BIOCHEMISTRY

Christian Osae Obirikorang, (PhD)

Department of Molecular Medicine

SMS, KNUST, Kumasi

Ground RULES

• Everyone is punctual- Everyone should try and attend lectures on time.

• Switch the phone to silent mode. No answering of phone calls in class.

• Show mutual respect and listen

• Avoid distraction

• Offer feedback

• Submit assignments on time. (Avoid plagiarism)

Ground RULES

• There is a STRONG correlation between attendance and pass rate.

• Please bring something to write with.

• Expect interactions

• Listen carefully and speak fearlessly.

INTRODUCTORY BIOCHEMISTRY

• This course is designed to help studentsunderstand basic concepts, techniques andapplications of Biochemistry in Medicine.

• This course introduces and overviews indepth molecular structure in the cell,biological oxidations, selected biosyntheticpathways.

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BIOCHEMISTRY

• sometimes called biological chemistry, is the study of chemical processes within, and relating to, living organisms.

• Biochemistry has become so successful at explaining living processes in almost all areas of the life sciences.

• Much of biochemistry deals with the structures, functions and interactions of biological macromolecules, such as proteins nucleic acid, carbohydrates and lipids

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Why Biochemistry??

• Chemicals are responsible for directing virtually all of our body functions

• Basic reactions occur in the body to maintain homeostasis

• Basic concepts in biochemistry contribute to this homeostasis.

BIOCHEMISTRY

• Basically biochemistry is the study of the chemistry of life!!!!.

• The mechanisms by which cells harness energy from their environment via chemical reactions are known as metabolism.

• The four main classes of molecules in biochemistry: carbohydrates, lipids, protein and nucleic acids.

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CARBOHYDRATES

• Carbohydrates are made from monomers called monosaccharides e.g. fructose and glucose.

• Two monosaccharides can be joined together to for a disaccharide. E.g.sucrose – glucose and fructose. Lactose- galactose and glucose

• When a few (around three to six) monosaccharides are joined together, it is called anoligosaccharide

• Many monosaccharides joined together make a polysaccharide. E.g. cellulose and glycogen

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PROTEINS• Proteins are very large molecules – macro-

biopolymers – made from monomers called amino acids. E.g. glycine and cysteine.

• When amino acids combine, they form a special bond called a peptide bond to become a protein

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Proteins• Many proteins are the enzymes that catalyze the

chemical reactions in metabolism.

• Other proteins have structural or mechanical functions, such as the proteins that form the cytoskeleton, a system of scaffolding that maintains the cell shape.

• Proteins are also important in cell signaling, immune responses, cell adhesion, active transport across membranes, and the cell cycle.

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PROTEIN STRUCTURE

• Primary structure: the amino acid sequence. A protein is a polyamide.

• Secondary structure: regularly repeating local structures stabilized by hydrogen bonds.

• Tertiary structure: the overall shape of a single protein molecule

• Quaternary structure: refers to the number and arrangement of the protein subunits with respect to one another. E.g. haemoglobin, DNA

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PROTEIN STRUCTURE

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Lipids• Are the most diverse group of metabolites.

• Their main structural uses are as part of biological membranes such as the cell membrane, or as a source of energy.

• are usually defined as hydrophobic or amphipathic biological molecules that will dissolve in organic solvents such as benzene or chloroform.

• The fats are a large group of compounds that contain fatty acids and glycerol; a glycerol molecule attached to three fatty acid esters is a triacylglyceride

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Metabolites

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Type of molecule Name of Monomer forms Name of Polymer forms Examples of polymer

forms

Protein Amino acids Proteins (polypeptides)Fibrous

proteins and globular proteins

Carbohydrates Monosaccharides PolysaccharidesStarch, glycogen and

cellulose

Nucleic acids Nucleotides Polynucleotides DNA and RNA

COURSE OUTLINE• Enzymes and Inhibition

• Basic concept and design of metabolism

• Glycolysis

• Metabolism of Fructose and Fructosuria

• Metabolism of Galatose and Galatosuria

• Gluconeogenesis

COURSE OUTLINE• TCA cycle

• Glyoxylate cycle

• Pentose phosphate Pathway

• Glycogenesis

• Glycogenolysis

• Electron Transport Chain

• Inhibition of oxidative Phosphorylation

• Beta-Oxidation of Fatty acids

RECOMMENDED BOOKS

• Biochemistry 7th Edition Author: Jeremy M. Berg, John Tymoczko, LubertStryer Publisher: W.H Freeman

