![Glucosidase enzyme](https://upload.wikimedia.org/wikipedia/commons/0/0a/Glucosidase_enzyme.png)
Enzymes () are
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s that act as biological
catalyst
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
s by accelerating
chemical reactions
A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and breaking ...
. The molecules upon which enzymes may act are called
substrates, and the enzyme converts the substrates into different molecules known as
products
Product may refer to:
Business
* Product (business), an item that serves as a solution to a specific consumer problem.
* Product (project management), a deliverable or set of deliverables that contribute to a business solution
Mathematics
* Produ ...
. Almost all
metabolic processes in the
cell
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
need
enzyme catalysis
Enzyme catalysis is the increase in the rate of a process by a biological molecule, an "enzyme". Most enzymes are proteins, and most such processes are chemical reactions. Within the enzyme, generally catalysis occurs at a localized site, calle ...
in order to occur at rates fast enough to sustain life.
Metabolic pathway
In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...
s depend upon enzymes to catalyze individual steps. The study of enzymes is called ''enzymology'' and the field of
pseudoenzyme analysis recognizes that during evolution, some enzymes have lost the ability to carry out biological catalysis, which is often reflected in their
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
sequences and unusual 'pseudocatalytic' properties.
Enzymes are known to catalyze more than 5,000 biochemical reaction types. Other biocatalysts are
catalytic RNA molecules, called ribozymes. Enzymes'
specificity comes from their unique
three-dimensional structures.
Like all catalysts, enzymes increase the
reaction rate
The reaction rate or rate of reaction is the speed at which a chemical reaction takes place, defined as proportional to the increase in the concentration of a product per unit time and to the decrease in the concentration of a reactant per unit ...
by lowering its
activation energy
In chemistry and physics, activation energy is the minimum amount of energy that must be provided for compounds to result in a chemical reaction. The activation energy (''E''a) of a reaction is measured in joules per mole (J/mol), kilojoules pe ...
. Some enzymes can make their conversion of substrate to product occur many millions of times faster. An extreme example is
orotidine 5'-phosphate decarboxylase
Orotidine 5'-phosphate decarboxylase (OMP decarboxylase) or orotidylate decarboxylase is an enzyme involved in pyrimidine biosynthesis. It catalyzes the decarboxylation of orotidine monophosphate (OMP) to form uridine monophosphate (UMP). The fu ...
, which allows a reaction that would otherwise take millions of years to occur in milliseconds.
Chemically, enzymes are like any catalyst and are not consumed in chemical reactions, nor do they alter the
equilibrium of a reaction. Enzymes differ from most other catalysts by being much more specific. Enzyme activity can be affected by other molecules:
inhibitors are molecules that decrease enzyme activity, and
activators are molecules that increase activity. Many therapeutic
drug
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...
s and
poison
Poison is a chemical substance that has a detrimental effect to life. The term is used in a wide range of scientific fields and industries, where it is often specifically defined. It may also be applied colloquially or figuratively, with a broa ...
s are enzyme inhibitors. An enzyme's activity decreases markedly outside its optimal
temperature
Temperature is a physical quantity that expresses quantitatively the perceptions of hotness and coldness. Temperature is measured with a thermometer.
Thermometers are calibrated in various temperature scales that historically have relied o ...
and
pH, and many enzymes are (permanently)
denatured when exposed to excessive heat, losing their structure and catalytic properties.
Some enzymes are used commercially, for example, in the synthesis of
antibiotics
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention o ...
. Some household products use enzymes to speed up chemical reactions: enzymes in
biological washing powders break down protein, starch or
fat
In nutrition science, nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such chemical compound, compounds, most commonly those that occur in living beings or in food.
The term often refers spec ...
stains on clothes, and enzymes in
meat tenderizer
A meat tenderizer, or meat pounder is a hand-powered tool used to tenderize slabs of meat in the preparation for cooking. Although a meat tenderizer can be made out of virtually any object, there are three types manufactured specifically for ...
break down proteins into smaller molecules, making the meat easier to chew.
Etymology and history
By the late 17th and early 18th centuries, the digestion of
meat
Meat is animal flesh that is eaten as food. Humans have hunted, farmed, and scavenged animals for meat since prehistoric times. The establishment of settlements in the Neolithic Revolution allowed the domestication of animals such as chic ...
by stomach secretions
and the conversion of
starch
Starch or amylum is a polymeric carbohydrate consisting of numerous glucose units joined by glycosidic bonds. This polysaccharide is produced by most green plants for energy storage. Worldwide, it is the most common carbohydrate in human diets ...
to
sugar
Sugar is the generic name for sweet-tasting, soluble carbohydrates, many of which are used in food. Simple sugars, also called monosaccharides, include glucose, fructose, and galactose. Compound sugars, also called disaccharides or double ...
s by plant extracts and
saliva
Saliva (commonly referred to as spit) is an extracellular fluid produced and secreted by salivary glands in the mouth. In humans, saliva is around 99% water, plus electrolytes, mucus, white blood cells, epithelial cells (from which DNA can be ...
were known but the mechanisms by which these occurred had not been identified.
French chemist
Anselme Payen
Anselme Payen (; 6 January 1795 – 12 May 1871) was a French chemist known for discovering the enzyme diastase, and the carbohydrate cellulose.
Biography
Payen was born in Paris. He began studying science with his father when he was a 13-yea ...
was the first to discover an enzyme,
diastase A diastase (; from Greek διάστασις, "separation") is any one of a group of enzymes that catalyses the breakdown of starch into maltose. Alpha amylase degrades starch to a mixture of the disaccharide maltose; the trisaccharide maltotriose, ...
