An enzyme is a protein that speeds up (catalyzes) a chemical reaction.

Some RNA
molecules also have catalytic activity, and they are referred to as RNA enzymes or
ribozymes.

Enzymes are essential for life because most chemical reactions in living cells would
occur too slowly, or would lead to different products without enzymes.

Like all catalysts, enzymes work by providing an alternate pathway of lower energy
for a reaction. This speeds up the reaction, sometimes making it many millions of
times faster. Chemically, enzymes are like any catalyst and are not consumed in
chemical reactions nor do they alter the equilibrium of a reaction. However, enzymes
do differ from most other catalysts in showing much higher levels of specificity.

Enzyme activity can be affected by other molecules. Inhibitors are molecules that
decrease or abolish enzyme activity; while activators are molecules that increase
activity. Drugs and poisons are often enzyme inhibitors.

Beside the many enzymes that have biological roles, some enzymes are used
commercially. Many household products use enzymes to speed up chemical reactions
(e.g., enzymes in biological washing powders break down protein or fat stains on
clothes).

About 4,000 reactions are known to be catalyzed by enzymes.[1] Enzymes are named
according to the reaction they catalyze. Typically the suffix -ase is added to the name
of the substrate (e.g., lactase is the enzyme that catalyzes the cleavage of lactose) or
the type of reaction (e.g., DNA polymerase catalyzes the formation of DNA
polymers).

Ribbon diagram of the enzyme TIM. TIM is catalytically perfect, meaning its
conversion rate is limited, or nearly limited to its substrate diffusion rate.
The word enzyme comes from Greek: "in leaven". As early as the late 1700s and early
1800s, the digestion of meat by stomach secretions and the conversion of starch to
sugars by plant extracts and saliva were known. However, the mechanism by which
this occurred was unknown.[2]

In the 19th century, when studying the fermentation of sugar to alcohol by yeast,
Louis Pasteur came to the conclusion that this fermentation was catalyzed by a vital
force contained within the yeast cells called "ferments", which were thought to
function only within a living organisms. He wrote that "Alcoholic fermentation is an
act correlated with the life and organisation of the yeast cells, not with the death or
putrefaction of the cells."[3]

In 1878 German physiologist Wilhelm Kühne (1837-1900) coined the term "enzyme,"
meaning "in leaven," to describe this process. The word enzyme was used later to
refer to non-living substances such as pepsin, and the word ferment was used to refer
to chemical activity produced by living organisms.

In 1897, Eduard Buchner began to study the ability of yeast extracts to ferment sugar,
despite the absence of living yeast cells. In a series of experiments at the University of
Berlin he found that the sugar was fermented, even when there were no living yeast
cells in the mixture [4]. He named the enzyme that brought about the fermentation of
sucrose "zymase". [5].

It was not until 1926, however, that pepsin became the first enzyme to be obtained in
pure form by Northrop, Sumner and Stanley. Their successful purification and
crystallization of pepsin proved that enzymes were proteins and they were awarded
the 1946 Nobel prize for Chemistry [6].

Enzyme structure and mechanism

Ribbon-diagram cartoon showing the active sites of Carbonic anhydrase. The grey
spheres are the zinc ions in the four active sites in this enzyme and are held within
two protein chains. Diagram drawn from PDB 1DDZ.
The activities of enzymes are determined by their three-dimensional structure[7].

As with any protein, each protein is actually produced as a long, linear chain of amino
acids, which folds in a particular fashion to produce a three-dimensional product with
a tertiary structure. Each amino acid sequence produces a unique structure, which can
have unique properties. Individual protein chains may sometimes group together to
form a protein complex. Most enzymes can be unfolded or inactivated by heating,
which destroys the three-dimensional structure of the protein.

Most enzymes are larger than the substrates they act on and only a very small portion
of the enzyme, around 10 amino acids, comes into contact with the substrate(s). This
region, where binding of the substrate(s) and then the reaction occurs, is known as the
active site. Some enzymes also contain sites that bind cofactors, which are needed for
catalysis.