• Lehninger Principles of Biochemistry 6th Edition November 21, 2012 Author: David L Nelson and Michael M Cox Publisher: W, H. Freeman

• Biochemistry (Lippincott illustrated Review Series) 6th Edition May 24, 2013 Author: Denise R. Ferrier Publisher: Lippincott Williams & Wilkins

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Basic Concept & Design of Metabolism

Christian Obirikorang, (PhD)

Metabolism

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Metabolism

• Metabolism is the entire network of chemical reactions carried out by living cells that sustain life.

• The sum of the chemical changes that convert nutrients into energy and the chemically complex products of cells.

• Hundreds of enzyme reactions organized into discrete pathways.

• Substrates are transformed to products via many specific intermediates

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Metabolism • These enzyme-catalyzed reactions allow organisms

to grow and reproduce, maintain their structures,and respond to their environments.

• Enzymes are crucial to metabolism because theyallow organisms to drive desirable reactions thatrequire energy and will not occur by themselves.

• The speed of metabolism, the metabolic rate,influences how much food an organism will require.

• A striking feature of metabolism is the similarity ofthe basic metabolic pathways and componentsbetween even vastly different species.

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Metabolism

• Metabolites are the small molecules that are intermediates in the degradation or biosynthesis of biopolymer.

• Metabolic design is a natural phenomenon employed by many professions for efficiency; GOD himself is a designer.

• Metabolism in its entirety is designed to sustain life

➢highly co-ordinated➢strictly regulated

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Metabolism

• Substrates are transformed to products via many specific intermediates.

• Metabolic maps portray the reactions

• Metabolism consists of catabolism and anabolism

• Catabolism: degradative pathways- Usually energy-yielding!

• Anabolism: biosynthetic pathways- Energy-requiring!27C. OBIRIKORANG

Catabolism

• is the set of metabolic pathways that break down molecules into smaller units and release energy.

• In catabolism, large molecules are broken down to smaller units– Polysaccharides to monosaccharides

– Lipids to fatty acids

– Nucleic acids to nucleotides

– Proteins to amino acids28C. OBIRIKORANG

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Anabolism • is the set of metabolic pathways that

construct molecules from smaller units.

• These reactions require energy.

• Anabolism is powered by catabolism

• Many anabolic processes are powered by adenosine triphosphate (ATP).

• Anabolic processes tend toward "building up" organs and tissues

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KEY POINTS

• Metabolism is essentially a series of chemical reactions that provides energy transformations: Energy is being extracted from fuels (nutrients) and used to power biosynthetic processes.

• Catabolism (catabolic reactions) converts chemical energy by decomposing foodstuffs into biologically useful forms.

• Anabolism (anabolic reactions) requires energy –useful forms of energy are employed to generate complex structures from simple ones, or energy-rich states from energy-poor ones.C. OBIRIKORANG 35

A Common Set of Pathways

• Organisms show a marked similarity in their major metabolic pathways.

• Evidence that all life descended from a common ancestral form.

• There is also significant diversity.

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A Common Set of Pathways

• Despite existing extraordinary diversity,

the biochemistry of living cells is similar

• More than 10 million species living on earth, having specialization of cell types or tissues

• Similar chemical composition, structure of cellular components

• Similar metabolic routes37C. OBIRIKORANG

Organisms demonstrate the following common themes:

• Maintain specific internal concentration of ions, metabolites, and enzymes.

• Cell membranes provide the physical barrier that segregates cell components from the environment

• Extract energy from external sources to drive energy-consuming reactions

• Metabolic pathways are specified by the genes in each organism

• Organisms and cells interact with their environment.

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Organization in Pathways

• Pathways consist of sequential steps.

• The enzymes may be separate.