, in 1833. A few decades later, when studying the
fermentation
Fermentation is a metabolic process that produces chemical changes in organic substrates through the action of enzymes. In biochemistry, it is narrowly defined as the extraction of energy from carbohydrates in the absence of oxygen. In food ...
of sugar to
alcohol
Alcohol most commonly refers to:
* Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom
* Alcohol (drug), an intoxicant found in alcoholic drinks
Alcohol may also refer to:
Chemicals
* Ethanol, one of sev ...
by
yeast
Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitut ...
,
Louis Pasteur
Louis Pasteur (, ; 27 December 1822 – 28 September 1895) was a French chemist and microbiologist renowned for his discoveries of the principles of vaccination, microbial fermentation and pasteurization, the latter of which was named afte ...
concluded that this fermentation was caused by a
vital force
Vitalism is a belief that starts from the premise that "living organisms are fundamentally different from non-living entities because they contain some non-physical element or are governed by different principles than are inanimate things." Wher ...
contained within the yeast cells called "ferments", which were thought to function only within living organisms. He wrote that "alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells."
In 1877, German physiologist
Wilhelm Kühne
Wilhelm Friedrich Kühne (28 March 183710 June 1900) was a German physiologist. Born in Hamburg, he is best known today for coining the word enzyme in 1878.
Biography
Kühne was born at Hamburg on 28 March 1837. After attending the gymnasium ...
(1837–1900) first used the term ''
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
'', which comes from
Greek
Greek may refer to:
Greece
Anything of, from, or related to Greece, a country in Southern Europe:
*Greeks, an ethnic group.
*Greek language, a branch of the Indo-European language family.
**Proto-Greek language, the assumed last common ancestor ...
ἔνζυμον, "leavened" or "in yeast", to describe this process. The word ''enzyme'' was used later to refer to nonliving substances such as
pepsin
Pepsin is an endopeptidase that breaks down proteins into smaller peptides. It is produced in the gastric chief cells of the stomach lining and is one of the main digestive enzymes in the digestive systems of humans and many other animals, w ...
, and the word ''ferment'' was used to refer to chemical activity produced by living organisms.
Eduard Buchner
Eduard Buchner (; 20 May 1860 – 13 August 1917) was a German chemist and zymologist, awarded the 1907 Nobel Prize in Chemistry for his work on fermentation.
Biography
Early years
Buchner was born in Munich to a physician and Doctor Extraor ...
submitted his first paper on the study of yeast extracts in 1897. In a series of experiments at the
University of Berlin
Humboldt-Universität zu Berlin (german: Humboldt-Universität zu Berlin, abbreviated HU Berlin) is a German public research university in the central borough of Mitte in Berlin. It was established by Frederick William III on the initiative o ...
, he found that sugar was fermented by yeast extracts even when there were no living yeast cells in the mixture.
He named the enzyme that brought about the fermentation of sucrose "
zymase
Zymase is an enzyme complex that catalyzes the fermentation of sugar into ethanol and carbon dioxide. It occurs naturally in yeasts. Zymase activity varies among yeast strains.
Zymase is also the brand name of the drug pancrelipase.
Cell-free ...
".
In 1907, he received the
Nobel Prize in Chemistry
)
, image = Nobel Prize.png
, alt = A golden medallion with an embossed image of a bearded man facing left in profile. To the left of the man is the text "ALFR•" then "NOBEL", and on the right, the text (smaller) "NAT•" then "M ...
for "his discovery of cell-free fermentation". Following Buchner's example, enzymes are usually named according to the reaction they carry out: the suffix ''
-ase
The suffix -ase is used in biochemistry to form names of enzymes. The most common way to name enzymes is to add this suffix onto the end of the substrate, ''e.g.'' an enzyme that breaks down peroxides may be called peroxidase; the enzyme that pro ...
'' is combined with the name of the
substrate (e.g.,
lactase
Lactase is an enzyme produced by many organisms. It is located in the brush border of the small intestine of humans and other mammals. Lactase is essential to the complete digestion of whole milk; it breaks down lactose, a sugar which gives m ...
is the enzyme that cleaves
lactose
Lactose is a disaccharide sugar synthesized by galactose and glucose subunits and has the molecular formula C12H22O11. Lactose makes up around 2–8% of milk (by mass). The name comes from ' (gen. '), the Latin word for milk, plus the suffix '' - ...
) or to the type of reaction (e.g.,
DNA polymerase
A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create ...
forms DNA polymers).
The biochemical identity of enzymes was still unknown in the early 1900s. Many scientists observed that enzymatic activity was associated with proteins, but others (such as Nobel laureate
Richard Willstätter
Richard Martin Willstätter FRS(For) HFRSE (, 13 August 1872 – 3 August 1942) was a German organic chemist whose study of the structure of plant pigments, chlorophyll included, won him the 1915 Nobel Prize for Chemistry. Willstätter invented ...
) argued that proteins were merely carriers for the true enzymes and that proteins ''per se'' were incapable of catalysis.
[ quoted in ] In 1926,
James B. Sumner showed that the enzyme
urease
Ureases (), functionally, belong to the superfamily of amidohydrolases and phosphotriesterases. Ureases are found in numerous bacteria, fungi, algae, plants, and some invertebrates, as well as in soils, as a soil enzyme. They are nickel-containin ...
was a pure protein and crystallized it; he did likewise for the enzyme
catalase
Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting t ...
in 1937. The conclusion that pure proteins can be enzymes was definitively demonstrated by
John Howard Northrop
John Howard Northrop (July 5, 1891 – May 27, 1987) was an American biochemist who, with James Batcheller Sumner and Wendell Meredith Stanley, won the 1946 Nobel Prize in Chemistry. The award was given for these scientists' isolation, crys ...
and
Wendell Meredith Stanley
Wendell Meredith Stanley (16 August 1904 – 15 June 1971) was an American biochemist, virologist and Nobel laureate.
Biography
Stanley was born in Ridgeville, Indiana, and earned a BSc in Chemistry at Earlham College in Richmond, Indiana. He ...
