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Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside
cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which a monk or religious recluse lives * Prison cell, a room used to hold peopl ...
, balancing the loss of cellular
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
s (via
degradation Degradation may refer to: Science * Degradation (geology), lowering of a fluvial surface by erosion * Degradation (telecommunications), of an electronic signal * Biodegradation of organic substances by living organisms * Environmental degradation i ...

degradation
or
export An export in international trade International trade is the exchange of capital, goods, and services across international borders or territories because there is a need or want of goods or services. In most countries, such trade rep ...
) through the production of new proteins. Proteins perform a number of critical functions as
enzyme Enzymes () are protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast array of functions within organisms, including , , , providing and , and from one location to another. Proteins diff ...

enzyme
s, structural proteins or
hormone A hormone (from the Greek#REDIRECT Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially the Hellenic Republic, is a country located in Southeast Europe. Its population is appr ...

hormone
s. Protein synthesis is a very similar process for both
prokaryote A prokaryote () is a single-celled organism A unicellular organism, also known as a single-celled organism, is an organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual contig ...
s and
eukaryote Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interact ...

eukaryote
s but there are some distinct differences. Protein synthesis can be divided broadly into two phases - transcription and
translation Translation is the communication of the meaning Meaning most commonly refers to: * Meaning (linguistics), meaning which is communicated through the use of language * Meaning (philosophy), definition, elements, and types of meaning discusse ...

translation
. During transcription, a section of
DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically neutral gro ...

DNA
encoding a protein, known as a
gene In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mecha ...

gene
, is converted into a template molecule called
messenger RNA In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, molecular synthesis, modification, m ...
(mRNA). This conversion is carried out by enzymes, known as
RNA polymerases In molecular biology, RNA polymerase (abbreviated RNAP or RNApol, and officially DNA-directed (dependent) RNA polymerase), is an enzyme that synthesizes RNA from a DNA template. Using the enzyme helicase, RNAP locally opens the double-strande ...
, in the
nucleus of the cell
nucleus of the cell
. In eukaryotes, this mRNA is initially produced in a premature form (
pre-mRNA Micrograph of gene transcription of ribosomal RNA illustrating the growing primary transcripts A primary transcript is the single-stranded ribonucleic acid (RNA) product synthesized by transcription of DNA, and processed to yield various mature ...
) which undergoes
post-transcriptional modification Post-transcriptional modification or co-transcriptional modification is a set of biological processes common to most eukaryotic Eukaryotes () are organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''or ...
s to produce
mature mRNA Mature messenger RNA, often abbreviated as mature mRNA is a eukaryotic RNA transcript that has been spliced and processed and is ready for translation Translation is the communication of the meaning of a source-language text by means of ...
. The mature mRNA is exported from the cell nucleus via
nuclear pore A nuclear pore is a part of a large complex of proteins, known as a nuclear pore complex that spans the nuclear envelope, which is the double membrane surrounding the eukaryotic Eukaryotes () are organism In biology, an organism ( ...
s to the
cytoplasm In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes ...
of the cell for translation to occur. During translation, the mRNA is read by
ribosome Ribosomes ( ), also called Palade granules, are macromolecular machines, found within all cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small ...

ribosome
s which use the
nucleotide Nucleotides are organic molecules , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, ...

nucleotide
sequence of the mRNA to determine the sequence of
amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acid
s. The ribosomes catalyze the formation of
covalent A covalent bond is a chemical bond A chemical bond is a lasting attraction between atom An atom is the smallest unit of ordinary matter In classical physics and general chemistry, matter is any substance that has mass and take ...
peptide bond In organic chemistry, a peptide bond is an amide type of Covalent bond, covalent chemical bond linking two consecutive alpha-amino acids from C1 (carbon number one) of one alpha-amino acid and N2 (nitrogen number two) of another, along a peptide o ...