Some enzymes have binding sites for small molecules, which are often direct or
indirect products or substrates of the reaction catalyzed. This binding can serve to
increase or decrease the enzyme's activity (depending on the molecule and enzyme),
providing a means for feedback regulation.

[edit]

Specificity

Enzymes are usually specific as to the reactions they catalyze and the substrates that
are involved in these reactions. Shape, charge complementarity, and
hydrophilic/hydrophobic characters of enzymes and substrates are responsible for this
specificity. Enzymes show impressive levels of stereospecificity, regioselectivity and
chemoselectivity.

[edit]

"Lock and key" model

Diagrams to show the induced fit hypothesis of enzyme action.
Enzymes are very specific and it was suggested by Emil Fischer in the 1890s that this
was because the enzyme had a particular shape into which the substrate(s) fit exactly.
[8]
This is often referred to as "the lock and key" model. An enzyme combines with its
substrate(s) to form a short-lived enzyme-substrate complex. However, while this
model explains enzyme specificity, it fails to explain the stabilisation of the transition
state which occurs.

[edit]

Induced fit model

In 1958 Daniel Koshland suggested a modification to the "lock and key" model.[9]
Enzymes are rather flexible structures. The active site of an enzyme can be modified
as the substrate interacts with the enzyme. The amino acids side chains which make
up the active site are moulded into a precise shape which enables the enzyme to
perform its catalytic function. In some cases the substrate molecule changes shape
slightly as it enters the active site. Unlike the "Lock and key" model, this model
explains enzyme specificity and the stabilisation of the transition state which occurs.

[edit]

Modifications

Many enzymes contain not only protein but require other additional modifications.
These modifications are made post-translationally; that is, after the polypeptide chain
has been synthesized. This usually involves chemical groups being added onto the
polypeptide chain, e.g., phosphorylation or glycosylation of the enzyme.

Another kind of post-translational modification is the cleavage of the polypeptide

chain. 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 stops the enzyme from digesting the pancreas or other tissues
before it enters the gut. This type of inactive precursor to an enzyme is known as a
zymogen.

[edit]

Enzyme cofactors

Some enzymes do not need any additional components to exhibit full activity.
However, others require non-protein molecules to be bound for activity. Cofactors can
be either inorganic (e.g., metal ions and Iron-sulfur clusters) or organic compounds,
which are also known as coenzymes (e.g., flavin and heme). An example of an
enzyme that contains a cofactor is carbonic anhydrase, and is shown in the diagram
above with four zinc cofactors bound in its active sites.

Enzymes that require a cofactor, but do not have one bound are called apoenzymes.
An apoenzyme together with its cofactor(s) is called a holoenzyme (i.e., the active
form). Most cofactors are not covalently attached to an enzyme, but are tightly bound.
However, some cofactors known as prosthetic groups are covalently bound (e.g.,
thiamine pyrophosphate in the enzyme Pyruvate dehydrogenase).

[edit]

Allosteric modulation

Allosteric enzymes change their structure in response to binding of effectors.

Modulation can be direct, where the effector binds directly to binding sites in the
enzyme, or indirect, where the effector binds to other proteins or protein subunits that
interact with the allosteric enzyme and thus influence catalytic activity.

[edit]

Thermodynamics

Diagram of a catalytic reaction, showing the energy niveau at each stage of the
reaction. The substrates usually need a large amount of energy to reach the transition
state, which then decays into the end product. The enzyme stabilizes the transition
state, reducing the energy needed to form this species and thus reducing the energy
required to form products.
As with all catalysts, all reactions catalyzed by enzymes must be "spontaneous"
(containing a net negative Gibbs free energy). In the presence of an enzyme, a
reaction runs in the same direction as it would without the enzyme, just more quickly.
However, the uncatalyzed, "spontaneous" reaction might lead to different products
than the catalyzed reaction. Furthermore, enzymes can couple two or more reactions,
so that a thermodynamically favorable reaction can be used to "drive" a
thermodynamically unfavorable one. For example, the cleavage of the high-energy
compound ATP is often used to drive other, energetically unfavorable chemical
reactions.

