Nonribosomal peptide
Encyclopedia
Nonribosomal peptides are a class of peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

 secondary metabolites, usually produced by microorganism
Microorganism
A microorganism or microbe is a microscopic organism that comprises either a single cell , cell clusters, or no cell at all...

s like bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranch
Nudibranch
A nudibranch is a member of what is now a taxonomic clade, and what was previously a suborder, of soft-bodied, marine gastropod mollusks which shed their shell after their larval stage. They are noted for their often extraordinary colors and striking forms...

s, but are thought to be made by bacteria inside
Commensalism
In ecology, commensalism is a class of relationship between two organisms where one organism benefits but the other is neutral...

 these organisms. While there exist a wide range of peptides that are not synthesized by ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....

s, the term nonribosomal peptide typically refers to a very specific set of these as discussed in this article.

Nonribosomal peptides are synthesized by nonribosomal peptide synthetases, which, unlike the ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....

s, are independent of messenger RNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...

. Each nonribosomal peptide synthetase can synthesize only one type of peptide. Nonribosomal peptides often have a cyclic
Cyclic compound
In chemistry, a cyclic compound is a compound in which a series of atoms is connected to form a loop or ring.While the vast majority of cyclic compounds are organic, a few inorganic substances form cyclic compounds as well, including sulfur, silanes, phosphanes, phosphoric acid, and triboric acid. ...

 and/or branched structures, can contain non-proteinogenic amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

s including D-amino acids, carry modifications like N
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...

-methyl and N-formyl groups, or are glycosylated
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...

, acylated
Acylation
In chemistry, acylation is the process of adding an acyl group to a compound. The compound providing the acyl group is called the acylating agent....

, halogenated
Halogenation
Halogenation is a chemical reaction that incorporates a halogen atom into a molecule in substitution of hydrogen atom. Halogenation takes place in the gas phase. There are four types of halogenation: fluorination, chlorination, bromination, and iodination...

, or hydroxylated
Hydroxylation
Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...

. Cyclization of amino acids against the peptide "backbone" is often performed, resulting in oxazoline
Oxazoline
Oxazoline is both the five-membered ring heterocyclic chemical compound with the formula C3H5NO and the class of compounds containing this ring.- See also :* Desoxazoline * Oxazole* Oxazolidine* Oxazolidinedione...

s and thiazoline
Thiazoline
Thiazoline is a heterocyclic compound containing both sulfur and nitrogen in the ring. Although thiazoline itself is rarely encountered, its derivatives are often bioactive. For example, in a common post-translational modification, cysteine residues are converted into...

s; these can be further oxidized or reduced. On occasion, dehydration is performed on serine
Serine
Serine 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:...

s, resulting in dehydroalanine
Dehydroalanine
Dehydroalanine is an uncommon amino acid found in peptides of microbial origin ....

. This is just a sampling of the various manipulations and variations that nonribosomal peptides can perform. Nonribosomal peptides are often dimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...

s or trimers of identical sequences chained together or cyclized, or even branched.

Nonribosomal peptides are a very diverse family of natural products with an extremely broad range of biological activities and pharmacological properties. They are often toxins, siderophore
Siderophore
Siderophores are small, high-affinity iron chelating compounds secreted by grasses and microorganisms such as bacteria and fungi...

s, or pigment
Pigment
A pigment is a material that changes the color of reflected or transmitted light as the result of wavelength-selective absorption. This physical process differs from fluorescence, phosphorescence, and other forms of luminescence, in which a material emits light.Many materials selectively absorb...

s. Nonribosomal peptide antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...

s, cytostatics, and immunosuppressant
Immunosuppressant
An immunosuppressant is any substance that performs immunosuppression of the immune system. They may be either exogenous, as immunosuppressive drugs, or endogenous, as ,e. g., testosterone...

s are in commercial use.