peptide bond
s between the encoded amino acids to form a
polypeptide chain Peptides (from Greek language Greek (modern , romanized: ''Elliniká'', Ancient Greek, ancient , ''Hellēnikḗ'') is an independent branch of the Indo-European languages, Indo-European family of languages, native to Greece, Cyprus, Albania, o ...
. Following translation the polypeptide chain must fold to form a functional protein; for example, to function as an enzyme the polypeptide chain must fold correctly to produce a functional
active site
active site
. In order to adopt a functional three-dimensional (3D) shape, the polypeptide chain must first form a series of smaller underlying structures called secondary structures. The polypeptide chain in these secondary structures then folds to produce the overall 3D
tertiary structure Biomolecular structure is the intricate folded, three-dimensional shape that is formed by a molecule A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an elect ...
. Once correctly folded, the protein can undergo further maturation through different
post-translational modification Post-translational modification (PTM) refers to the covalent and generally enzyme, enzymatic modification of proteins following protein biosynthesis. Proteins are synthesized by ribosomes translation (biology), translating mRNA into polypeptide c ...
s. Post-translational modifications can alter the protein's ability to function, where it is located within the cell (e.g. cytoplasm or nucleus) and the protein's ability to interact with other proteins. Protein biosynthesis has a key role in disease as changes and errors in this process, through underlying DNA mutations or protein misfolding, are often the underlying causes of a disease. DNA mutations change the subsequent mRNA sequence, which then alters the mRNA encoded amino acid sequence. Mutations can cause the polypeptide chain to be shorter by generating a stop sequence which causes early termination of translation. Alternatively, a mutation in the mRNA sequence changes the specific amino acid encoded at that position in the polypeptide chain. This amino acid change can impact the protein's ability to function or to fold correctly. Misfolded proteins are often implicated in disease as improperly folded proteins have a tendency to stick together to form dense protein clumps. These clumps are linked to a range of diseases, often
neurological Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is a branch of medicine Medicine is the Art (skill), art, science, and Praxis (process) , practice of caring for a patient and managing the d ...
, including
Alzheimer's disease Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of . The most common early symptom is difficulty in . As the disease advance ...
and
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a of the that mainly affects the . The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms become more common. The most obvious early symptoms are , , , and . an ...
.


Transcription

Transcription occurs in the nucleus using DNA as a template to produce mRNA. In eukaryotes, this mRNA molecule is known as pre-mRNA as it undergoes post-transcriptional modifications in the nucleus to produce a mature mRNA molecule. However, in prokaryotes post-transcriptional modifications are not required so the mature mRNA molecule is immediately produced by transcription. Initially, an enzyme known as a
helicase Helicases are a class of enzyme Enzymes () are s that act as s (biocatalysts). Catalysts accelerate . The molecules upon which enzymes may act are called , and the enzyme converts the substrates into different molecules known as . Almost ...

helicase
acts on the molecule of DNA. DNA has an antiparallel, double helix structure composed of two, complementary
polynucleotide A polynucleotide molecule is a biopolymer Biopolymers are natural polymers produced by the cells of Organism, living organisms. Biopolymers consist of monomeric units that are Covalent_bond, covalently bonded to form larger molecules. There are th ...
strands, held together by
hydrogen bond A hydrogen bond (or H-bond) is a primarily electrostatic Electrostatics is a branch of physics Physics is the that studies , its , its and behavior through , and the related entities of and . "Physical science is that department ...

hydrogen bond
s between the base pairs. The helicase disrupts the hydrogen bonds causing a region of DNA - corresponding to a gene - to unwind, separating the two DNA strands and exposing a series of bases. Despite DNA being a double stranded molecule, only one of the strands acts as a template for pre-mRNA synthesis - this strand is known as the template strand. The other DNA strand (which is
complementary A complement is often something that completes something else, or at least adds to it in some useful way. Thus it may be: * Complement (linguistics), a word or phrase having a particular syntactic role ** Subject complement, a word or phrase addi ...
to the template strand) is known as the coding strand. Both DNA and RNA have intrinsic directionality, meaning there are two distinct ends of the molecule. This property of directionality is due to the asymmetrical underlying nucleotide subunits, with a phosphate group on one side of the pentose sugar and a base on the other. The five carbons in the pentose sugar are numbered from 1' (where ' means prime) to 5'. Therefore, the phosphodiester bonds connecting the nucleotides are formed by joining the
hydroxyl A hydroxy or hydroxyl group is a functional group with the chemical formula -OH and composed of one oxygen Oxygen is the chemical element Image:Simple Periodic Table Chart-blocks.svg, 400px, Periodic table, The periodic table of the ...

hydroxyl
group of on the 3' carbon of one nucleotide to the phosphate group on the 5' carbon of another nucleotide. Hence, the coding strand of DNA runs in a 5' to 3' direction and the complementary, template DNA strand runs in the opposite direction from 3' to 5'. The enzyme
RNA polymerase In molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, molecular synthesis, modification, m ...