, who worked on the digestive enzymes
pepsin
Pepsin is an endopeptidase that breaks down proteins into smaller peptides. It is produced in the gastric chief cells of the stomach lining and is one of the main digestive enzymes in the digestive systems of humans and many other animals, w ...
(1930),
trypsin
Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting these long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the dig ...
and
chymotrypsin
Chymotrypsin (, chymotrypsins A and B, alpha-chymar ophth, avazyme, chymar, chymotest, enzeon, quimar, quimotrase, alpha-chymar, alpha-chymotrypsin A, alpha-chymotrypsin) is a digestive enzyme component of pancreatic juice acting in the duodenu ...
. These three scientists were awarded the 1946 Nobel Prize in Chemistry.
The discovery that enzymes could be crystallized eventually allowed their structures to be solved by
x-ray crystallography
X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
. This was first done for
lysozyme
Lysozyme (EC 3.2.1.17, muramidase, ''N''-acetylmuramide glycanhydrolase; systematic name peptidoglycan ''N''-acetylmuramoylhydrolase) is an antimicrobial enzyme produced by animals that forms part of the innate immune system. It is a glycoside ...
, an enzyme found in tears, saliva and
egg white
Egg white is the clear liquid (also called the albumen or the glair/glaire) contained within an egg. In chickens it is formed from the layers of secretions of the anterior section of the hen's oviduct during the passage of the egg. It forms arou ...
s that digests the coating of some bacteria; the structure was solved by a group led by
David Chilton Phillips
David Chilton Phillips, Baron Phillips of Ellesmere, KBE, FRS (7 March 1924 – 23 February 1999) was a pioneering, British structural biologist and an influential figure in science and government.
Research
Phillips lead the team which determ ...
and published in 1965. This high-resolution structure of lysozyme marked the beginning of the field of
structural biology
Structural biology is a field that is many centuries old which, and as defined by the Journal of Structural Biology, deals with structural analysis of living material (formed, composed of, and/or maintained and refined by living cells) at every le ...
and the effort to understand how enzymes work at an atomic level of detail.
Classification and nomenclature
Enzymes can be classified by two main criteria: either
amino acid sequence
Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthes ...
similarity (and thus evolutionary relationship) or enzymatic activity.
Enzyme activity. An enzyme's name is often derived from its substrate or the chemical reaction it catalyzes, with the word ending in ''-ase''.
Examples are
lactase
Lactase is an enzyme produced by many organisms. It is located in the brush border of the small intestine of humans and other mammals. Lactase is essential to the complete digestion of whole milk; it breaks down lactose, a sugar which gives m ...
,
alcohol dehydrogenase
Alcohol dehydrogenases (ADH) () are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+) to N ...
and
DNA polymerase
A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create ...
. Different enzymes that catalyze the same chemical reaction are called
isozymes In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. dif ...
.
The
International Union of Biochemistry and Molecular Biology
The International Union of Biochemistry and Molecular Biology (IUBMB) is an international non-governmental organisation concerned with biochemistry and molecular biology. Formed in 1955 as the International Union of Biochemistry (IUB), the union ...
have developed a
nomenclature
Nomenclature (, ) is a system of names or terms, or the rules for forming these terms in a particular field of arts or sciences. The principles of naming vary from the relatively informal naming conventions, conventions of everyday speech to the i ...
for enzymes, the
EC numbers (for "Enzyme Commission"). Each enzyme is described by "EC" followed by a sequence of four numbers which represent the hierarchy of enzymatic activity (from very general to very specific). That is, the first number broadly classifies the enzyme based on its mechanism while the other digits add more and more specificity.
The top-level classification is:
*EC 1,
Oxidoreductase
In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule, the reductant, also called the electron donor, to another, the oxidant, also called the electron acceptor. This group of enzymes usually ut ...
s: catalyze
oxidation
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
/reduction reactions
*EC 2,
Transferase
A transferase is any one of a class of enzymes that catalyse the transfer of specific functional groups (e.g. a methyl or glycosyl group) from one molecule (called the donor) to another (called the acceptor). They are involved in hundreds of di ...
s: transfer a
functional group
In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the rest ...
(''e.g.'' a methyl or phosphate group)
*EC 3,
Hydrolase
Hydrolase is a class of enzyme that commonly perform as biochemical catalysts that use water to break a chemical bond, which typically results in dividing a larger molecule into smaller molecules. Some common examples of hydrolase enzymes are este ...
s: catalyze the
hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
of various bonds
*EC 4,
Lyase
In biochemistry, a lyase is an enzyme that catalyzes the breaking (an elimination reaction) of various chemical bonds by means other than hydrolysis (a substitution reaction) and oxidation, often forming a new double bond or a new ring structure. ...
s: cleave various bonds by means other than hydrolysis and oxidation
*EC 5,
Isomerase
Isomerases are a general class of enzymes that convert a molecule from one isomer to another. Isomerases facilitate intramolecular rearrangements in which bonds are broken and formed. The general form of such a reaction is as follows:
A–B ↠...
s: catalyze
isomer
In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers.
Iso ...
ization changes within a single molecule
*EC 6,
Ligase
In biochemistry, a ligase is an enzyme that can catalyze the joining (ligation) of two large molecules by forming a new chemical bond. This is typically via hydrolysis of a small pendant chemical group on one of the larger molecules or the enzym ...
s: join two molecules with
covalent bond
A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...
s.
*EC 7,
Translocase
Translocase is a general term for a protein that assists in moving another molecule, usually across a cell membrane. These enzymes catalyze the movement of ions or molecules across membranes or their separation within membranes. The reaction is des ...
s: catalyze the movement of ions or molecules across membranes, or their separation within membranes.
These sections are subdivided by other features such as the substrate, products, and
chemical mechanism
In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs.
