Polyketide synthase
Encyclopedia
Polyketide synthases are a family of multi-domain
enzyme
s or enzyme complexes that produce polyketide
s, a large class of secondary metabolites, in bacteria, fungi, plant
s, and a few animal
lineages. The biosyntheses
of polyketides share striking similarities with fatty acid
biosynthesis.
The PKS genes for a certain polyketide are usually organized in one operon
in bacteria and in gene cluster
s in eukaryote
s.
Type I PKSs are further subdivided:
Iterative PKSs (IPKSs) can be still further subdivided:
Each type I polyketide-synthase module consists of several domain
s with defined functions, separated by short spacer regions. The order of modules and domains of a complete polyketide-synthase is as follows (in the order N-terminus to C-terminus):
Domains:
The polyketide chain and the starter groups are bound with their carboxy functional group
to the SH
groups of the ACP and the KS domain through a thioester
linkage: R-C
(=O
)O
H
+ H
S
-protein <=> R-C
(=O
)S
-protein + H2O
.
group to the next by trans-acylations
and is released at the end by hydrolysis
or by cyclization (alcoholysis or aminolysis
).
Starting stage:
Elongation stages:
Termination stage:
(antibiotic), lovastatin
(anticholesterol drug), and epothilone B (anticancer drug).
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s or enzyme complexes that produce polyketide
Polyketide
Polyketides are secondary metabolites from bacteria, fungi, plants, and animals. Polyketides are usually biosynthesized through the decarboxylative condensation of malonyl-CoA derived extender units in a similar process to fatty acid synthesis...
s, a large class of secondary metabolites, in bacteria, fungi, plant
Plant
Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or...
s, and a few animal
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...
lineages. The biosyntheses
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
of polyketides share striking similarities with fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
biosynthesis.
The PKS genes for a certain polyketide are usually organized in one operon
Operon
In genetics, an operon is a functioning unit of genomic DNA containing a cluster of genes under the control of a single regulatory signal or promoter. The genes are transcribed together into an mRNA strand and either translated together in the cytoplasm, or undergo trans-splicing to create...
in bacteria and in gene cluster
Gene cluster
A gene cluster is a set of two or more genes that serve to encode for the same or similar products. Because populations from a common ancestor tend to possess the same varieties of gene clusters, they are useful for tracing back recent evolutionary history...
s in eukaryote
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
s.
Classification
PKSs can be classified into three groups:- Type I polyketide synthases are large, highly modular proteins.
- Type II polyketide synthases are aggregates of monofunctional proteins.
- Type III polyketide synthases do not use ACPAcyl carrier proteinThe acyl carrier protein is an important component in both fatty acid and polyketide biosynthesis with the growing chain bound during synthesis as a thiol ester at the distal thiol of a 4'-phosphopantethiene moiety...
domains.
Type I PKSs are further subdivided:
- Iterative PKSs reuse domains in a cyclic fashion.
- Modular PKSs contain a sequence of separate modules and do not repeat domains.
Iterative PKSs (IPKSs) can be still further subdivided:
- NR-PKSs — non-reducing PKSs, the products of which are true polyketides
- PR-PKSs — partially reducing PKSs
- FR-PKSs — fully reducing PKSs, the products of which are fatty acidFatty acidIn chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
derivatives
Modules and domains
Domain (biology)
In biological taxonomy, a domain is the highest taxonomic rank of organisms, higher than a kingdom. According to the three-domain system of Carl Woese, introduced in 1990, the Tree of Life consists of three domains: Archaea, Bacteria and Eukarya...
s with defined functions, separated by short spacer regions. The order of modules and domains of a complete polyketide-synthase is as follows (in the order N-terminus to C-terminus):
- Starting or loading module: AT-ACP-
- Elongation or extending modules: -KS-AT-[DH-ER-KR]-ACP-
- Termination or releasing module: -TE
Domains:
- AT: AcyltransferaseAcyltransferaseAcyltransferase is a type of transferase enzyme that acts upon acyl groups.Examples include:* Glyceronephosphate O-acyltransferase* Lecithin-cholesterol acyltransferase...
- ACP: Acyl carrier proteinAcyl carrier proteinThe acyl carrier protein is an important component in both fatty acid and polyketide biosynthesis with the growing chain bound during synthesis as a thiol ester at the distal thiol of a 4'-phosphopantethiene moiety...
with an SHThiolIn organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...
group on the cofactorCofactor (biochemistry)A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
, a serineSerineSerine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
-attached 4'-phosphopantetheinePhosphopantetheine4'-Phosphopantetheine is an essential prosthetic group of acyl carrier protein and peptidyl carrier proteins and aryl carrier proteins derived from Coenzyme A... - KS: Keto-synthase with an SHThiolIn organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...
group on a cysteineCysteineCysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
side-chain - KR: Ketoreductase
- DH: DehydrataseDehydrataseDehydratase is an enzyme that catalyzes the removal of oxygen and hydrogen from organic compounds in the form of water. This process is also known as dehydration.There are four classes of dehydratases:...