RNA polymerase
binds to the exposed template strand and reads from the gene in the 3' to 5' direction. Simultaneously, the RNA polymerase synthesizes a single strand of pre-mRNA in the 5'-to-3' direction by catalysing the formation of
phosphodiester bondsImage:Phosphodiester Bond Diagram.svg, 200px, Diagram of phosphodiester bonds (PO43−) between three nucleotides. A phosphodiester bond occurs when exactly two of the hydroxyl groups in phosphoric acid react with hydroxyl groups on other molecules ...
between activated nucleotides (free in the nucleus) that are capable of complementary
base pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids Nucleic acids are biopolymer Biopolymers are natural polymers produced by the cells of Organism, living organisms. Biopolymers consist of monomeric units that are Covalent_ ...
ing with the template strand. Behind the moving RNA polymerase the two strands of DNA rejoin, so only 12 base pairs of DNA are exposed at one time. RNA polymerase builds the pre-mRNA molecule at a rate of 20 nucleotides per second enabling the production of thousands of pre-mRNA molecules from the same gene in an hour. Despite the fast rate of synthesis, the RNA polymerase enzyme contains its own proofreading mechanism. The proofreading mechanisms allows the RNA polymerase to remove incorrect nucleotides (which are not complementary to the template strand of DNA) from the growing pre-mRNA molecule through an excision reaction. When RNA polymerases reaches a specific DNA sequence which terminates transcription, RNA polymerase detaches and pre-mRNA synthesis is complete. The pre-mRNA molecule synthesized is complementary to the template DNA strand and shares the same nucleotide sequence as the coding DNA strand. However, there is one crucial difference in the nucleotide composition of DNA and mRNA molecules. DNA is composed of the bases -
guanine Guanine () (symbol A symbol is a mark, sign, or word In linguistics, a word of a spoken language can be defined as the smallest sequence of phonemes that can be uttered in isolation with semantic, objective or pragmatics, practical meaning ...

guanine
,
cytosine Cytosine () (symbol A symbol is a mark, sign, or that indicates, signifies, or is understood as representing an , , or . Symbols allow people to go beyond what is n or seen by creating linkages between otherwise very different s and s. Al ...

cytosine
,
adenine Adenine (A, Ade) is a nucleobase 230px, Pyrimidine nucleobases are simple ring molecules. Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides Nucleos ...

adenine
and
thymine Thymine () (symbol A symbol is a mark, sign, or word In linguistics, a word of a spoken language can be defined as the smallest sequence of phonemes that can be uttered in isolation with semantic, objective or pragmatics, practical meaning ...

thymine
(G, C, A and T) - RNA is also composed of four bases - guanine, cytosine, adenine and
uracil Uracil () ( U or Ura) is one of the four s in the that are represented by the letters A, G, C and U. The others are (A), (C), and (G). In RNA, uracil binds to via two . In , the uracil nucleobase is replaced by . Uracil is a form of . Ura ...

uracil
. In RNA molecules, the DNA base thymine is replaced by uracil which is able to base pair with adenine. Therefore, in the pre-mRNA molecule, all complementary bases which would be thymine in the coding DNA strand are replaced by uracil.


Post-transcriptional modifications

Once transcription is complete, the pre-mRNA molecule undergoes
post-transcriptional modification Post-transcriptional modification or co-transcriptional modification is a set of biological processes common to most eukaryotic Eukaryotes () are organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''or ...
s to produce a mature mRNA molecule. There are 3 key steps within post-transcriptional modifications: # Addition of a
5' cap In molecular biology Molecular biology is the branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molec ...
to the 5' end of the pre-mRNA molecule # Addition of a 3'
poly(A) tail Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA Image:MRNA-interaction.png, 500px, The "life cycle" of an mRNA in a eukaryote, eukaryotic cell. RNA is transcription (genetics), transcribed in the ...

poly(A) tail
is added to the 3' end pre-mRNA molecule # Removal of
intron An intron (for ''intragenic region'') is any nucleotide sequence A nucleic acid sequence is a succession of bases signified by a series of a set of five different letters that indicate the order of nucleotides Nucleotides are organic molecul ...

intron
s via
RNA splicing RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcription (biology), transcript is transformed into a mature messenger RNA (Messenger RNA, mRNA). It works by removing introns (non-coding re ...

