Presentation Metabo

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Metabolism


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Series of chemical reactions Require a set enzymes that carry out different

functions

Each molecule along its path differs from any

other molecule in the pathway. Each substrate transforms into a product that

serves as as substrate for another enzymereaction until a final product (the end product)

is generated. Usually run in one direction.


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Diagnosis of pathogenic microbes

Determination of a diseased state

Identification of targets for drugs and vaccines Toxicogenomics, Pharmacokinetics

Fundamental biology (e.g. How do we storeinformation in our brains?)

Pathways may serve as a tool to trace evolution(Evolution of pathways Evolution oforganisms)


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AC D E F

BC D X F

C D X Y F

C D F

C

D

X

G

F

Suggested reading:Heymans and Singh (2002). Deriving phylogenetic trees from the similarity analysis of metabolic patPDF-file available on the web.


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mouse

house

horse

substrate

product/substrate

(end)product

m-h

u-r

Enzyme # 2

Enzyme # 1


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Anabolic pathways

Catabolic pathways


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Catabolic pathways degrade complexmolecules to smaller molecules. Thesepathways generally produce life sustaining

energy in the form of ATP and heat.

SP1 P2

ADP ATP NAD NADH + H+


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Overview of catabolism

Complex metabolites are broken down

into their monomeric units

Then to the common intermediate, acetyl-

CoA

The acetyl group is then oxidized to CO2

via the citric acid cycle while NAD+ and

FAD are reduced to NADH and FADH2.

Reoxidation of NADH and FADH2 by O2during oxidative phosphorylation yields

H2O and ATP


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Anabolic pathways

Anabolic pathways use chemical energy inform of ATP and NADH or NADPH to

synthesize cellular components from simpleprecursor molecules.

EPP2S

ATP ADP NADH + H+ NAD


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Autotrophs

self-feeders (synthesize their owncellular constituents from H2O, CO2, NH3, and H2S)

Photoautotrophs - acquire free energy from sunlight

Chemolithotrophs

obtain free energy fromoxidation of inorganic compounds such as NH3, H2S,or Fe2+.

Heterotrophs

oxidize organic compounds to make

ATP

ATP is the energy carrier for most biological

reactions

How do living things acquire the energyneeded for these functions?


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Organisms can be classified by the

identity of the oxidizing agent.

Obligate aerobes: must use O2

Anaerobes: use sulfate or nitrate

Facultative anaerobes: can grow in

presence or absence of O2 (e.g. E. coli)

Obligate anaerobes: poisoned by O2


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Metabolic pathwaysare series ofconnected enzymatic

reactions thatproduce specificproducts.

Their reactants, inter-mediates, andproducts are calledmetabolites.

There are over 2000known metabolicreactions see figure

to the left.


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Hierarchical Nature ofMetabolism

Fourclasses ofmacromolecules (proteins,nucleic acids, carbohydrates,

and lipids)

Six primary metabolitegroups (amino acids,nucleotides, fatty acids,

glucose, pyruvate, acetyl CoA)

Seven small biomolecules(NH4

+, CO2, NADH, FADH2,

O2, ATP, H2O)


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The six major groups of

pathways can be

subdivided into thoseresponsible for energy

conversion, and those

involved in the synthesis

and degradation ofmacromolecules.

Moreover, the major

groups themselvesconsist of several

metabolic modules, all of

which will be examined

individually.


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1. What does glycolysis accomplish for the cell?

Generates a small amount of ATP which iscritical under anaerobic conditions.

Generates pyruvate, a precursor to acetylCoA, lactate, and ethanol (in yeast).

2. What is the overall net reaction of glycolysis?

Glucose + 2NAD+ + 2ADP + 2 Pi 2 pyruvate + 2NADH + 2H+ + 2ATP + 2H2O

G = -35.5 kJ/mol


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3. What are the key regulated enzymes inglycolysis?Hexokinase, Phosphofructokinase 1, Pyruvatekinase

4. What are examples of glycolysis in real life?Glycolysis is the sole source of ATP underanaerobic conditions which can occur in animal

muscle tissue during intense exercise.Fermentation also relies on glycolysis which is aprocess that is used to make alcoholic beverageswhen yeast cells are provided glucose without

oxygen.


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Glycolysis is a central

pathway that takes glucose

generated by carbohydrate

metabolism and converts it to

pyruvate. Under aerobicconditions, the pyruvate is

oxidized in the citrate cycle

which generates reducing

power for redox reactions inthe electron transport system

that result in ATP production

by oxidative phosphorylation.