• Or may form a multienzyme complex

• Or may be a membrane-bound system

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Multi-enzyme complex

Separateenzymes

Membrane Bound System

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Organization in Pathways

Three forms of metabolic pathway:• A linear metabolic pathway

the upstream product is the substrate for the next reaction. Such as the biosynthesis of serine

• A cyclic metabolic pathwaySuch as the citric acid cycle, forms a closed loop. The intermediate are regenerated with every turn

• A spiral metabolic pathwaySuch as the biosynthesis of fatty acids. The same set of enzymes is used repeatedly for lengthening the chain

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Organization of Pathways

Linear(product of rxns are

substrates for subsequent rxns)

Closed Loop(intermediates recycled)

Spiral(same set of enzymes used

repeatedly)

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METABOLISM PROCEEDS IN DISCRETE STEPS

•Enzyme specificity defines biosynthetic route

•Controls energy input and output

•Allow for the establishment of control points.

•Allows for interaction between pathways

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REGULATION OF METABOLIC PATHWAYS

• Pathways are regulated to allow the organism to respond to changing conditions.

• Most regulatory response occur in millisecond time frames.

• Most metabolic pathways are irreversible under physiological conditions.

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Common mechanisms

• feedback inhibition – product of pathway down regulates activity of early step in pathway

• Feed forward activation – metabolite produced early in pathway activates down stream enzyme

Enzyme Regulation of Flux

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METABOLIC PATHWAYS ARE NOT AT EQUILIBRIUM

• Metabolic pathways are not at equilibrium: A B

• Instead pathways are at steady state A B C

• The rate of formation of B = rate of utilization of B.

• Maintains concentration of B at constant level.

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GIBBS FREE ENERGY

• The maximal amount of useful energy that can be gained in the reaction (at constant temperature and pressure).

• Net driving force in a reaction

• Relates to entropy change (ΔS), enthalpy change (ΔH) and temperature (T) as

ΔG = ΔH – TΔS

• Predicts the direction in which a reaction will spontaneously proceed

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PREDICTING SPONTANEITY OF REACTIONS

• If ΔG is negative and large, reaction is

i. Exergonic or exothermic

ii. Spontaneous

iii. Proceed in forward direction

• If ΔG is positive and large, reaction is

i. Endergonic or endothermic

ii. Not spontaneous

iii. Proceeds in the reverse direction

• If ΔG is zero, reaction is

i. In equilibrium

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ENERGY CURRENCY• Energy currencies are activated species which have high

energy bonds and for that reason release large amount of energy on hydrolysis.

• The high energy bonds in energy currencies are as a result of the following factors:

a) The less resonance stabilization of phosphoanhydride bonds

b) High electrostatic repulsion between the charged groups

c) The energy released on hydrolysis of the phosphoanhydride bond in energy currencies is used to drive biological processes

• Thus, hydrolysis of ATP yields ADP , P₁ and energy , where the energy released is used to drive a biological reaction by phosphorylating a substrate.

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Christian Obirikorang, (PhD)Department of Molecular Medicine

SMS, KNUST, Kumasi

Course outline

• Introduction to enzymes

• Characteristics of enzymes

• Name of enzymes

• Structure of enzymes

• Classes of enzymes

• Enzyme specificity

• Biological function of enzymes

• Mechanism of enzymes 57C. Obirikorang

Course outline

• Lock and Key model

• Induced fit

• Cofactor

• Active site

• Factors affecting reaction rate

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Enzymes

• Enzymes are proteins and certain class of RNA(ribozymes) which enhance the rate of a thermodynamically feasible reaction and are not permanently altered in the process.

• Most enzymes have tertiary and quaternarystructures

• Catalysts for biological reactions.

• Does not effect equilibrium

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Enzymes

• Remains unchanged in overall process.

• Reactants bind to enzymes, products are released.

• Activity lost if denatured.

• May contain cofactors such as metal ions or organic (vitamins)

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Enzymes• Are specific for

what they will catalyze

• Are Reusable

• End in –ase-Sucrase-Lactase-Maltase

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Characteristics of Enzymes

• Accelerate the rate of making and breaking of covalent catalysis.

• Highly specific: React with one substrate

• Not changed in the reaction.