RNA splicing
The 5' cap is added to the 5' end of the pre-mRNA molecule and is composed of a guanine nucleotide modified through
methylation In the chemical sciences, methylation denotes the addition of a methyl group A methyl group is an alkyl derived from methane, containing one carbon atom chemical bond, bonded to three hydrogen atoms — CH3. In chemical formula, fo ...
. The purpose of the 5' cap is to prevent break down of mature mRNA molecules before translation, the cap also aids binding of the ribosome to the mRNA to start translation and enables mRNA to be differentiated from other RNAs in the cell. In contrast, the 3' Poly(A) tail is added to the 3' end of the mRNA molecule and is composed of 100-200 adenine bases. These distinct mRNA modifications enable the cell to detect that the full mRNA message is intact if both the 5' cap and 3' tail are present. This modified pre-mRNA molecule then undergoes the process of RNA splicing. Genes are composed of a series of introns and
exon An exon is any part of a gene In biology, a gene (from ''genos'' "...Wilhelm Johannsen coined the word gene to describe the Mendelian_inheritance#History, Mendelian units of heredity..." (Greek language, Greek) meaning ''generation'' or ...
s, introns are nucleotide sequences which do not encode a protein while, exons are nucleotide sequences that directly encode a protein. Introns and exons are present in both the underlying DNA sequence and the pre-mRNA molecule, therefore, in order to produce a mature mRNA molecule encoding a protein, splicing must occur. During splicing, the intervening introns are removed from the pre-mRNA molecule by a multi-protein complex known as a
spliceosome A spliceosome is a large ribonucleoprotein (RNP) complex found primarily within the nucleus ''Nucleus'' (plural nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom ...
(composed of over 150 proteins and RNA). This mature mRNA molecule is then exported into the cytoplasm through nuclear pores in the envelope of the nucleus.


Translation

During translation, ribosomes synthesize polypeptide chains from mRNA template molecules. In eukaryotes, translation occurs in the cytoplasm of the cell, where the ribosomes are located either free floating or attached to the
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle In cell biology Cell biology (also cellular biology o ...
. In prokaryotes, which lack a nucleus, the processes of both transcription and translation occur in the cytoplasm.
Ribosome Ribosomes ( ), also called Palade granules, are macromolecular machines, found within all cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small ...

Ribosome
s are complex
molecular machine A molecular machine, nanite, or nanomachine is a molecular component that produces quasi-mechanical movements (output) in response to specific stimuli (input). In cellular biology Cell biology (also cellular biology or cytology) is a branch of ...
s, made of a mixture of protein and
ribosomal RNA Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA A non-coding RNA (ncRNA) is an RNA Ribonucleic acid (RNA) is a polymer A polymer (; Greek '' poly-'', "many" + '' -mer'', "part") is a substance or material consis ...
, arranged into two subunits (a large and a small subunit), which surround the mRNA molecule. The ribosome reads the mRNA molecule in a 5'-3' direction and uses it as a template to determine the order of amino acids in the polypeptide chain. In order to translate the mRNA molecule, the ribosome uses small molecules, known as
transfer RNA Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an e ...
s (tRNA), to deliver the correct amino acids to the ribosome. Each tRNA is composed of 70-80 nucleotides and adopts a characteristic cloverleaf structure due to the formation of hydrogen bonds between the nucleotides within the molecule. There are around 60 different types of tRNAs, each tRNA binds to a specific sequence of three nucleotides (known as a
codon The genetic code is the set of rules used by living cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which a monk or reli ...

codon
) within the mRNA molecule and delivers a specific amino acid. The ribosome initially attaches to the mRNA at the
start codon The start codon is the first codon The genetic code is the set of rules used by living cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, ...
(AUG) and begins to translate the molecule. The mRNA nucleotide sequence is read in
triplets A multiple birth is the culmination of one multiple pregnancy, wherein the mother delivers two or more offspring. A term most applicable to vertebrate species, multiple births occur in most kinds of mammals, with varying frequencies. Such births a ...