Examples

  • Antibiotic
    Antibiotic
    An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...

    s
    • Actinomycin
      Actinomycin
      The actinomycins are a class of polypeptide antibiotics isolated from soil bacteria of the genus Streptomyces, of which the most significant is actinomycin D. It was the first antibiotic isolated by Selman Waksman and his co-worker H. B. Woodruff in 1940.-Mechanism:Actinomycin D is primarily used...

    • Bacitracin
      Bacitracin
      Bacitracin is a mixture of related cyclic polypeptides produced by organisms of the licheniformis group of Bacillus subtilis var Tracy, isolation of which was first reported in 1945....

    • Calcium dependent antibiotic
    • Daptomycin
      Daptomycin
      Daptomycin is a novel lipopeptide antibiotic used in the treatment of certain infections caused by Gram-positive organisms. It is a naturally occurring compound found in the soil saprotroph Streptomyces roseosporus. Its distinct mechanism of action means that it may be useful in treating infections...

    • Vancomycin
      Vancomycin
      Vancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...

    • Tyrocidine
      Tyrocidine
      Tyrocidine is a mixture of cyclic decapeptides produced by the bacteria Bacillus brevis found in soil. It can be composed of 4 different amino acid sequences, giving tyrocidine A–D . Tyrocidine is the major constituent of tyrothricin, which also contains gramicidin...

    • Gramicidin
      Gramicidin
      Gramicidin is a heterogeneous mixture of six antibiotic compounds, gramicidins A, B and C, making up 80%, 6%,and 14% respectively, all of which are obtained from the soil bacterial species Bacillus brevis and called collectively gramicidin D. Gramicidin D are linear pentadecapeptides; that is...

    • Zwittermicin A
      Zwittermicin A
      Zwittermicin A is an antibiotic that has been identified from the bacterium Bacillus cereus UW85.. It is a molecule of interest to agricultural industry because it has the potential to suppress plant disease due to its broad spectrum activity against certain gram positive and gram negative...

  • Antibiotic
    Antibiotic
    An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...

     precursors
    • ACV-Tripeptide
      Penicillin
      Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....

  • Cytostatics
    • Epothilone
      Epothilone
      The epothilones are a new class of cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials epithilones have better efficacy and milder adverse effects than taxanes....

    • Bleomycin
      Bleomycin
      Bleomycin is a glycopeptide antibiotic produced by the bacterium Streptomyces verticillus. Bleomycin refers to a family of structurally related compounds. When used as an anticancer agent, the chemotherapeutical forms are primarily bleomycin A2 and B2. It works by causing breaks in DNA...

  • Immunosuppressant
    Immunosuppressant
    An immunosuppressant is any substance that performs immunosuppression of the immune system. They may be either exogenous, as immunosuppressive drugs, or endogenous, as ,e. g., testosterone...

    s
    • Ciclosporin
      Ciclosporin
      Ciclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...

       (Cyclosporine A)
  • Siderophore
    Siderophore
    Siderophores are small, high-affinity iron chelating compounds secreted by grasses and microorganisms such as bacteria and fungi...

    s
    • Enterobactin
      Enterobactin
      Enterobactin is a high affinity siderophore that acquires iron for microbial systems. It is primarily found in Gram-negative bacteria, such as Escherichia coli and Salmonella typhimurium....

    • Myxochelin A
  • Pigment
    Pigment
    A pigment is a material that changes the color of reflected or transmitted light as the result of wavelength-selective absorption. This physical process differs from fluorescence, phosphorescence, and other forms of luminescence, in which a material emits light.Many materials selectively absorb...

    s
    • Indigoidine
  • Toxin
    Toxin
    A toxin is a poisonous substance produced within living cells or organisms; man-made substances created by artificial processes are thus excluded...

    s
    • Microcystin
      Microcystin
      Microcystins are cyclic nonribosomal peptides produced by cyanobacteria . They are cyanotoxins and can be very toxic for plants and animals including humans. Their hepatotoxicity may cause serious damage to the liver. Microcystins can strongly inhibit protein phosphatases type 1 and 2A , and are...