• Catalyze many cycles (turnovers) of the reaction.

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Characteristics of Enzymes

• Usually proteins, but can be RNA.

• Bind substrates in special regions called ‘active sites’.

• Catalyze the forward and reverse reactions equal extent.

• They do not change the position of the equilibrium.

• Function by stabilizing the transition state. 63C. Obirikorang

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Name of Enzymes

• End in –ase

• Identifies a reacting substancesucrase – reacts sucroselipase - reacts lipid

• Describes function of enzymeoxidase – catalyzes oxidationhydrolase – catalyzes hydrolysis

• Common names of digestion enzymes still use –inpepsin, trypsin

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Structure of enzymes• are in general globular proteins and range from

just 62 amino acid residues in size to over 2,500 residues.

• Most enzymes are much larger than the substrates they act on.

• only a small portion of the enzyme (around 2–4 amino acids) is directly involved in catalysis.

• The region that contains these catalytic residues, binds the substrate, and then carries out the reaction is known as the active site.

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Structure of enzymes

• Enzymes are long, linear chains of amino acids that fold to produce a three-dimensional product.

• Each unique amino acid sequence produces a specific structure, which has unique properties.

• Most enzymes can be denatured—that is, unfolded and inactivated—by heating or chemicaldenaturants, which disrupt the three-dimensional structure of the protein.

• Depending on the enzyme, denaturation may be reversible or irreversible.

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ACTIVE SITE

• Three dimensional

• Small part of the enzyme

• Cleft or crevices

• Bound to substrate through multiple weak interaction

• Specificity depends on spatial arrangement of atoms within the active site

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FEATURES OF ACTIVE AND CATALYTIC SITE

The active sites may be denoted as clefts or crevices.

Specificity of binding depends on the spatial arrangement of the catalytic groups at the active site.

The substrate is usually bound to the enzyme at the active site through multiple weak interactions.

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FEATURES OF ACTIVE AND CATALYTIC SITE

• Is essentially the region of the enzyme that binds the substrate and where possible the prosthetic group; & contains the residues which directly participate in the making or breaking of bonds.

It has the ff features:

– It constitutes a relatively small part of the total volume of a given enzyme.

–It is a 3-D entity and is formed through the interaction of groups located at different points in the primary structure of the enzyme.

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Classes of enzymes1. Oxidoreductases (EC 1) = catalyze oxidation-reduction

reactions (NADH)

2. Transferases (EC 2) = catalyze transfer of functional groups from one molecule to another.

3. Hydrolases (EC 3) = catalyze hydrolytic cleavage

4. Lyases (EC 4) = cleave various bonds by means other than hydrolysis and oxidation.

5. Isomerases (EC 5) = catalyze intramolecularrearrangement.

6. Ligases (EC 6) = catalyze reactions in which two molecules are joined.

NB: Enzymes named for the substrates and type of reaction

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Enzyme Specificity

• are usually very specific as to which reactions they catalyze and the substrates that are involved in these reactions.

• Complementary shape, charge and hydrophilic/hydrophobic characteristics of enzymes and substrates are responsible.

• Enzymes can also show impressive levels of stereospecificity, regioselectivity andchemoselectivity.

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Enzyme Specificity

• Some enzymes do ‘proof reading’ after each step.

• An enzyme such as DNA polymerase catalyzes a reaction in a first step and then checks that the product is correct in a second step.

• This two-step process results in average error rates of less than 1 error in 100 million reactions

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BIOLOGICAL FUNCTION OF ENZYMES

• They are indispensable for signal transduction and cell regulation, often via kinases and phosphatases.

• An important function of enzymes is in the digestive systems of animals.

• Several enzymes can work together in a specific order, creating metabolic pathways.

• Enzymes are also involved in some exotic functions e.g. Luciferase generating light in fireflies

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MECHANISM OF ENZYME CATALYSIS

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Enzyme Mechanism• Enzymes can act in several ways, all of which lowers the

activation energy:

• Creating an environment in which the transition state is stabilized.

• Lowering the energy of the transition state

• Providing an alternative pathway.

• Reducing the reaction entropy change by bringing substrates together in the correct orientation to react.