triplets
- three adjacent nucleotides in the mRNA molecule correspond to a single codon. Each tRNA has an exposed sequence of three nucleotides, known as the anticodon, which are complementary in sequence to a specific codon that may be present in mRNA. For example, the first codon encountered is the start codon composed of the nucleotides AUG. The correct tRNA with the anticodon (complementary 3 nucleotide sequence UAC) binds to the mRNA using the ribosome. This tRNA delivers the correct amino acid corresponding to the mRNA codon, in the case of the start codon, this is the amino acid methionine. The next codon (adjacent to the start codon) is then bound by the correct tRNA with complementary anticodon, delivering the next amino acid to ribosome. The ribosome then uses its
peptidyl transferase The peptidyl transferase is an aminoacyltransferase () as well as the primary enzymatic Enzymes () are protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid residue (biochem ...
enzymatic activity to catalyze the formation of the covalent peptide bond between the two adjacent amino acids. The ribosome then moves along the mRNA molecule to the third codon. The ribosome then releases the first tRNA molecule, as only two tRNA molecules can be brought together by a single ribosome at one time. The next complementary tRNA with the correct anticodon complementary to the third codon is selected, delivering the next amino acid to the ribosome which is covalently joined to the growing polypeptide chain. This process continues with the ribosome moving along the mRNA molecule adding up to 15 amino acids per second to the polypeptide chain. Behind the first ribosome, up to 50 additional ribosomes can bind to the mRNA molecule forming a
polysome A polyribosome (or polysome or ergosome) is a group of ribosomes bound to an mRNA molecule like “beads” on a “thread”. It consists of a complex of an mRNA molecule and two or more ribosome Ribosomes ( ), also called Palade granules, are ...
, this enables simultaneous synthesis of multiple identical polypeptide chains. Termination of the growing polypeptide chain occurs when the ribosome encounters a stop codon (UAA, UAG, or UGA) in the mRNA molecule. When this occurs, no tRNA can recognise it and a
release factor A release factor is a protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including E ...

release factor
induces the release of the complete polypeptide chain from the ribosome. Dr.
Har Gobind Khorana Har Gobind Khorana (9 January 1922 – 9 November 2011) was an Indian Americans, Indian American biochemist. While on the faculty of the University of Wisconsin–Madison, he shared the 1968 Nobel Prize for Physiology or Medicine with Marshall ...

Har Gobind Khorana
, a scientist originating from India, decoded the RNA sequences for about 20 amino acids. He was awarded the
Nobel Prize The Nobel Prizes ( ; sv, Nobelpriset ; no, Nobelprisen ) are five separate prizes that, according to Alfred Nobel Alfred Bernhard Nobel ( , ; 21 October 1833 – 10 December 1896) was a Swedish chemist, engineer, inventor, busines ...
in 1968, along with two other scientists, for his work.


Protein folding

Once synthesis of the polypeptide chain is complete, the polypeptide chain folds to adopt a specific structure which enables the protein to carry out its functions. The basic form of
protein structure Protein structure is the three-dimensional arrangement of atoms in an amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that c ...

protein structure
is known as the
primary structure Biomolecular structure is the intricate folded, three-dimensional shape that is formed by a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon ...

primary structure
, which is simply the polypeptide chain i.e. a sequence of covalently bonded amino acids. The primary structure of a protein is encoded by a gene. Therefore, any changes to the sequence of the gene can alter the primary structure of the protein and all subsequent levels of protein structure, ultimately changing the overall structure and function. The primary structure of a protein (the polypeptide chain) can then fold or coil to form the secondary structure of the protein. The most common types of secondary structure are known as an
alpha helix The alpha helix (α-helix) is a common motif Motif may refer to: General concepts * Motif (chess composition), an element of a move in the consideration of its purpose * Motif (folkloristics), a recurring element that creates recognizable patte ...