      s and
    • Nodularin
      Nodularin
      Nodularin-R is a cyclic nonribosomal peptide produced by the planktonic cyanobacterium Nodularia spumigena. This cyanobacterium forms blooms in brackish water bodies throughout the world. The late summer blooms of Nodularia spumigena are among the largest cyanobacterial mass occurrences in the world...

      s, cyanotoxin
      Cyanotoxin
      Cyanotoxins are toxins produced by bacteria called cyanobacteria . Cyanobacteria are found almost everywhere, but particularly in lakes and in the ocean where, under certain conditions, they reproduce exponentially to form blooms. Blooming cyanobacteria can produce cyanotoxins in such...

      s from cyanobacteria.
  • Nitrogen storage polymers
    • Cyanophycin
      Cyanophycin
      Cyanophycin, or multi-L-arginyl-poly , is a non-protein, non-ribosomally produced amino acid polymer composed of an aspartic acid backbone and arginine side groups....

       - produced by some cyanobacteria
  • Phytotoxins
    • HC-toxin - a virulence factor made by the plant pathogenic fungus Cochliobolus
      Cochliobolus
      The fungal genus Cochliobolus includes 55 species , including the following plant pathogenic species: C. carbonum, C. heterostrophus, C. miyabeanus, C. sativus and C...

       (Helminthosporium) carbonum
    • AM-toxin - made by the plant pathogenic fungus Alternaria
      Alternaria
      Alternaria is a genus of ascomycete fungi. Alternaria species are known as major plant pathogens. They are also common allergens in humans, growing indoors and causing hay fever or hypersensitivity reactions that sometimes lead to asthma...

       alternata
      pv. Mali
    • victorin - a chlorinated cyclic pentapeptide made by the pathogenic fungus Cochliobolus
      Cochliobolus
      The fungal genus Cochliobolus includes 55 species , including the following plant pathogenic species: C. carbonum, C. heterostrophus, C. miyabeanus, C. sativus and C...

       victoriae
      . Its nonribosomal synthesis has not been established.

Biosynthesis

Nonribosomal peptides are synthesized by one or more specialized nonribosomal peptide-synthetase (NRPS) 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. The NRPS genes for a certain peptide 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. However the first fungal NRP to be found was ciclosporin
Ciclosporin
Ciclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...

. It is synthesized by a single 1.6MDa NRPS . The enzymes are organized in modules that are responsible for the introduction of one additional amino acid. Each module consists of several domains with defined functions, separated by short spacer regions of about 15 amino acids.

The biosynthesis
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 nonribosomal peptides shares characteristics with the 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...

 and 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. Due to these structural and mechanistic similarities, some nonribosomal peptide synthetases contain polyketide synthase
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...

 modules for the insertion of acetate
Acetate
An acetate is a derivative of acetic acid. This term includes salts and esters, as well as the anion found in solution. Most of the approximately 5 billion kilograms of acetic acid produced annually in industry are used in the production of acetates, which usually take the form of polymers. In...

 or propionate
Propionic acid
Propanoic acid is a naturally occurring carboxylic acid with chemical formula CH3CH2COOH. It is a clear liquid with a pungent odor...

-derived subunits into the peptide chain.