A chemical mechanism is a theoretical conjecture that tries to describe in detail what takes place at each stage of ...
. An enzyme is fully specified by four numerical designations. For example,
hexokinase
A hexokinase is an enzyme that phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate for hexokinases, and glucose-6-phosphate is the most important product. Hexokina ...
(EC 2.7.1.1) is a transferase (EC 2) that adds a phosphate group (EC 2.7) to a hexose sugar, a molecule containing an alcohol group (EC 2.7.1).
Sequence similarity. EC categories do not reflect sequence similarity. For instance, two ligases of the same EC number that catalyze exactly the same reaction can have completely different sequences. Independent of their function, enzymes, like any other proteins, have been classified by their sequence similarity into numerous families. These families have been documented in dozens of different protein and protein family databases such as
Pfam
Pfam is a database of protein families that includes their annotations and multiple sequence alignments generated using hidden Markov models. The most recent version, Pfam 35.0, was released in November 2021 and contains 19,632 families.
Uses
...
.
Structure
![Q10 graph c](https://upload.wikimedia.org/wikipedia/commons/d/d5/Q10_graph_c.svg)
Enzymes are generally
globular protein
In biochemistry, globular proteins or spheroproteins are spherical ("globe-like") proteins and are one of the common protein types (the others being fibrous, disordered and membrane proteins). Globular proteins are somewhat water-soluble (formi ...
s, acting alone or in larger
complexes. The sequence of the amino acids specifies the structure which in turn determines the catalytic activity of the enzyme. Although structure determines function, a novel enzymatic activity cannot yet be predicted from structure alone. Enzyme structures unfold (
denature) when heated or exposed to chemical denaturants and this disruption to the structure typically causes a loss of activity. Enzyme denaturation is normally linked to temperatures above a species' normal level; as a result, enzymes from bacteria living in volcanic environments such as
hot spring
A hot spring, hydrothermal spring, or geothermal spring is a spring produced by the emergence of geothermally heated groundwater onto the surface of the Earth. The groundwater is heated either by shallow bodies of magma (molten rock) or by circ ...
s are prized by industrial users for their ability to function at high temperatures, allowing enzyme-catalysed reactions to be operated at a very high rate.
Enzymes are usually much larger than their substrates. Sizes range from just 62 amino acid residues, for the
monomer
In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization.
Classification
Mo ...
of
4-oxalocrotonate tautomerase
4-Oxalocrotonate tautomerase (EC 5.3.2.6) or 4-OT is an enzyme that converts 2-hydroxymuconate to the αβ-unsaturated ketone, 2-oxo-3-hexenedioate. This enzyme forms part of a bacterial metabolic pathway that oxidatively catabolizes toluene, o ...
, to over 2,500 residues in the animal
fatty acid synthase
Fatty acid synthase (FAS) is an enzyme that in humans is encoded by the ''FASN'' gene.
Fatty acid synthase is a multi-enzyme protein that catalyzes fatty acid synthesis. It is not a single enzyme but a whole enzymatic system composed of two iden ...
. Only a small portion of their structure (around 2–4 amino acids) is directly involved in catalysis: the catalytic site. This catalytic site is located next to one or more
binding site
In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may inclu ...
s where residues orient the substrates. The catalytic site and binding site together compose the enzyme's
active site
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
. The remaining majority of the enzyme structure serves to maintain the precise orientation and dynamics of the active site.
In some enzymes, no amino acids are directly involved in catalysis; instead, the enzyme contains sites to bind and orient catalytic
cofactors
Cofactor may also refer to:
* Cofactor (biochemistry), a substance that needs to be present in addition to an enzyme for a certain reaction to be catalysed
* A domain parameter in elliptic curve cryptography, defined as the ratio between the order ...
.
Enzyme structures may also contain
allosteric site
In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site.
The site to which the effector binds is termed the ''allosteric site ...
s where the binding of a small molecule causes a
conformational change
In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors.
A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...
that increases or decreases activity.
A small number of
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
-based biological catalysts called
ribozyme
Ribozymes (ribonucleic acid enzymes) are RNA molecules that have the ability to catalyze specific biochemical reactions, including RNA splicing in gene expression, similar to the action of protein enzymes. The 1982 discovery of ribozymes demonst ...
s exist, which again can act alone or in complex with proteins. The most common of these is the
ribosome
Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...
which is a complex of protein and catalytic RNA components.
Mechanism
Substrate binding
Enzymes must bind their substrates before they can catalyse any chemical reaction. Enzymes are usually very specific as to what
substrates they bind and then the chemical reaction catalysed.
Specificity is achieved by binding pockets with complementary shape, charge and
hydrophilic
A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press.
In contrast, hydrophobes are no ...
/
hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, th ...
characteristics to the substrates. Enzymes can therefore distinguish between very similar substrate molecules to be
chemoselective
Chemoselectivity is the preferential outcome of a chemical reaction over a set of possible alternative reactions.
In another definition, chemoselectivity refers to the selective reactivity of one functional group in the presence of others; often ...
,
regioselective
In chemistry, regioselectivity is the preference of chemical bonding or breaking in one direction over all other possible directions. It can often apply to which of many possible positions a reagent will affect, such as which proton a strong base ...
and
stereospecific.
Some of the enzymes showing the highest specificity and accuracy are involved in the copying and
expression
Expression may refer to:
Linguistics
* Expression (linguistics), a word, phrase, or sentence
* Fixed expression, a form of words with a specific meaning
* Idiom, a type of fixed expression
* Metaphorical expression, a particular word, phrase, o ...
of the
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
. Some of these enzymes have "
proof-reading" mechanisms. Here, an enzyme such as
DNA polymerase
A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create ...
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 in high-fidelity mammalian polymerases.
Similar proofreading mechanisms are also found in
RNA polymerase
In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that synthesizes RNA from a DNA template.