Enzymes catalyze the forward and backward reactions equally. They do not alter the
equilibrium itself, but only the speed at which it is reached. For example, carbonic
anhydrase catalyzes its reaction in either direction, depending on the concentration of
its reactants.

(in tissues - high CO2

concentration)
(in lungs - low CO2
concentration)

Nevertheless, if the physiological concentrations of the substrates and products has a

large negative Gibbs free energy (exergonic) then the reaction is effectively
irreversible. Under these conditions it is possible that the enzyme will only catalyse
the reaction in one direction.

Kinetics
 Main article: Enzyme kinetics
Enzyme kinetics is the investigation of how enzymes bind substrates and turn them
into products. In 1913, Leonor Michaelis and Maud Menten proposed a quantitative
theory of enzyme kinetics, which is referred to as Michaelis-Menten kinetics.[10] Their
work was further developed by G. E. Briggs and J. B. S. Haldane, who derived
numerous kinetic equations that are still widely used today[11].

A mechanism for an single substrate enzyme-catalysed reaction. The enzyme (E)

binds a substrate (S) and produces a product (P).

The major contribution of Michaelis and Menten was to divide enzyme reactions into
two stages. In the first, the substrate binds reversibly to the enzyme, forming the
enzyme-substrate complex. This is sometimes called the Michaelis-Menten complex
in their honour. The enzyme then catalyzes the chemical step in the reaction and
releases the product.

Enzymes can catalyze up to several million reactions per second. To find the
maximum speed of an enzymatic reaction, the substrate concentration is increased
until a constant rate of product formation is seen. This saturation happens because, as
substrate concentration increases, more and more of the free enzyme is converted into
the substrate-bound ES form. At the maximum velocity (Vmax) of the enzyme, all
enzyme active sites are saturated with substrate, and the amount of ES complex is the
same as the amount of enzyme.

However, Vmax is only one kinetic constant of enzymes. The amount of substrate
needed to achieve a given rate of reaction is also of interest. This can be expressed by
the Michaelis-Menten constant (Km), which is the substrate concentration required for
an enzyme to reach one-half its maximum velocity. Each enzyme has a characteristic
Km for a given substrate and this can show how tight the binding of the substrate is to
the enzyme.

The efficiency of an enzyme can be expressed in terms of kcat/Km. This is also called
the specificity constant and incorporates the rate constants for all steps in the reaction.
Because the specificity constant reflects both affinity and catalytic ability, it is useful
for comparing different enzymes against each other, or the same enzyme with
different substrates. The theoretical maximum for the specificity constant is called the
diffusion limit and is about 108 to 109 (M-1 s-1). At this point, every collision of the
enzyme with its substrate will result in catalysis and the rate of product formation is
not limited by the reaction rate but by the diffusion rate. Enzymes with this property
are called catalytically perfect or kinetically perfect. Example of such enzymes are
triose-phosphate isomerase, carbonic anhydrase, acetylcholinesterase, catalase,
fumarase, ß-lactamase, and superoxide dismutase.

Some enzymes operate with kinetics which are faster than diffusion rates, which
would seem to be impossible. Several mechanisms have been invoked to explain this
phenomenon. Some proteins are believed to accelerate catalysis by drawing their
substrate in and pre-orienting them by using dipolar electric fields. Other models
invoke a quantum-mechanical tunneling explanation whereby a proton or an electron
can tunnel through activation barriers, although for protons tunneling remains
somewhat controversial. [12][13]

[edit]

Coenzymes
Coenzymes are small molecules that transport chemical groups from one enzyme to
another. The chemical groups carried can be as simple as the hydride ion (H+ + 2e-)
carried by NAD or the larger acetyl group carried by coenzyme A. Since coenzymes
are chemically changed as a consequence of enzyme action, it is often useful to
consider coenzymes to be a special class of substrates, or second substrates, which are
common to many different enzymes.

[edit]

Inhibition

A competitive inhibitor binds reversibly to the enzyme, preventing the binding of

substrate. On the other hand, binding of substrate prevents binding of the inhibitor.
Substrate and inhibitor compete for the enzyme.
Non-competitive inhibitors do not bind at the same site as the substrate. Substrate and
inhibitor do not compete
Main article: Enzyme inhibition

Enzymes reaction rates can be decreased by various types of enzyme inhibitors.