Modules

The order of modules and domains of a complete nonribosomal peptide synthetase is as follows:
  • Initiation or Starting module: [F/NMT]-A-PCP-
  • Elongation or Extending modules: -(C/Cy)-[NMT]-A-PCP-[E]-
  • Termination or Releasing module: -(TE/R)


(Order: N-terminus to C-terminus; []: optionally; : alternatively)

Domains

  • F: Formylation (optional)
  • A: Adenylation (required in a module)
  • PCP: Thiolation and Peptide Carrier Protein with attached 4'-phospho-pantetheine (required in a module)
  • C: Condensation forming the amide bond (required in a module)
  • Cy: Cylization into thiazoline or oxazolines (optional)
  • Ox: Oxidation of thiazolines or oxazolines to thiazoles or oxazoles (optional)
  • Red: Reduction of thiazolines or oxazolines to thiazolidines or oxazolidines (optional)
  • E: Epimerization into D-amino acids (optional)
  • NMT: N-methylation (optional)
  • TE: Termination by a thio-esterase (only found once in a NRPS)
  • R: Reduction to terminal aldehyde or alcohol (optional)

Starting stage

  • Loading: The first amino acid is activated with ATP
    Adenosine triphosphate
    Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

     as a mixed acyl
    Acyl
    An acyl group is a functional group derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids.In organic chemistry, the acyl group is usually derived from a carboxylic acid . Therefore, it has the formula RCO-, where R represents an alkyl group that is...

    -phosphoric acid
    Phosphoric acid
    Phosphoric acid, also known as orthophosphoric acid or phosphoric acid, is a mineral acid having the chemical formula H3PO4. Orthophosphoric acid molecules can combine with themselves to form a variety of compounds which are also referred to as phosphoric acids, but in a more general way...

     anhydride with AMP
    Adenosine monophosphate
    Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...

     by the A-domain and loaded onto the serine
    Serine
    Serine 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'-phospho-pantethine
    Pantethine
    Pantethine is a dimeric form of pantothenic acid . It is composed of two molecules of pantothenic acid linked by cysteamine bridging groups. The monomer of this compound is known as pantetheine and is an intermediate in the production of Coenzyme A by the body...

     (4'PP) sidechain of the PCP-domain catalyzed by the PCP-domain (thiolation) .

  • Sometimes the amino group of the bound amino acid is formylated
    Formylation
    Formylation is a type of posttranslational modification in which a formyl group is added to the N-terminus of a protein....

     by an F-domain or methylated
    Methylation
    In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...

     by an NMT-domain.

Elongation stages

  • Loading: Analogous to the starting stage, each module loads its specific amino acid onto its PCP-domain.

  • Condensation
    Condensation
    Condensation is the change of the physical state of matter from gaseous phase into liquid phase, and is the reverse of vaporization. When the transition happens from the gaseous phase into the solid phase directly, the change is called deposition....

    : The C-domain catalyzes the amide
    Amide
    In chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...

     bond
    Chemical bond
    A chemical bond is an attraction between atoms that allows the formation of chemical substances that contain two or more atoms. The bond is caused by the electromagnetic force attraction between opposite charges, either between electrons and nuclei, or as the result of a dipole attraction...

     formation between the 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:...

     group of the growing peptide chain from the previous module with the amino group of the current module. The extended peptide is now attached to the current PCP-domain.

  • Condensation
    Condensation
    Condensation is the change of the physical state of matter from gaseous phase into liquid phase, and is the reverse of vaporization. When the transition happens from the gaseous phase into the solid phase directly, the change is called deposition....

    -Cyclization: Sometimes the C-domain is replaced by a Cy-domain, which, in addition to the amide bond formation, catalyzes the reaction of the serine
    Serine
    Serine 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:...

    , threonine
    Threonine
    Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...

    , or cysteine
    Cysteine
    Cysteine 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...

     sidechain with the amide-N
    Nitrogen
    Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...

    , thereby forming oxazolidine
    Oxazolidine
    Oxazolidine is a five-membered ring compound consisting of three carbons, a nitrogen, a hydrogen, and an oxygen. The oxygen and NH are the 1 and 3 positions, respectively. In oxazolidine derivatives, there is always a carbon between the oxygen and the nitrogen . All of the carbons in oxazolidines...

    s and thiazolidine
    Thiazolidine
    Thiazolidines are a class of heterocyclic organic compounds with a 5-membered saturated ring with a thioether group and an amine group in the 1 and 3 positions, respectively. It is a sulfur analogue of oxazolidine. The drug pioglitazone contains a thiazolidine ring. It is a drug usually indicated...