alpha helix
or
beta sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif Motif may refer to: General concepts * Motif (chess composition), an element of a move in the consideration of its purpose * Motif (folkloristics), a recurring element that cre ...
, these are small structures produced by hydrogen bonds forming within the polypeptide chain. This secondary structure then folds to produce the tertiary structure of the protein. The tertiary structure is the proteins overall 3D structure which is made of different secondary structures folding together. In the tertiary structure, key protein features e.g. the active site, are folded and formed enabling the protein to function. Finally, some proteins may adopt a complex
quaternary structure Biomolecular structure is the intricate folded, three-dimensional shape that is formed by a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon ...
. Most proteins are made of a single polypeptide chain, however, some proteins are composed of multiple polypeptide chains (known as subunits) which fold and interact to form the quaternary structure. Hence, the overall protein is a multi-subunit complex composed of multiple folded, polypeptide chain subunits e.g.
haemoglobin Hemoglobin or haemoglobin (spelling differences) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein in the red blood ce ...

haemoglobin
.


Post-translational modifications

When protein folding into the mature, functional 3D state is complete, it is not necessarily the end of the protein maturation pathway. A folded protein can still undergo further processing through post-translational modifications. There are over 200 known types of post-translational modification, these modifications can alter protein activity, the ability of the protein to interact with other proteins and where the protein is found within the cell e.g. in the cell nucleus or cytoplasm. Through post-translational modifications, the diversity of proteins encoded by the genome is expanded by 2 to 3
orders of magnitude An order of magnitude is an approximation of the logarithm In mathematics Mathematics (from Ancient Greek, Greek: ) includes the study of such topics as quantity (number theory), mathematical structure, structure (algebra), space (geome ...
. There are four key classes of post-translational modification: # Cleavage # Addition of chemical groups # Addition of complex molecules # Formation of intramolecular bonds


Cleavage

Cleavage Cleavage may refer to: Science * Cleavage (crystal), in mineralogy and materials science, a process of splitting a crystal * Cleavage (geology), the foliation perpendicular to stress as a result of ductile deformation * Cleavage (embryo), in embr ...

Cleavage
of proteins is an irreversible post-translational modification carried out by enzymes known as
proteases A protease (also called a peptidase or proteinase) is an enzyme that catalysis, catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of n ...
. These proteases are often highly specific and cause
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 Substitution may refer to: Arts and media *Chord substitution, in music, swapping one chord for ...

hydrolysis
of a limited number of peptide bonds within the target protein. The resulting shortened protein has an altered polypeptide chain with different amino acids at the start and end of the chain. This post-translational modification often alters the proteins function, the protein can be inactivated or activated by the cleavage and can display new biological activities.


Addition of chemical groups

Following translation, small chemical groups can be added onto amino acids within the mature protein structure. Examples of processes which add chemical groups to the target protein include methylation,
acetylation Acetylation (or in IUPAC nomenclature The International Union of Pure and Applied Chemistry The International Union of Pure and Applied Chemistry (IUPAC ) is an international federation of National Adhering Organizations that represents chemi ...
and
phosphorylation In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and the changes they undergo during ...
. Methylation is the reversible addition of a
methyl group A methyl group is an alkyl derived from methane, containing one carbon atom chemical bond, bonded to three hydrogen atoms — CH3. In chemical formula, formulas, the group is often skeletal formula#Pseudoelement symbols, abbreviated ...

methyl group
onto an amino acid catalyzed by
methyltransferase Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossm ...
enzymes. Methylation occurs on at least 9 of the 20 common amino acids, however, it mainly occurs on the amino acids
lysine Lysine (symbol Lys or K) is an α-amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, ...

lysine
and
arginine Arginine, also known as -arginine (symbol Arg or R), is an α-amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain car ...

arginine
. One example of a protein which is commonly methylated is a
histone In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanisms ...
. Histones are proteins found in the nucleus of the cell. DNA is tightly wrapped round histones and held in place by other proteins and interactions between negative charges in the DNA and positive charges on the histone. A highly specific pattern of amino acid methylation on the histone proteins is used to determine which regions of DNA are tightly wound and unable to be transcribed and which regions are loosely wound and able to be transcribed. Histone-based regulation of DNA transcription is also modified by acetylation. Acetylation is the reversible covalent addition of an
acetyl group In organic chemistry Organic chemistry is a branch of chemistry that studies the structure, properties and reactions of organic compounds, which contain carbon in covalent bonding.Clayden, J.; Greeves, N. and Warren, S. (2012) ''Organic Chemis ...

