1 Metabolism

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to Level 1 BiochemistryDr Brian Green

School of Biological Sciences
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Recommended text

McKee & McKeeBiochemistry

Chapters: 1 & 16

Ch 16 available through QoL

2
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Control and integration of metabolism

Lectures:

1. Basic principles and regulators of

metabolism2. Hormones and the Endocrine System

3. How can hormone signalling be exploited

in the real world? Insulin and diabetesmellitus

4. The Nervous System

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Basic principles of metabolism

What is metabolism?

Biochemical pathways & how are they

controlled Organs: dividing up the tasks

Hormones controlling metabolism

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Metabolism

The first controlled experiments in human

metabolism were published by Santorio

Santorio in 1614 in his book Ars de statica

medecina that made him famous throughout

Europe. He describes his long series ofexperiments in which he weighed himself in a

chair suspended from a steelyard balance (see

image), before and after eating, sleeping,

working, sex, fasting, drinking and excreting.

He found that by far the greatest part of the

food he took in was lost from the body through

perspiratio insensibilis (insensible

perspiration).


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Whats it all for???

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3 4


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What is metabolism needed for?

1. Acquisition and utilisation of ENERGY

2. SYNTHESIS of molecules needed for cell

structure and function

3. GROWTH and development

4. REMOVAL of waste products


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Integration of Metabolism

Vast number of chemical reactions and

processes occurring simultaneously in cells

and organisms. Cells/organisms have to deliver the right

metabolites, in the right place, at the right

amounts, at the right time..... ....and at the minimum cost in energetic

terms.

10= highly organised complexity


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Factors influencing/regulating metabolism?

Temperature

Enzyme activity

Actions of hormones and other signalling

molecules

Nervous system

Amount of free energy available

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Biochemical pathways

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Metabolic cycle

Reactants/precursors Enzymes End products

Common intermediates Branching point

Metabolites


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Initial substrates for the metabolic pathway

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Reactants/precursors

Enzymes

Catalyse the individual steps in a metabolic

pathway. These enzymes are highlyspecific, the first in a metabolic pathway is

often subject to allosteric control by an end

product.


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Compounds which occur at cross-over or

branching points in metabolic pathways

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Point at which an intermediate may proceed

down one of several alternative pathways,depending on the cells needs. Pathways can

be selected by altering activity of the

enzymes at a branching point.

Common intermediates

Branching point


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Compounds involved in metabolic

pathways; often they are intermediates

between reactants and end products.

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Metabolic hubs which allow the use and re-

use of relatively small numbers of

molecules in the acceptance of products of

one metabolic pathway. E.g. Krebs (TCA)

cycle, urea cycle.

Metabolic Cycles

Metabolites


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+

E

Controlling enzyme activity


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E

Controlling enzyme activity

-

+

Compounds fromother pathways+

Substrate+

Activation

-+

TranscriptionTranslocationP.T Modification-egradation

-+

CompartmentalisationOf E & S-

Inhibition

-

End-product

-

+


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Negative feedback

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Example:

Excessive amounts of product E build up

E binds to the enzyme X that catalyses the reaction between A &B.

The binding of E changes the shape of the enzyme. This closes the active site of the enzyme.

No more reactions can take place and the pathway is halted.

x

This is allostery process is known as allosteric inhibition.


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Flux through a pathway usually determined

by a rate limiting step.

Rate limiting steps often occur at branchingpoints.

After a branching point a compound usually

has several possible fates.

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Metabolic Regulation


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Metabolic Regulation

- Sequential feedback inhibition

XX XM1 M2 M3 M4

M5

P1

P2

E1 E2 E4

E3

The common steps are inhibited by the product before the branch,

and the first enzyme of each branch is inhibited by the branch

product.

High levels ofP1 and P2 inhibit enzymes E3 and E4,

respectively M3 will accumulate the pathway is

inactivated if both P1 and P2 are high.


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Negative feedbacksystems are the

primary homeostatic mechanisms.

If a desired value, the set point, isdeviated from, compensatory action

begins.

The set zone refers to the range oftolerance in a system.


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Positive feedback

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Example:

Excessive amounts of product E build up

E binds to the enzyme X that catalyses the reaction between A &B.

The binding of E changes the shape of the enzyme. This INCREASES the activity the enzyme.

More reactions can take place and more E and F are produced

x

This is allostery process is known as allosteric stimulation.


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+

P+

INACTIVEACTIVE

Modifications to enzymes can activate/inactivate

e.g. phosphorylation


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Enzyme cascade

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Primary messenger (hormone)

Second messenger

Enzyme 1 (I) Enzyme 1 (A)

E2 (I)

E2 (A)

E5 (I)

E5 (A)E3 (I)

E3 (A)

E4 (I)

E4 (A)

Activates multiple targets

Activates multiple targets

Signal amplification

Catalytic amplification


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Amplified enzyme cascade

Powerful mechanism to amplify and

diversify the action of a hormone.

Uses second messengers such as cyclicAMP to amplify and transduce the message.

In the cascade multiple enzymes are

switched on (activated). Occurs by enzymesundergoing conformational change.

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Metabolism

As nutrient molecules are degraded

(catabolised) into smaller, simpler

molecules ENERGY (ATP) and REDUCINGPOWER (e.g. NADH) are produced

Nutrients are converted

to waste products

such as CO2 and water


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Energy

Energy is defined as the capacity to do work. Living organisms generate most of their energy by

using redox reactions.

In these reactions electrons are often removed or addedas hydrogen atoms (H)

NAD+ (nicotinamide ring shown)

N

C

O

NH2

+ H:-

H

+

R

NADH

N

C

O

NH2

HH

RR = adenine dinucleotide


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Energy

NAD+, FAD+,NADP+ NADH, FADH2,NADPH

The more reduced a molecule (i.e. the more Hatoms it contains) the more energy it contains

Per molecule FAs contain more H atoms thansugars -this is the reason why oxidation of FAsyields more energy than sugars

1g of fat = 9 Kcal : 1g of CHO = 4 Kcal

+ H


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Energy: ATP (p101, McKee)

Hydrolysis of adenosine triposphate (ATP)

immediately and directly provides free

energy for a huge number of biochemicalreactions

e.g. biosynthesis of molecules, active

transport of substances across membranes,mechanical work.

macromolecules


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e.g. digestion e.g. growth, storage, biosynthesis

small molecules


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Metabolism

Anabolicbuilding up (synthesis)

Catabolicbreaking down (degradation)

Amphibolic- involves both anabolic and catabolicprocesses

Organisms must strike a balance between

anabolic and catabolic processes

Hormones are messengers which communicate

most of the information needed to sustain

biological processes


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Metabolism

How does the bodymanage the synthesis

degradation and

interconversion of

biomolecules?

How do all these processes

work in terms of

catabolism and

anabolism?


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Organs

Each human organ performs several roles

and contributes to the bodys overall

function Some heavy consumers of energy to

perform intense tasks (e.g. Muscle, Liver).

Some responsible for supplying energy-richnutrients (e.g. Small intestine, hepatic portal

vein).

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Organs

Using p534-6 in McKee examine:

Small intestine

Liver

Muscle

Adipose tissue

BrainKidney

Give one reason for each being so IMPORTANT

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1 Metabolism