Using the enzyme helicase, RNAP locally opens the ...
,
aminoacyl tRNA synthetase
An aminoacyl-tRNA synthetase (aaRS or ARS), also called tRNA-ligase, is an enzyme that attaches the appropriate amino acid onto its corresponding tRNA. It does so by catalyzing the transesterification of a specific cognate amino acid or its pre ...
s and
ribosome
Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...
s.
Conversely, some enzymes display
enzyme promiscuity
Enzyme promiscuity is the ability of an enzyme to catalyse a fortuitous side reaction in addition to its main reaction. Although enzymes are remarkably specific catalysts, they can often perform side reactions in addition to their main, native cata ...
, having broad specificity and acting on a range of different physiologically relevant substrates. Many enzymes possess small side activities which arose fortuitously (i.e.
neutrally), which may be the starting point for the evolutionary selection of a new function.
"Lock and key" model
To explain the observed specificity of enzymes, in 1894
Emil Fischer
Hermann Emil Louis Fischer (; 9 October 1852 – 15 July 1919) was a German chemist and 1902 recipient of the Nobel Prize in Chemistry. He discovered the Fischer esterification. He also developed the Fischer projection, a symbolic way of dra ...
proposed that both the enzyme and the substrate possess specific complementary geometric shapes that fit exactly into one another. This is often referred to as "the lock and key" model.
This early model explains enzyme specificity, but fails to explain the stabilization of the transition state that enzymes achieve.
Induced fit model
In 1958,
Daniel Koshland suggested a modification to the lock and key model: since enzymes are rather flexible structures, the active site is continuously reshaped by interactions with the substrate as the substrate interacts with the enzyme. As a result, the substrate does not simply bind to a rigid active site; the amino acid
side-chains that make up the active site are molded into the precise positions that enable the enzyme to perform its catalytic function. In some cases, such as
glycosidases
Glycoside hydrolases (also called glycosidases or glycosyl hydrolases) catalyze
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the rea ...
, the substrate
molecule
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...
also changes shape slightly as it enters the active site. The active site continues to change until the substrate is completely bound, at which point the final shape and charge distribution is determined.
Induced fit may enhance the fidelity of molecular recognition in the presence of competition and noise via the
conformational proofreading
Conformational proofreading or conformational selection is a general mechanism of molecular recognition systems in which introducing a structural mismatch between a molecular recognizer and its target, or an energetic barrier, enhances the recogn ...
mechanism.
Catalysis
Enzymes can accelerate reactions in several ways, all of which lower the
activation energy
In chemistry and physics, activation energy is the minimum amount of energy that must be provided for compounds to result in a chemical reaction. The activation energy (''E''a) of a reaction is measured in joules per mole (J/mol), kilojoules pe ...
(ΔG
‡,
Gibbs free energy
In thermodynamics, the Gibbs free energy (or Gibbs energy; symbol G) is a thermodynamic potential that can be used to calculate the maximum amount of work that may be performed by a thermodynamically closed system at constant temperature and pr ...
)
# By stabilizing the transition state:
#* Creating an environment with a charge distribution complementary to that of the transition state to lower its energy
# By providing an alternative reaction pathway:
#* Temporarily reacting with the substrate, forming a covalent intermediate to provide a lower energy transition state
# By destabilising the substrate ground state:
#* Distorting bound substrate(s) into their transition state form to reduce the energy required to reach the transition state
#* By orienting the substrates into a productive arrangement to reduce the reaction entropy change (the contribution of this mechanism to catalysis is relatively small)
Enzymes may use several of these mechanisms simultaneously. For example, proteases such as
trypsin
Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting these long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the dig ...
perform covalent catalysis using a catalytic triad, stabilise charge build-up on the transition states using an oxyanion hole, complete
hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
using an oriented water substrate.
Dynamics
Enzymes are not rigid, static structures; instead they have complex internal dynamic motions – that is, movements of parts of the enzyme's structure such as individual amino acid residues, groups of residues forming a turn (biochemistry), protein loop or unit of protein secondary structure, secondary structure, or even an entire protein domain. These motions give rise to a conformational ensemble of slightly different structures that interconvert with one another at thermodynamic equilibrium, equilibrium. Different states within this ensemble may be associated with different aspects of an enzyme's function. For example, different conformations of the enzyme dihydrofolate reductase are associated with the substrate binding, catalysis, cofactor release, and product release steps of the catalytic cycle, consistent with catalytic resonance theory.
Substrate presentation
Substrate presentation is a process where the enzyme is sequestered away from its substrate. Enzymes can be sequestered to the plasma membrane away from a substrate in the nucleus or cytosol. Or within the membrane, an enzyme can be sequestered into lipid rafts away from its substrate in the disordered region. When the enzyme is released it mixes with its substrate. Alternatively, the enzyme can be sequestered near its substrate to activate the enzyme. For example, the enzyme can be soluble and upon activation bind to a lipid in the plasma membrane and then act upon molecules in the plasma membrane.
Allosteric modulation
Allosteric sites are pockets on the enzyme, distinct from the active site, that bind to molecules in the cellular environment. These molecules then cause a change in the conformation or dynamics of the enzyme that is transduced to the active site and thus affects the reaction rate of the enzyme. In this way, allosteric interactions can either inhibit or activate enzymes. Allosteric interactions with metabolites upstream or downstream in an enzyme's metabolic pathway cause feedback regulation, altering the activity of the enzyme according to the Flux (metabolism), flux through the rest of the pathway.