acetyl group
onto a lysine amino acid by the enzyme
acetyltransferase Chemical structure of an acetyl group bound to the remainder R of a molecule. Acetyltransferase (or transacetylase) is a type of transferase '' complexed with α-amanitin (in red). Despite the use of the term "polymerase," RNA polymerases are cla ...
. The acetyl group is removed from a donor molecule known as
acetyl coenzyme A Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reaction Biochemistry or biological chemistry, is the study of chemical processes within and relating to living organism In biology, an organism (from A ...

acetyl coenzyme A
and transferred onto the target protein. on their lysine residues by enzymes known as
histone acetyltransferase Histone acetyltransferases (HATs) are enzyme Enzymes () are protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast array of functions within organisms, including , , , providing and , ...
. The effect of acetylation is to weaken the charge interactions between the histone and DNA, thereby making more genes in the DNA accessible for transcription. The final, prevalent post-translational chemical group modification is phosphorylation. Phosphorylation is the reversible, covalent addition of a
phosphate In chemistry, a phosphate is an anion, salt (chemistry), salt, functional group or ester derived from a phosphoric acids and phosphates, phosphoric acid. It most commonly means orthophosphate, a derivative of phosphoric acid, orthophosphoric a ...

phosphate
group to specific amino acids (
serine Serine (symbol Ser or S) is an α-amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, ...

serine
,
threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated ...

threonine
and
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemi ...

tyrosine
) within the protein. The phosphate group is removed from the donor molecule
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals * American Technical Publishers * ', a Danish pension * Armenia Tree Project * Association for Transpersonal Psychology * ATP architects engineers office * ATP ...

ATP
by a protein
kinase In biochemistry Biochemistry or biological chemistry, is the study of chemical process In a scientific Science () is a systematic enterprise that Scientific method, builds and organizes knowledge in the form of Testability, testable ...
and transferred onto the
hydroxyl A hydroxy or hydroxyl group is a functional group with the chemical formula -OH and composed of one oxygen Oxygen is the chemical element Image:Simple Periodic Table Chart-blocks.svg, 400px, Periodic table, The periodic table of the ...

hydroxyl
group of the target amino acid, this produces
adenosine diphosphate Adenosine diphosphate (ADP), also known as adenosine pyrophosphate (APP), is an important organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of o ...

adenosine diphosphate
as a biproduct. This process can be reversed and the phosphate group removed by the enzyme protein phosphatase. Phosphorylation can create a binding site on the phosphorylated protein which enables it to interact with other proteins and generate large, multi-protein complexes. Alternatively, phosphorylation can change the level of protein activity by altering the ability of the protein to bind its substrate.


Addition of complex molecules

Post-translational modifications can incorporate more complex, large molecules into the folded protein structure. One common example of this is glycosylation, the addition of a polysaccharide molecule, which is widely considered to be most common post-translational modification. In glycosylation, a polysaccharide molecule (known as a glycan) is covalently added to the target protein by glycosyltransferases enzymes and modified by glycoside hydrolases, glycosidases in the
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle In cell biology Cell biology (also cellular biology o ...
and Golgi apparatus. Glycosylation can have a critical role in determining the final, folded 3D structure of the target protein. In some cases glycosylation is necessary for correct folding. N-linked glycosylation promotes protein folding by increasing solubility and mediates the protein binding to chaperone (protein), protein chaperones. Chaperones are proteins responsible for folding and maintaining the structure of other proteins. There are broadly two types of glycosylation, N-linked glycosylation and O-linked glycosylation. N-linked glycosylation starts in the endoplasmic reticulum with the addition of a precursor glycan. The precursor glycan is modified in the Golgi apparatus to produce complex glycan bound covalently to the nitrogen in an asparagine amino acid. In contrast, O-linked glycosylation is the sequential covalent addition of Monosaccharide, individual sugars onto the oxygen in the amino acids serine and threonine within the mature protein structure.