• Increases in temperatures speed up reactions.78C. Obirikorang

MECHANISM OF ENZYMIC ACTIVITY

✓The energy diagram shows that an enzyme lowers the activation energy of a reaction. This is how an enzyme can increase the rate of reaction.

✓A lower energy barrier means substrate is converted into product at a faster rate.

Note: an enzyme does not change the free energy of the reaction and does not change the equilibrium.

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Enzyme Mechanism

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"Lock and key" model

• This model was suggested by Emil Fischer in 1894 .

• Enzyme and the substrate possess specific complementary geometric shapes that fit exactly into one another.

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LOCK AND KEY" MODEL

The lock and key hypothesis states that the enzymeactive site is an exact complement to the substrate at alltimes. The substrate fits immediately in the active sitelike a key in a lock.

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Induced Fit Model

• In 1958, Daniel Koshland suggested a modification to the lock and key model.

• The induced fit model.

• Enzymes are rather flexible structures, the active site is continuously reshaped by interactions with the substrate as the substrate interacts with the enzyme.

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INDUCED FIT MODEL

The induced fit hypothesis states that the shape of the active site changes in the presence of the substrate to yield a precise fit. 85C. Obirikorang

Hexokinase (Induce Fit)

• The enzyme, hexokinase provides a good example of induced fit.

• The enzyme alters its conformation when the substrate is bound.

• The active site, which starts out as an open cleft, undergoes a three dimensional change and wraps around its substrate, glucose.

Cofactor

• Some enzymes do not need any additional components to show full activity.

• However, others require non-protein molecules called cofactors to be bound for activity

• is a non-protein chemical compound that is bound to an enzyme.

• Cofactors can be considered "helper molecules" that assist in biochemical transformations.

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Cofactor

• Are either organic or inorganic.

• classified depending on how tightly they bind to an enzyme.

• Loosely bound- Coenzyme

• Tightly bound- Prosthetic group.

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PROSTHETIC GROUPS

• Prosthetic groups are distinguished by theirtight, stable incorporation into a protein’sstructure by covalent or noncovalent forces

• e.g. pyridoxal phosphate, flavinmononucleotide (FMN), flavin dinucleotide(FAD), thiamin pyrophosphate, biotin, and themetal ions of Co, Cu, Mg, Mn, Se, and Zn(metalloenzymes).

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Coenzyme• Coenzymes are small organic molecules that can be

loosely bound to an enzyme.

• Coenzymes transport chemical groups from one enzyme to another.

• Organic co-enzymes – Thiamin, Riboflavin, Niacin, Biotin

• Inorganic co-enzymes – Mg++, Fe++, Zn++, Mn++

• Enzyme + Co-enzyme = holoenzyme

• Enzyme alone = apoenzyme90C. Obirikorang

FACTORS AFFECTING REACTION RATES

•Temperature

• pH

• Substrate Concentration

• Enzyme Concentration

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Temperature

•Enzymes typically operate best in a relatively

narrow range of environmental conditions.

•Like all proteins, enzymes are made as long,

linear chains of amino acids that fold to give a

3-D product.

•As temp. rises, Enzyme activity increases because there are more molecular collisions.

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Effect of Temperature

• The temperature has a significant effect on enzyme activity.

• Most enzymes function well within a certain temperature range, and they become less active or irreversibly denatured if the temperature is raised above that range.

Temperature

•Enzyme activity declines rapidly when enzyme is denatured at a certain T-that is, unfolded and

inactivated by heating, which destroys the 3-D

structure of the protein.

•Depending on the enzyme, denaturation may be

reversible or irreversible resulting in change in

shape of enzyme.

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EFFECT OF TEMPERATURE

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pH

Each enzyme has optimal pH that maintains itsnormal configuration.

As the pH is decreased or increased, the natureof the various acid and amine groups on sidechains is altered with resulting changes in theoverall structure of the enzyme.

A change in pH can alter the ionization of the Rgroups of the amino acids side chains, eventually resulting in denaturation.

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EFFECT OF pH

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Substrate Concentration

To achieve max product per unit time, enoughsubstrate is needed to fill active sites.