    , respectively.

  • Epimerization: Sometimes an E-domain epimerizes the innermost amino acid of the peptide chain into the D-configuration.

  • This cycle is repeated for each elongation module.

Termination stage

  • Termination: The TE-domain (thio-esterase domain) hydrolyzes
    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...

     the completed polypeptide chain from the ACP-domain of the previous module, thereby often forming cyclic amides (lactam
    Lactam
    A lactam is a cyclic amide. Prefixes indicate how many carbon atoms are present in the ring: β-lactam , γ-lactam , δ-lactam...

    s) or cyclic ester
    Ester
    Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...

    s (lactone
    Lactone
    In chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...

    s).

  • Also, the peptide can be released by an R-domain that reduces
    Redox
    Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....

     the thioester bond to terminal aldehyde
    Aldehyde
    An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....

     or alcohol
    Alcohol
    In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....

    .

Processing

The final peptide is often modified, e.g., by glycosylation
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...

, acylation
Acylation
In chemistry, acylation is the process of adding an acyl group to a compound. The compound providing the acyl group is called the acylating agent....

, halogenation
Halogenation
Halogenation is a chemical reaction that incorporates a halogen atom into a molecule in substitution of hydrogen atom. Halogenation takes place in the gas phase. There are four types of halogenation: fluorination, chlorination, bromination, and iodination...

, or hydroxylation
Hydroxylation
Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...

. The responsible enzymes are usually associated to the synthetase complex and their genes are organized in the same 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...

s or 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.

Priming and Deblocking

To become functional, the 4'-phospho-pantetheine sidechain of acyl-CoA
COA
COA can refer to:*Codename Amscray*Cash on Arrival*Cause of action*CedarOpenAccounts*Center of Attention*Certificate of Appealability*Certificate of Approval for marriage or civil partnership in the United Kingdom*Certificate of Authenticity...

 molecules has to be attached to the PCP-domain by 4'PP transferases (Priming) and the 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...

-attached acyl
Acyl
An acyl group is a functional group derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids.In organic chemistry, the acyl group is usually derived from a carboxylic acid . Therefore, it has the formula RCO-, where R represents an alkyl group that is...

 group has to be removed by specialized associated thioesterases (TE-II) (Deblocking).

Substrate specificities

Most domains have a very broad substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...

 specificity and usually only the A-domain determines which amino acid is incorporated in a module. Ten amino acids that control substrate specificity and can be considered the 'codons' of nonribosomal peptide synthesis have been identified. The condensation C-domain
Condensation domain
In molecular biology, the condensation domain is a protein domain found in many multi-domain enzymes which synthesise peptide antibiotics. This domain catalyses a condensation reaction to form peptide bonds in non-ribosomal peptide biosynthesis. It is usually found to the carboxy side of a...

 is also believed to have substrate specificity, especially if located behind an epimerase E-domain-containing module where it functions as a 'filter' for the epimerized isomer
Isomer
In chemistry, isomers are compounds with the same molecular formula but different structural formulas. Isomers do not necessarily share similar properties, unless they also have the same functional groups. There are many different classes of isomers, like stereoisomers, enantiomers, geometrical...

.

Mixed with Polyketides

Due to the similarity with polyketide synthetases (PKS), many secondary metabolites are, in fact, fusions of NRPs and polyketides. In essence, this occurs when PK modules follow NRP modules, and vice versa. Although there is high degree of similarity between the PCP domains of both types of sythetases, the mechanism of condensation is different from a chemical standpoint (claisen vs. transamidation).
  • Epothilone
    Epothilone
    The epothilones are a new class of cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials epithilones have better efficacy and milder adverse effects than taxanes....

The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.
 
x
OK