Cofactors
![Transketolase + TPP](https://upload.wikimedia.org/wikipedia/commons/f/f4/Transketolase_%2B_TPP.png)
Some enzymes do not need additional components to show full activity. Others require non-protein molecules called cofactors to be bound for activity. Cofactors can be either inorganic (e.g., ion, metal ions and iron–sulfur clusters) or organic molecules, organic compounds (e.g., flavin group, flavin and heme). These cofactors serve many purposes; for instance, metal ions can help in stabilizing nucleophilic species within the active site. Organic cofactors can be either coenzymes, which are released from the enzyme's active site during the reaction, or prosthetic groups, which are tightly bound to an enzyme. Organic prosthetic groups can be covalently bound (e.g., biotin in enzymes such as pyruvate carboxylase).
An example of an enzyme that contains a cofactor is carbonic anhydrase, which uses a zinc cofactor bound as part of its active site. These tightly bound ions or molecules are usually found in the active site and are involved in catalysis.
For example, flavin and heme cofactors are often involved in redox reactions.
Enzymes that require a cofactor but do not have one bound are called ''apoenzymes'' or ''apoproteins''. An enzyme together with the cofactor(s) required for activity is called a ''holoenzyme'' (or haloenzyme). The term ''holoenzyme'' can also be applied to enzymes that contain multiple protein subunits, such as the
DNA polymerase
A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create ...
s; here the holoenzyme is the complete complex containing all the subunits needed for activity.
Coenzymes
Coenzymes are small organic molecules that can be loosely or tightly bound to an enzyme. Coenzymes transport chemical groups from one enzyme to another.
Examples include Nicotinamide adenine dinucleotide, NADH, Nicotinamide adenine dinucleotide phosphate, NADPH and adenosine triphosphate (ATP). Some coenzymes, such as flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), thiamine pyrophosphate (TPP), and tetrahydrofolate (THF), are derived from vitamins. These coenzymes cannot be synthesized by the body ''De novo synthesis, de novo'' and closely related compounds (vitamins) must be acquired from the diet. The chemical groups carried include:
* the hydride ion (H
−), carried by nicotinamide adenine dinucleotide, NAD or NADP
+
* the phosphate group, carried by adenosine triphosphate
* the acetyl group, carried by coenzyme A
* formyl, methenyl or methyl groups, carried by folic acid and
* the methyl group, carried by S-adenosylmethionine
Since coenzymes are chemically changed as a consequence of enzyme action, it is useful to consider coenzymes to be a special class of substrates, or second substrates, which are common to many different enzymes. For example, about 1000 enzymes are known to use the coenzyme NADH.
Coenzymes are usually continuously regenerated and their concentrations maintained at a steady level inside the cell. For example, NADPH is regenerated through the pentose phosphate pathway and ''S''-adenosylmethionine by methionine adenosyltransferase. This continuous regeneration means that small amounts of coenzymes can be used very intensively. For example, the human body turns over its own weight in ATP each day.
Thermodynamics
![Enzyme catalysis energy levels 2](https://upload.wikimedia.org/wikipedia/commons/c/c0/Enzyme_catalysis_energy_levels_2.svg)
As with all catalysts, enzymes do not alter the position of the chemical equilibrium of the reaction. In the presence of an enzyme, the reaction runs in the same direction as it would without the enzyme, just more quickly.
For example, carbonic anhydrase catalyzes its reaction in either direction depending on the concentration of its reactants:
The rate of a reaction is dependent on the
activation energy
In chemistry and physics, activation energy is the minimum amount of energy that must be provided for compounds to result in a chemical reaction. The activation energy (''E''a) of a reaction is measured in joules per mole (J/mol), kilojoules pe ...
needed to form the transition state which then decays into products. Enzymes increase reaction rates by lowering the energy of the transition state. First, binding forms a low energy enzyme-substrate complex (ES). Second, the enzyme stabilises the transition state such that it requires less energy to achieve compared to the uncatalyzed reaction (ES
‡). Finally the enzyme-product complex (EP) dissociates to release the products.
Enzymes can couple two or more reactions, so that a thermodynamically favorable reaction can be used to "drive" a thermodynamically unfavourable one so that the combined energy of the products is lower than the substrates. For example, the hydrolysis of Adenosine triphosphate, ATP is often used to drive other chemical reactions.
Kinetics
Enzyme kinetics is the investigation of how enzymes bind substrates and turn them into products. The rate data used in kinetic analyses are commonly obtained from enzyme assays. In 1913 Leonor Michaelis and Maud Leonora Menten proposed a quantitative theory of enzyme kinetics, which is referred to as Michaelis–Menten kinetics. The major contribution of Michaelis and Menten was to think of enzyme reactions in 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 honor. The enzyme then catalyzes the chemical step in the reaction and releases the product. This work was further developed by George Edward Briggs, G. E. Briggs and J. B. S. Haldane, who derived kinetic equations that are still widely used today.
Enzyme rates depend on Solution (chemistry), solution conditions and substrate concentration. To find the maximum speed of an enzymatic reaction, the substrate concentration is increased until a constant rate of product formation is seen. This is shown in the saturation curve on the right. Saturation happens because, as substrate concentration increases, more and more of the free enzyme is converted into the substrate-bound ES complex. At the maximum reaction rate (''V''
max) of the enzyme, all the enzyme active sites are bound to substrate, and the amount of ES complex is the same as the total amount of enzyme.
''V''
max is only one of several important kinetic parameters. The amount of substrate needed to achieve a given rate of reaction is also important. This is given by the Michaelis–Menten constant (''K''
m), which is the substrate concentration required for an enzyme to reach one-half its maximum reaction rate; generally, each enzyme has a characteristic ''K''
M for a given substrate. Another useful constant is ''k''
cat, also called the ''turnover number'', which is the number of substrate molecules handled by one active site per second.
The efficiency of an enzyme can be expressed in terms of ''k''
cat/''K''
m. This is also called the specificity constant and incorporates the rate constants for all steps in the reaction up to and including the first irreversible step. 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 10
8 to 10
9 (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 enzyme, catalytically perfect'' or ''kinetically perfect''. Example of such enzymes are triosephosphateisomerase, triose-phosphate isomerase, carbonic anhydrase, acetylcholinesterase,
catalase
Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting t ...