[edit]

Mechanisms of enzyme inhibitors

Competitive inhibition

In competitive inhibition, the inhibitor binds to the substrate binding site as shown
(right top), thus preventing substrate from binding. Often competitive inhibitors
strongly resemble the real substrate of the enzyme. For example, malonate is a
competitive inhibitor of the enzyme succinate dehydrogenase, which catalyzes the
oxidation of succinate to fumarate.

Non-competitive inhibition

Non-competitive inhibitors never bind to the active site, but to other parts of the
enzyme that can be far away from the substrate binding site, (right, bottom).
Consequently, since there is no competition between the substrate and inhibitor for the
enzyme, the extent of inhibition depends only on the inhibitor concentration and will
not be affected by the substrate concentration.

By changing the conformation (the three-dimensional structure) of the enzyme, the

inhibitors disable the ability of the enzyme to bind or turn over its substrate. When the
inhibitor is bound, the enzyme has no activity.

Mixed inhibition
Mixed inhibitors can bind to both the enzyme and the enzyme-substrate complex. It
has the properties of both competitive and uncompetitive inhibition.

The types of enzyme inhibitor are discussed in more detail in the enzyme inhibition
page.

[edit]

Uses of enzyme inhibitors

Inhibitors are often used as drugs, but they can also act as poisons. However, the
difference between a drug and a poison is usually only a matter of amount, since most
drugs are toxic at some level, as Paracelsus wrote "The dose makes the poison."
Equally, antibiotics and other anti-infective drugs are just specific poisons that can kill
a pathogen but not its host.

An example of an inhibitor being used as a drug is aspirin, which inhibits the COX-1
and COX-2 enzymes that produce the inflammation messenger prostaglandin, thus
suppressing pain and inflammation. The poison cyanide is an irreversible enzyme
inhibitor that combines with the copper prosthetic groups of the enzyme cytochrome c
oxidase and blocks cellular respiration.

In many organisms, inhibitors may act as part of a feedback mechanism. If an enzyme

produces too much of one substance in the organism, that substance may act as an
inhibitor for the enzyme that produces it, causing production of the substance to slow
down or stop when there is sufficient amount. This is a form of negative feedback.

[edit]

Function and control of enzymes in the cell

[edit]

Metabolic pathways

Several enzymes can work together in a specific order, creating metabolic pathways.
In a metabolic pathway, one enzyme takes the product of another enzyme as a
substrate. After the catalytic reaction, the product is then passed on to another
enzyme.

[edit]

Control of enzyme activity

There are three main ways that enzyme activity is controlled in the cell
 1. Enzymes can be compartmentalised, with different metabolic pathways
occurring in different cellular compartments. For example, fatty acids are
synthesised by one set of enzymes in the cytosol, endoplasmic reticulum and
golgi and used by a different set of enzymes as a source of energy in the
mitochondrion, through β-oxidation[14]
2. Enzymes can be regulated by inhibitors and activators. 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. Such a
regulatory mechanism is called a negative feedback mechanism, because the
amount of the end product produced is regulated by its own concentration.
Negative feedback mechanism can effectively adjust the rate of synthesis of
intermediate metabolites according to the demands of the cells. This helps
with effective allocations of materials and energy economy, and it prevents the
excess manufacture of end products. Like other homeostatic devices, the
control of enzymatic action helps to maintain a stable internal environment in
living organisms.
3. Enzymes can be regulated through post-translational modification. For
example, in the response to insulin, the phosphorylation of multiple enzymes,
including glycogen synthase helps control the synthesis or degradation of
glycogen and allows the cell to respond to changes in blood sugar[15].

[edit]

Errors in metabolism

Since the tight control of enzyme activity is essential for homeostasis, any
malfunction (mutation, overproduction, underproduction or deletion) of a single
critical enzyme can lead to disease. For example, the most common type of
phenylketonuria is caused by a single amino acid mutation in the enzyme
phenylalanine hydroxylase, which catalyzes the first step in the degradation of
phenylalanine. The resulting build-up of phenylalanine and related products can lead
to mental retardation if the disease is untreated [16].