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In glycolysis (from the Greekglykys, meaningsweet,and lysis, meaning splitting), a molecule of

glucose is degraded in a series of enzyme-catalyzedreactions to yield two molecules of the three-carboncompound pyruvate.

During the sequential reactions of glycolysis, some ofthe free energy released from glucose is conserved inthe form of ATP and NADH.

Glycolysis was the first metabolic pathway to beelucidated and is probably the best understood.


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Eduard Buchners discovery in 1897 of fermentationin broken extracts of yeast cells until the elucidation

of the whole pathway in yeast (by Otto Warburg andHans von Euler-Chelpin) and in muscle (by GustavEmbden and Otto Meyerhof) in the 1930s, thereactions of glycolysis in extracts of yeast and muscle

were a major focus of biochemical research.


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By 1940 all of the reactions of the glycolysis

pathway were known from the research of

Embden, Meyerhof, Parnas and Warburg.

Glycolysis is sometimes known as the

Embden-Meyerhof pathway in the older

textbooks.


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Glycolytic Pathway


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The two stages of glycolysis

The ATP investment stage

generates the high energyintermediate glyceraldehyde-3-P

(GAP) which is then oxidized to

produce NADH and 1,3-

bisphosphoglycerate. The nextfour reactions lead to the

production of FOUR total ATP

because each glucose molecule

results in the production of TWOpyruvate. The net yieldof ATPin glycolysis is therefore TWOATP.


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Investment of 2 ATP

Production of 2

Glyceraldehyde-3-P

(GAP)

The two highlyregulated steps are

hexokinase and

phosphofructokinase 1

(both respond directly

or indirectly to energy

charge).

Stage 1


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Each molecule of GAP

Reducing power is

captured in the formof NADH; this is a

critical step.

Phosphoglycerate

kinase and pyruvate

kinase catalyze a

substrate level

phosphorylation

reaction yielding 4

ATP (2 net ATP).

The two pyruvate

molecules are

further metabolized.

Stage 2


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The six carbons and six

oxygens present in glucose

are stoichiometrically

conserved by glycolysis inthe two molecules of

pyruvate that are produced.

Hydrogen atoms in glucose

are lost as H2O molecules

and in the reduction of

NAD+.

No loss of carbons or

oxygen in glycolysis


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Oxidation of

glucose Products:

2 Pyruvate

2 ATP

2 NADH

Cytosolic


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Provide ATP energy

Generate intermediates for other pathways

Hexose monophosphate pathway Glycogen synthesis

Pyruvate dehydrogenase Fatty acid synthesis

Krebs Cycle

Glycerol-phosphate (TG synthesis)


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Glycolysis is an almost universal central pathwayof glucose catabolism, the pathway with the

largest flux of carbon in most cells. The glycolyticbreakdown of glucose is the sole source ofmetabolic energy in some mammalian tissues and

cell types (erythrocytes, renal medulla, brain, andsperm, for example). Some plant tissuesthat are modified to store starch (such as potato

tubers) and some aquatic plants (watercress, forexample) derive most of their energy fromglycolysis; many anaerobic microorganisms areentirely dependent on glycolysis.


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T ti d t t


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Ten reactions and two stages:

Stage1:Glucose is

phosphorylated and cleaved to

form two molecules of

glyceralbehyde-3-phosphate.Thetwo ATP molecules consumed.

Stage2: Glycerahyde-3-

phosphate is converted to

pyruvate. Four ATP molecules

and two NADH are produced.

Total reactions:

D-Glucose+2ADP+2Pi+2NAD+

2pyryvate+2ATP+2NADH+2H+

+2H2O

Key notes:

Fates of pyruvate, energy field,

Metabolism of fructose or

galactose,regulation of glycolysis


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In aerobic respiration:

Pyruvate+NAD++CoA=acetylCoA+CO2+NADH

In anaerobic organism :Pyruvate+NADH+H+=lactate+NAD+

G=-25.1 kJ/mol

In alcoholic fermentation:

Pyruvate+ H+=acetaldehyde+CO2

Acetadehyde+NADH+H+=ethanol+NAD+


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Oxidation of Pyruvate to

Acetyl-CoA

The Pyruvate Dehydrogenase

Complex

-- huge

-- highly regulated

Activators:

ADP, NAD, CoA

Inhibitors:

ATP, NADH, acCoA


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Hierarchical Nature ofMetabolism

Fourclasses of

macromolecules (proteins,nucleic acids, carbohydrates,

and lipids)

Six primary metabolitegroups (amino acids,nucleotides, fatty acids,

glucose, pyruvate, acetyl

CoA)

Seven small biomolecules

(NH4+

, CO2, NADH, FADH2,O2, ATP, H2O)

Krebs Cycle


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Krebs Cycle

Reactions Citrate In aSentence Should Form More Oxaloacetate

CIASSFMO


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How does fermentation allow

cells to produce ATP in the

absence of oxygen?

-- detoxifying of pyruvate

-- regeneration of NAD

What happens to the lactate?

Cori-cycle (a little physiology)

Lactic Acidosis

Using NADH to make ATP


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Electron transport and oxidative

phosphorylation

From glucose

Glycolysis ATP yield

____ NADH x ____ ATP _______

____ ATP _______

Transition Rx

____ NADH x ____ ATP x 2 pyr _______Krebs cycle

____ NADH x ____ ATP x 2 pyr _______

____ FADH x ____ ATP x 2 pyr _______

____ GTP x ____ ATP x 2 pyr _______

Total 30

From a 12 carbon fatty acid

B-oxidation ATP yi

____ FADH x ____ ATP x 6 acCoA

____ NADH x ____ ATP x 6 acCoA

Krebs cycle

____ NADH x ____ ATP x 6 acCoA

____ FADH x ____ ATP x 6 acCoA

____ GTP x ____ ATP x 6 acCoA

Total 84

You should be able to complete a table to calculate energy yields from glucose or fatty acids (of any given

length)

-- assuming 2.5 ATP per NADH (1.5 per glycolytic NADH) and 1.5 ATP per FADH


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What are the biosynthetic roles

Of these pathways?


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eat teaseat

at

eating

rearrangement

condensation

transferdeletion

east insertion

ing

s

shihis

t

st


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Metabolic pathways are highly interdependent and

exquisitely controlled by substrate availability and enzymeactivity levels.

Key to understanding metabolic integration in terms ofnutrition, exercise, and disease (e.g., diabetes and obesity) is

learning how metabolic flux between pathways is regulatedand controlled.

1.Anaerobic and aerobic respiration2.Photosynthesis and carbon fixation

3.Carbohydrate metabolism

4.Lipid metabolism

5.Amino acid metabolism6.Nucleotide metabolism


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Should WE memorize this chart?


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1. What does the pathway accomplish for thecell?

2. What is the overall net reaction of thepathway?

3. What are the key regulated enzymes in thepathway?

4. What are examples of this pathway in reallife?

Glucose occupies a central position in the


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Glucose occupies a central position in themetabolism of plants, animals, and manymicroorganisms. It is relatively rich in potential

energy, and thus a good fuel; the completeoxidation of glucose to carbon dioxide and waterproceeds with a standard free-energy change of

2,840 kJ/mol. By storing glucose as a highmolecular weight polymer such as starch orglycogen, a cell can stockpile large quantities ofhexose units while maintaining a relatively low

cytosolic osmolarity. When energy demandsincrease, glucose can be released from theseintracellular storage polymers and used to produce

ATP either aerobically or anaerobically.


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The breakdown of the six-carbon glucose into two

molecules of the three-carbon pyruvate occurs in tensteps, the first five of which constitute thepreparatory

phase (See Fig.). In these reactions, glucose is firstphosphorylated at the hydroxyl group on C-6 (step 1 ).

The D-glucose 6-phosphate thus formed is converted toD-fructose 6-phosphate (step 2 ), which is againphosphorylated, this time at C-1, to yield D-fructose 1,6-bisphosphate (step 3 ). For both phosphorylations, ATPis the phosphoryl group donor. As all sugar derivativesin glycolysis are the D isomers, we will usually omit theD designation except when emphasizing

stereochemistry.


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Organisms that do not have access to glucosefrom other sources must make it.Photosynthetic organisms make glucose by firstreducing atmospheric CO2 to trioses, thenconverting the trioses to glucose.

Nonphotosynthetic cells make glucose fromsimpler three and four-carbon precursors by the

process of gluconeogenesis, effectivelyreversing glycolysis in a pathway that usesmany of the glycolytic enzymes.


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