, fumarase, β-lactamase, and superoxide dismutase.
The turnover of such enzymes can reach several million reactions per second.
But most enzymes are far from perfect: the average values of
and
are about
and
, respectively.
Michaelis–Menten kinetics relies on the law of mass action, which is derived from the assumptions of free diffusion and thermodynamically driven random collision. Many biochemical or cellular processes deviate significantly from these conditions, because of macromolecular crowding and constrained molecular movement. More recent, complex extensions of the model attempt to correct for these effects.
Inhibition
Enzyme reaction rates can be decreased by various types of enzyme inhibitors.
Types of inhibition
Competitive
A competitive inhibitor and substrate cannot bind to the enzyme at the same time.
Often competitive inhibitors strongly resemble the real substrate of the enzyme. For example, the drug methotrexate is a competitive inhibitor of the enzyme dihydrofolate reductase, which catalyzes the reduction of folic acid, dihydrofolate to tetrahydrofolate.
The similarity between the structures of dihydrofolate and this drug are shown in the accompanying figure. This type of inhibition can be overcome with high substrate concentration. In some cases, the inhibitor can bind to a site other than the binding-site of the usual substrate and exert an #Allosteric modulation, allosteric effect to change the shape of the usual binding-site.
Non-competitive
A non-competitive inhibition, non-competitive inhibitor binds to a site other than where the substrate binds. The substrate still binds with its usual affinity and hence K
m remains the same. However the inhibitor reduces the catalytic efficiency of the enzyme so that V
max is reduced. In contrast to competitive inhibition, non-competitive inhibition cannot be overcome with high substrate concentration.
Uncompetitive
An uncompetitive inhibitor cannot bind to the free enzyme, only to the enzyme-substrate complex; hence, these types of inhibitors are most effective at high substrate concentration. In the presence of the inhibitor, the enzyme-substrate complex is inactive.
This type of inhibition is rare.
Mixed
A mixed inhibition, mixed inhibitor binds to an allosteric site and the binding of the substrate and the inhibitor affect each other. The enzyme's function is reduced but not eliminated when bound to the inhibitor. This type of inhibitor does not follow the Michaelis–Menten equation.
Irreversible
An irreversible inhibitor permanently inactivates the enzyme, usually by forming a
covalent bond
A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...
to the protein. Penicillin and aspirin
are common drugs that act in this manner.
Functions of inhibitors
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 at the beginning of the pathway 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. Major metabolic pathways such as the citric acid cycle make use of this mechanism.
Since inhibitors modulate the function of enzymes they are often used as drugs. Many such drugs are reversible competitive inhibitors that resemble the enzyme's native substrate, similar to methotrexate above; other well-known examples include statins used to treat high cholesterol,
and protease inhibitor (pharmacology), protease inhibitors used to treat retrovirus, retroviral infections such as HIV. A common example of an irreversible inhibitor that is used as a drug is aspirin, which inhibits the Cyclooxygenase, COX-1 and Cyclooxygenase, COX-2 enzymes that produce the inflammation messenger prostaglandin.
Other enzyme inhibitors are poisons. For example, the poison cyanide is an irreversible enzyme inhibitor that combines with the copper and iron in the active site of the enzyme cytochrome c oxidase and blocks cellular respiration.
Factors affecting enzyme activity
As enzymes are made up of proteins, their actions are sensitive to change in many physio chemical factors such as pH, temperature, substrate concentration, etc.
The following table shows pH optima for various enzymes.
Biological function
Enzymes serve a wide variety of function (biology), functions inside living organisms. They are indispensable for signal transduction and cell regulation, often via kinases and phosphatases. They also generate movement, with myosin hydrolyzing ATP to generate muscle contraction, and also transport cargo around the cell as part of the cytoskeleton. Other ATPases in the cell membrane are ion pump (biology), ion pumps involved in active transport. Enzymes are also involved in more exotic functions, such as luciferase generating light in firefly, fireflies. Viruses can also contain enzymes for infecting cells, such as the HIV integrase and reverse transcriptase, or for viral release from cells, like the influenza virus neuraminidase.
An important function of enzymes is in the digestive systems of animals. Enzymes such as amylases and proteases break down large molecules (
starch
Starch or amylum is a polymeric carbohydrate consisting of numerous glucose units joined by glycosidic bonds. This polysaccharide is produced by most green plants for energy storage. Worldwide, it is the most common carbohydrate in human diets ...
or
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s, respectively) into smaller ones, so they can be absorbed by the intestines. Starch molecules, for example, are too large to be absorbed from the intestine, but enzymes hydrolyze the starch chains into smaller molecules such as maltose and eventually glucose, which can then be absorbed. Different enzymes digest different food substances. In ruminants, which have Herbivore, herbivorous diets, microorganisms in the gut produce another enzyme, cellulase, to break down the cellulose cell walls of plant fiber.
Metabolism
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. Sometimes more than one enzyme can catalyze the same reaction in parallel; this can allow more complex regulation: with, for example, a low constant activity provided by one enzyme but an inducible high activity from a second enzyme.
Enzymes determine what steps occur in these pathways. Without enzymes, metabolism would neither progress through the same steps and could not be regulated to serve the needs of the cell. Most central metabolic pathways are regulated at a few key steps, typically through enzymes whose activity involves the hydrolysis of Adenosine triphosphate, ATP. Because this reaction releases so much energy, other reactions that are endothermic, thermodynamically unfavorable can be coupled to ATP hydrolysis, driving the overall series of linked metabolic reactions.
Control of activity
There are five main ways that enzyme activity is controlled in the cell.
Regulation
Enzymes can be either enzyme activator, activated or enzyme inhibitor, inhibited by other molecules. 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, 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 homeostasis, homeostatic devices, the control of enzymatic action helps to maintain a stable internal environment in living organisms.