[edit]

Enzyme-naming conventions
By common convention, an enzyme's name consists of a description of what it does,
with the word ending in -ase. Examples are alcohol dehydrogenase and DNA
polymerase. Kinases are enzymes that transfer phosphate groups. This results in
different enzymes with the same function having the same basic name; they are
therefore distinguished by other characteristics, such as their optimal pH (alkaline
phosphatase) or their location (membrane ATPase). Furthermore, the reversibility of
chemical reactions means that the normal physiological direction of an enzyme's
function may not be observed under laboratory conditions. This can result in the same
enzyme being identified with two different names: one coming from the laboratory
identification as described above and the other from its behavior in the cell. For
instance the enzyme formally known as xylitol:NAD+ 2-oxidoreductase (D-xylulose-
forming) is more commonly referred to in the cellular physiological sense as D-
xylulose reductase, since the function of the enzyme in the cell is actually the reverse
of what is often seen under laboratory conditions.

The International Union of Biochemistry and Molecular Biology has developed a

nomenclature for enzymes, the EC numbers; each enzyme is described by a sequence
of four numbers, preceded by "EC". However, this is not a perfect solution, as
enzymes from different species or even very similar enzymes in the same species may
have identical EC numbers.

The first number broadly classifies the enzyme based on its mechanism:

The top-level classification is

 EC 1 Oxidoreductases: catalyze oxidation/reduction reactions

 EC 2 Transferases: transfer a functional group (e.g. a methyl or phosphate
group)
 EC 3 Hydrolases: catalyze the hydrolysis of various bonds
 EC 4 Lyases: cleave various bonds by means other than hydrolysis and
oxidation
 EC 5 Isomerases: catalyze isomerization changes within a single molecule
 EC 6 Ligases: join two molecules with covalent bonds

The complete nomenclature can be browsed at

http://www.chem.qmul.ac.uk/iubmb/enzyme/

Industrial Applications

Application Enzymes used Uses Notes and examples

Biological Used for
detergent presoak
conditions and
Primarily proteases,
direct liquid
produced in an
applications
extracellular form
helping with
from bacteria
removal of
protein stains
from clothes.
Detergents for
machine dish
washing to
Amylase enzymes
remove
resistant starch
residues.
Used to assist
in the removal
Lipase enzymes
of fatty and oily
stains
Used in
biological
Cellulase enzymes
fabric
conditioners
Catalyze
breakdown of
Fungal alpha- starch in the
amylase enzymes: flour to sugar.
normally Yeast action on
inactivated at about sugar produces
50 degrees Celsius, carbon dioxide.
destroyed during Used in
Baking baking process production of alpha-amylase catalyzes the release of sugar
industry white bread, monomers from starch
buns, and rolls
Biscuit
manufacturers
use them to
Protease enzymes
lower the
protein level of
flour.
To predigest
Baby foods Trypsin
baby foods
 They degrade
starch and
proteins to
Enzymes from
produce simple
barley are released
sugar, amino
during the mashing
acids and
stage of beer
peptides that
production.
are used by
yeast for
fermentation.
Widely used in
the brewing
Industrially process to
produced barley substitute for
enzymes. the natural Germinating barley used for malt.
Brewing enzymes found
industry in barley.
Split
Amylase,
polysaccharides
glucanases,
and proteins in
proteases
the malt
Improve the
Betaglucosidase filtration
characteristics.
Low-calorie
Amyloglucosidase
beer
Remove
cloudiness
Proteases produced
during storage
of beers.
Cellulases, Clarify fruit
Fruit juices
pectinases juices
Note: As animals age rennin production
Rennin, derived decreases and is replaced by another protease,
Manufacture of
from the stomachs pepsin, which is not suitable for cheese
cheese, used to
of young ruminant production. In recent years the increase in
hydrolyse
animals (calves, cheese consumption, as well as increased beef
Dairy protein
lambs) production, has resulted in a shortage of rennin
industry and escalating prices.
Now finding
Microbially increasing use
produced enzyme in the dairy
industry
 Is implemented
during the
production of
Roquefort
Lipases cheese to
enhance the
ripening of the
blue-mould
cheese.
Break down
lactose to Roquefort cheese
Lactases
glucose and
galactose
Converts starch
Amylases,
into glucose
amyloglucosideases
and various
and glucoamylases
syrups
Converts
glucose into
fructose (high
Starch fructose syrups
industry derived from
starchy
Glucose isomerase
materials have
Glucose Fructose
enhanced
sweetening
properties and
lower calorific
values)
To generate
oxygen from
Rubber peroxide to
Catalase
industry convert latex
into foam
rubber