At lower concentrations, the active sites onmost of the Enzyme molecules are not filledBecause there is not much Substrate.

Higher concentration of substrate cause morecollisions between the molecules.

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Substrate Concentration

With more molecules and collisions, Enzymesare more likely to encounter molecules ofsubstrate.

The maximum velocity of a reaction is reachedwhen the active sites are almost continuouslyfilled.

Increased Substrate concentration after thispoint will not increase the rate.

Reaction rate therefore increases as substrateconcentration is increased but it levels off.

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EFFECT OF SUBSTRATE CONCENTRATION

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ENZYME CONCENTRATION

If insufficient Enzyme is present, the reaction willnot proceed as fast as it otherwise would becausethere is not enough Enzyme for all of the reactantmolecules.

As the amount of E is increased, the rate ofreaction increases.

If there are more enzyme molecules than areneeded, adding additional enzyme will notincrease the rate.

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Enzyme Inhibitors

Dr. Christian Obirikorang

Department of Molecular Medicine

SMS, KNUST, Kumasi

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ENZYME INHIBITORS

• Inhibitors: compounds that decrease the activity of enzymes

• Most drugs are enzyme inhibitors.

• Inhibitors are also important for determining enzyme mechanisms and nature of the active site.

• Important to know how inhibitors work facilitates drug design, inhibitor design

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ENZYME INHIBITION

• Inhibitor – substance that binds to an enzyme and interferes with its activity

• Can prevent formation of ES complex or prevent ES breakdown to E + P.

• Irreversible and Reversible Inhibitors

• Irreversible inhibitor binds to enzyme through covalent bonds (binds irreversibly), slow dissociation

• Reversible Inhibitors bind through non-covalent interactions (disassociates from enzyme easily)

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EFFECTS OF ENZYME INHIBITION

• Antibiotics inhibit enzymes by affecting bacterial metabolism.

• Nerve gas causes irreversible enzyme inhibition.

• Insecticides – choline esterase

• Many heavy metals poisons work irreversibly inhibiting enzymes esp. Cysteine residues

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TYPES OF ENZYME INHIBITION

Reversible inhibition(inhibitors that can reversibly bind and dissociate from enzyme, activity of enzyme recovers when inhibitor is

diluted out, usually in a non-covalent interaction)

– Competitive

– Mixed (noncompetitive)

– Uncompetitive

Irreversible inhibition

(Inactivators that irreversibly associate with enzyme, activity of enzyme does not recover with dilution or removal of inhibitor, usually by covalent interaction)

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Types of Reversible Enzyme Inhibitors

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Enzyme Regulation

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Enzyme Regulation

• There are various ways that enzyme activity is controlled in the cell.

Enzyme production-Transcription and translation of enzyme genes.

-Can be enhanced or diminished by a cell in response to changes in the cell's environment.

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Enzyme Regulation

Enzyme Compartmentalisation

• Enzymes can be compartmentalized, with different metabolic pathways occurring in different cellular compartments.

• For example, fatty acids are synthesized by one set of enzymes in the cytosol, endoplasmic reticulum and the Golgi apparatus and used by a different set of enzymes as a source of energy in the mitochondrion, through β-oxidation.

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Enzyme Regulation

• Enzymes can be regulated by inhibitors and activators (allosteric regulation).

• For example, the end product(s) of a metabolic pathway are often inhibitors for one of the first enzymes of the pathway (usually the first irreversible step, called committed step), thus regulating the amount of end product made by the pathways.

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FEEDBACK INHIBITION

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Enzyme Regulation

• Enzymes can be regulated through post-translational modification.

• This can include phosphorylation and glycosylation.

• Chymotrypsin, a digestive protease, is produced in inactive form as chymotrypsinogen in the pancreas and transported in this form to the stomach where it is activated.

• This prevents damage to the pancreas

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Enzyme Regulation

• Some enzymes may become activated when localized to a different environment.

• From a reducing (cytoplasm) to an oxidizing (periplasm) environment, high pH to low pH.

• For example, hemagglutinin in the influenza virus is activated by a conformational change caused by the acidic conditions, these occur when it is taken up inside its host cell and enters the lysosome.

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