Post-translational modification
Examples of post-translational modification include phosphorylation, myristoylation and glycosylation.
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.
Another example 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
or proenzyme.
Quantity
Enzyme production (Transcription (genetics), transcription and Translation (genetics), translation of enzyme genes) can be enhanced or diminished by a cell in response to changes in the cell's environment. This form of regulation of gene expression, gene regulation is called enzyme induction. For example, bacteria may become antibiotic resistance, resistant to antibiotics such as penicillin because enzymes called beta-lactamases are induced that hydrolyse the crucial Beta-lactam, beta-lactam ring within the penicillin molecule.
Another example comes from enzymes in the liver called cytochrome P450 oxidases, which are important in drug metabolism. Induction or inhibition of these enzymes can cause drug interactions.
Enzyme levels can also be regulated by changing the rate of enzyme catabolism, degradation.
The opposite of enzyme induction is enzyme repression.
Subcellular distribution
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 golgi apparatus, Golgi and used by a different set of enzymes as a source of energy in the mitochondrion, through β-oxidation. In addition, protein targeting, trafficking of the enzyme to different compartments may change the degree of protonation (e.g., the neutral cytoplasm and the acidic lysosome) or oxidative state (e.g., oxidizing periplasm or reducing cytoplasm) which in turn affects enzyme activity.
In contrast to partitioning into membrane bound organelles, enzyme subcellular localisation may also be altered through polymerisation of enzymes into macromolecular cytoplasmic filaments.
Organ specialization
In multicellular eukaryotes, cells in different organ (anatomy), organs and tissue (biology), tissues have different patterns of gene expression and therefore have different sets of enzymes (known as isozymes) available for metabolic reactions. This provides a mechanism for regulating the overall metabolism of the organism. For example,
hexokinase
A hexokinase is an enzyme that phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate for hexokinases, and glucose-6-phosphate is the most important product. Hexokina ...
, the first enzyme in the glycolysis pathway, has a specialized form called glucokinase expressed in the liver and pancreas that has a lower affinity (pharmacology), affinity for glucose yet is more sensitive to glucose concentration. This enzyme is involved in sensing blood sugar and regulating insulin production.
Involvement in disease
![Phenylalanine hydroxylase mutations](https://upload.wikimedia.org/wikipedia/commons/0/0b/Phenylalanine_hydroxylase_mutations.svg)
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 a genetic disease. The malfunction of just one type of enzyme out of the thousands of types present in the human body can be fatal. An example of a fatal genetic disease due to enzyme insufficiency is Tay–Sachs disease, in which patients lack the enzyme hexosaminidase.
One example of enzyme deficiency is the most common type of phenylketonuria. Many different single amino acid mutations in the enzyme phenylalanine hydroxylase, which catalyzes the first step in the degradation of phenylalanine, result in build-up of phenylalanine and related products. Some mutations are in the active site, directly disrupting binding and catalysis, but many are far from the active site and reduce activity by destabilising the protein structure, or affecting correct oligomerisation.
This can lead to intellectual disability if the disease is untreated. Another example is pseudocholinesterase deficiency, in which the body's ability to break down choline ester drugs is impaired.
Oral administration of enzymes can be used to treat some functional enzyme deficiencies, such as pancreatic insufficiency and lactose intolerance.
Another way enzyme malfunctions can cause disease comes from germline mutations in genes coding for DNA repair enzymes. Defects in these enzymes cause cancer because cells are less able to repair mutations in their
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
s. This causes a slow accumulation of mutations and results in the carcinogenesis, development of cancers. An example of such a hereditary cancer syndrome is xeroderma pigmentosum, which causes the development of skin cancers in response to even minimal exposure to ultraviolet light.
Evolution
Similar to any other protein, enzymes change over time through mutations and sequence divergence. Given their central role in metabolism, enzyme evolution plays a critical role in adaptation. A key question is therefore whether and how enzymes can change their enzymatic activities alongside. It is generally accepted that many new enzyme activities have evolved through gene duplication and mutation of the duplicate copies although evolution can also happen without duplication. One example of an enzyme that has changed its activity is the ancestor of Methionyl aminopeptidase, methionyl amino peptidase (MAP) and creatine amidinohydrolase (creatinase) which are clearly homologous but catalyze very different reactions (MAP removes the amino-terminal methionine in new proteins while creatinase hydrolyses creatine to sarcosine and urea). In addition, MAP is metal-ion dependent while creatinase is not, hence this property was also lost over time. Small changes of enzymatic activity are extremely common among enzymes. In particular, substrate binding specificity (see above) can easily and quickly change with single amino acid changes in their substrate binding pockets. This is frequently seen in the main enzyme classes such as kinases.
Artificial (in vitro) evolution is now commonly used to modify enzyme activity or specificity for industrial applications (see below).
Industrial applications
Enzymes are used in the chemical industry and other industrial applications when extremely specific catalysts are required. Enzymes in general are limited in the number of reactions they have evolved to catalyze and also by their lack of stability in organic solvents and at high temperatures. As a consequence, protein engineering is an active area of research and involves attempts to create new enzymes with novel properties, either through rational design or ''in vitro'' evolution. These efforts have begun to be successful, and a few enzymes have now been designed "from scratch" to catalyze reactions that do not occur in nature.
See also
* Industrial enzymes
* List of enzymes
* Molecular machine
Enzyme databases
* BRENDA
* ExPASy
* IntEnz
* KEGG
* MetaCyc
References
Further reading
General
* , A biochemistry textbook available free online through NCBI Bookshelf.
Etymology and history
*, A history of early enzymology.
Enzyme structure and mechanism
*
Kinetics and inhibition
*
External links
*
{{Authority control
Enzymes,
Biomolecules
Catalysis
Metabolism
Process chemicals