Degrade starch
to a lower
Paper viscosity
Amylases
industry product needed
for sizing and
coating paper

Photographic Protease (ficin) Dissolve gelatin

industry off scrap film
 allowing
recovery of its
silver content
[edit]

External links

Wikimedia Commons has media related to:

Category:Enzymes
 ExPASy enzyme
database, links to
Swiss-Prot
sequence data,
entries in other
databases and to
related literature
searches.
 PDBsum links to
the known 3-D
structure data of
enzymes in the
Protein Data
Bank.
 MACiE, database
of enzyme
reaction
mechanisms.
 Enzyme
Companies
 BRENDA,
comprehensive
compilation of
information and
literature
references about
all known
enzymes;
requires payment
by commercial
users.
 Weizmann
Institute's
Genecards
Database,
 extensive
database of
protein properties
and their
associated genes.
 Cytochrome
P450 enzymes
site lists over
4000 versions of
enzymes from
this cytochrome
in plants and
animals.

[edit]

Further reading
Etymology and history

 New Beer in an
Old Bottle:
Eduard Buchner
and the Growth
of Biochemical
Knowledge,
edited by Athel
Cornish-Bowden
and published by
Universitat de
València (1997):
ISBN 84-370-
3328-4, A history
of early
enzymology.
 Williams, Henry
Smith, 1863-
1943. A History
of Science: in
Five Volumes.
Volume IV:
Modern
Development of
the Chemical and
Biological
Sciences, A
 textbook from the
19th century.

Kleyn, J. and Hough J. The Microbiology of Brewing. Annual Review of

Microbiology Vol. 25: 583-608

Enzyme structure and mechanism

 PDB Molecule of
the Month, The
"Molecule of the
Month", presents
short accounts on
selected
molecules from
the Protein Data
Bank.
 Structure/Functio
n of Enzymes,
Web tutorial on
enzyme structure.

Fersht, A. Structure and Mechanism in Protein Science : A Guide to Enzyme Catalysis

and Protein Folding. W. H. Freeman, 1998 ISBN 0716732688

Walsh, C., Enzymatic Reaction Mechanisms. W. H. Freeman and Company. 1979.

Page, M. I., and Williams, A. (Eds.), 1987. Enzyme Mechanisms. Royal Society of
Chemistry.

Thermodynamics

 Reactions and
Enzymes Chapter
10 of On-Line
Biology Book at
Estrella Mountain
Community
College.

Kinetics and Inhibition

Athel Cornish-Bowden, Fundamentals of Enzyme Kinetics. (3rd edition), Portland

Press (2004), ISBN 1855781581.

Irwin H. Segel, Enzyme Kinetics : Behavior and Analysis of Rapid Equilibrium and
Steady-State Enzyme Systems. Wiley-Interscience; New Ed edition (1993), ISBN
0471303097.
Function and control of enzymes in the cell

Price, N. and Stevens, L., Fundamentals of Enzymology (second edition) Oxford

University Press, 1996.

 Nutritional and
Metabolic
Diseases

Enzyme-naming conventions

 Enzyme
Nomenclature,
Recommendation
s for enzyme
names from the
Nomenclature
Committee of the
International
Union of
Biochemistry and
Molecular
Biology.

Industrial Applications

 History of
industrial
enzymes, Article
about the history
of industrial
enzymes, from
the late 1900's to
the present times.

[edit]

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