD+

-OOC-C-CH2-CH2-COO-

O

α-ketoglutarate

glutamatedehydrogenase

+ NH4+ + NADH + H+

Urea cycle

- Ammonium ion (NH4+) is highly toxic.

- Combines with CO2 to produce urea (excreted in urine).

- If urea is not properly excreted, BUN (Blood Urea Nitrogen) level in blood becomes high and it build up a toxic level (renal disease).

- Protein intake must be reduced and hemodialysis may be needed.

H2N-C-NH2 + 2H+ + H2O

O

urea

2NH4+ + CO2

Energy from amino acids

- C from transamination are used as intermediates of the citric acid cycle.

- amino acid with 3C: pyruvate- amino acid with 4C: oxaloacetate- amino acid with 5C: α-ketoglutarate

- 10% of our energy comes from amino acids.

- But, if carbohydrates and fat stores are finished, we take energy from them.