Formation of covalent bonds

Many proteins produced within the cell are secreted outside the cell to function as extracellular proteins. Extracellular proteins are exposed to a wide variety of conditions. In order to stabilize the 3D protein structure, covalent bonds are formed either within the protein or between the different polypeptide chains in the quaternary structure. The most prevalent type is a disulfide, disulfide bond (also known as a disulfide bridge). A disulfide bond is formed between two cysteine amino acids using their side chain chemical groups containing a Sulphur atom, these chemical groups are known as thiol functional groups. Disulfide bonds act to stabilize the protein structure, pre-existing structure of the protein. Disulfide bonds are formed in an redox, oxidation reaction between two thiol groups and therefore, need an oxidizing environment to react. As a result, disulfide bonds are typically formed in the oxidizing environment of the endoplasmic reticulum catalyzed by enzymes called protein disulfide isomerases. Disulfide bonds are rarely formed in the cytoplasm as it is a reducing environment.


Role of protein synthesis in disease

Many diseases are caused by mutations in genes, due to the direct connection between the DNA nucleotide sequence and the amino acid sequence of the encoded protein. Changes to the primary structure of the protein can result in the protein mis-folding or malfunctioning. Mutations within a single gene have been identified as a cause of multiple diseases, including sickle cell disease, known as single gene disorders.


Sickle cell disease

Sickle cell disease is a group of diseases caused by a mutation in a subunit of hemoglobin, a protein found in red blood cells responsible for transporting oxygen. The most dangerous of the sickle cell diseases is known as sickle cell anemia. Sickle cell anemia is the most common genetic disorder, homozygous recessive single gene disorder, meaning the sufferer must carry a mutation in both copies of the affected gene (one inherited from each parent) to suffer from the disease. Hemoglobin has a complex quaternary structure and is composed of four polypeptide subunits - two A subunits and two B subunits. Patients suffering from sickle cell anemia have a missense or substitution mutation in the gene encoding the hemoglobin B subunit polypeptide chain. A missense mutation means the nucleotide mutation alters the overall codon triplet such that a different amino acid is paired with the new codon. In the case of sickle cell anemia, the most common missense mutation is a single nucleotide mutation from thymine to adenine in the hemoglobin B subunit gene. This changes codon 6 from encoding the amino acid glutamic acid to encoding valine. This change in the primary structure of the hemoglobin B subunit polypeptide chain alters the functionality of the hemoglobin multi-subunit complex in low oxygen conditions. When red blood cells unload oxygen into the tissues of the body, the mutated haemoglobin protein starts to stick together to form a semi-solid structure within the red blood cell. This distorts the shape of the red blood cell, resulting in the characteristic "sickle" shape, and reduces cell flexibility. This rigid, distorted red blood cell can accumulate in blood vessels creating a blockage. The blockage prevents blood flow to tissues and can lead to necrosis, tissue death which causes great pain to the individual.


Cancer

Cancers form as a result of gene mutations as well as improper protein translation. In addition to cancer cells proliferating abnormally, they suppress the expression of anti-apoptotic or pro-apoptotic genes or proteins. Most cancer cells see a mutation in the signaling protein Ras, which functions as an on/off signal transductor in cells. In cancer cells, the RAS protein becomes persistently active, thus promoting the proliferation of the cell due to the absence of any regulation. Additionally, most cancer cells carry two mutant copies of the regulator gene p53, which acts as a gatekeeper for damaged genes and initiates apoptosis in malignant cells. In its absence, the cell cannot initiate apoptosis or signal for other cells to destroy it. As the tumor cells proliferate, they either remain confined to one area and are called benign, or become malignant cells that migrate to other areas of the body. Oftentimes, these malignant cells secrete proteases that break apart the extracellular matrix of tissues. This then allows the cancer to enter its terminal stage called Metastasis, in which the cells enter the bloodstream or the lymphatic system to travel to a new part of the body.


See also

*Central dogma of molecular biology *Genetic code *Gene expression *Post-translational modification *Protein folding


References


External links


A useful video visualising the process of converting DNA to protein via transcription and translation

Video visualising the process of protein folding from the non-functional primary structure to a mature, folded 3D protein structure with reference to the role of mutations and protein mis-folding in disease

A more advanced video detailing the different types of post-translational modifications and their chemical structures
{{Authority control Protein biosynthesis, Gene expression Proteins Biosynthesis Metabolism