- ER: Enoylreductase
- MT: MethyltransferaseMethyltransferaseA methyltransferase is a type of transferase enzyme that transfers a methyl group from a donor to an acceptor.Methylation often occurs on nucleic bases in DNA or amino acids in protein structures...
O- or C- (α or β) - SH: Sulfhydrolase
- TE: ThioesteraseThioesteraseThioesterases are enzymes which belong to the Esterase family. Esterases, in turn, are one type of the several hydrolases known.Thioesterases exhibit Esterase activity specifically at a thiol group.Thioesterases or thiolester hydrolases are identified as members of E.C.3.1.2.-Examples:Acetyl-coA...
The polyketide chain and the starter groups are bound with their carboxy functional group
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
to the SH
Thiol
In organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...
groups of the ACP and the KS domain through a thioester
Thioester
Thioesters are compounds with the functional group C-S-CO-C. They are the product of esterification between a carboxylic acid and a thiol. Thioesters are widespread in biochemistry, the best-known derivative being acetyl-CoA.-Synthesis:...
linkage: R-C
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...
(=O
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
)O
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
H
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
+ H
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
S
Sulfur
Sulfur or sulphur is the chemical element with atomic number 16. In the periodic table it is represented by the symbol S. It is an abundant, multivalent non-metal. Under normal conditions, sulfur atoms form cyclic octatomic molecules with chemical formula S8. Elemental sulfur is a bright yellow...
-protein <=> R-C
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...
(=O
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
)S
Sulfur
Sulfur or sulphur is the chemical element with atomic number 16. In the periodic table it is represented by the symbol S. It is an abundant, multivalent non-metal. Under normal conditions, sulfur atoms form cyclic octatomic molecules with chemical formula S8. Elemental sulfur is a bright yellow...
-protein + H2O
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
.
Stages
The growing chain is handed over from one thiolThiol
In organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...
group to the next by trans-acylations
and is released at the end by hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
or by cyclization (alcoholysis or aminolysis
Aminolysis
Aminolysis is any chemical reaction in which a molecule is split into two parts by reacting with a molecule of ammonia or an amine.An example of an aminolysis reaction is the replacement of a halogen in an alkyl group by an amine and the elimination of hydrogen halide .Another common example is...
).
Starting stage:
- The starter group, usually acetyl-CoAAcetyl-CoAAcetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...
or malonyl-CoAMalonyl-CoAMalonyl-CoA is a coenzyme A derivative.-Functions:It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis....
, is loaded onto the ACP domain of the starter module catalyzed by the starter module's AT domain.
Elongation stages:
- The polyketide chain is handed over from the ACP domain of the previous module to the KS domain of the current module, catalyzed by the KS domain.
- The elongation group, usually malonyl-CoAMalonyl-CoAMalonyl-CoA is a coenzyme A derivative.-Functions:It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis....
or methylmalonyl-CoAMethylmalonyl-CoAMethylmalonyl-CoA is the coenzyme A linked form of methylmalonic acid. Methylmalonyl-CoA is formed from propionyl-CoA by propionyl-CoA carboxylase by help of biotin . It is converted into succinyl-CoA by methylmalonyl-CoA mutase, in a reaction that requires vitamin B12 as a cofactor...
, is loaded onto the current ACP domain catalyzed by the current AT domain. - The ACP-bound elongation group reacts in a Claisen condensationClaisen condensationThe Claisen condensation is a carbon–carbon bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base, resulting in a β-keto ester or a β-diketone...
with the KS-bound polyketide chain under CO2Carbon dioxideCarbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...
evolution, leaving a free KS domain and an ACP-bound elongated polyketide chain. The reaction takes place at the KSn-bound end of the chain, so that the chain moves out one position and the elongation group becomes the new bound group. - Optionally, the fragment of the polyketide chain can be altered stepwise by additional domains. The KR (keto-reductase) domain reduces the β-keto group to a β-hydroxy group, the DH (dehydratase) domain splits off H2O, resulting in the α-β-unsaturated alkeneAlkeneIn organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...
, and the ER (enoyl-reductase) domain reduces the α-β-double-bondCovalent bondA covalent bond is a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms. The stable balance of attractive and repulsive forces between atoms when they share electrons is known as covalent bonding....
to a single-bond. It is important to note that these modification domains actually affect the previous addition to the chain (i.e. the group added in the previous module), not the component recruited to the ACP domain of the module containing the modification domain. - This cycle is repeated for each elongation module.
Termination stage:
- The TE (thio-esterase) domain hydrolyzesHydrolysisHydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
the completed polyketide chain from the ACP-domain of the previous module.
Pharmacological Relevance
Polyketide synthases are an important source of naturally occurring small molecules used for chemotherapy . For example, many of the commonly used antibiotics, such as tetracyclin, and macrolides are produced by polyketide synthases. Other industrially important polyketides are rapamycin (immunosuppressant), erythromycinErythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
(antibiotic), lovastatin
Lovastatin
Lovastatin is a member of the drug class of statins, used for lowering cholesterol in those with hypercholesterolemia and so preventing cardiovascular disease...
(anticholesterol drug), and epothilone B (anticancer drug).