Classification Overview

The NaPDoS2 classification scheme is summarized below. For more detailed descriptions of the KS and C domain categories, structures, and relevant literature see the downloadable DOCUMENTATION and representative EXAMPLE files.

Database sequences have been given class and subclass designations based on their phylogenetic clade topology and established functions in their respective PKS or NRPS genes. Note that individual domains in the same gene may be classified differently. These classifications can provide insight into:

product structural features (e.g., PUFAs, enediynes, aromatic polyketides)

gene architecture (e.g., cis- or trans-AT)

taxonomic groups in which the sequence resides (e.g., bacteria, fungi, protist, metazoa).

Query sequences are assigned classifications according to their the top NaPDoS2 BLAST match, providing insight into the biosynthetic potential of the sample. The abbreviations used in the database, reference tree, and NaPDoS2 output are given in parentheses below.

KS Domains

Delineated into three primary groups: FAS, type I PKS, and type II PKS.

1. Fatty Acid Synthase (FAS)

Class: Type I FAS
Large multifunctional proteins responsible for fatty acid biosynthesis.

• Subclass: Bacteria and fungi (bfFASI)
  Observed in bacteria and fungi.
  
  
• Subclass: Metazoa (MetazoaFASI)
  Observed in the phyla Chordata and Nematoda
  
  
• Subclass: Protist (ProtistFASI)
  Observed in the phylum Apicomplexa (Alveolata)
  

Class: Type II FAS (FASII)
Discrete, monofunctional proteins responsible for fatty acid biosynthesis.

2. Type I

Canonical type I PKSs containing KS, AT, and ACP domains and functioning in an assembly-line fashion.

Class: Modular cis-AT (cisAT)
Canonical type I PKSs containing KS, AT, and ACP domains and functioning in an assembly-line fashion.

• Subclass: Olefin synthase (cisOLS)
  Associated with the biosynthesis of a terminal olefin.
  
  
• Subclass: Loading module (cisloading)
  KS in the first module of cis-AT modular PKS in which the catalytic cysteine has been replaced with glutamine (sometimes called KSQ).
  
  
• Subclass: Hybrid (cisHybridKS)
  Downstream of a peptidyl carrier protein (PCP) domain. Catalyzes the condensation of an acyl group on a PCP-tethered intermediate.
  
  
• Subclass: Tandem ECH (cistandemECH)
  Found in modules immediately downstream of beta-branching cassettes (gene cassettes involved in the introduction of a beta-branch). Contain a cis-acting ECH domain that performs the final decarboxylation to produce an unsaturated beta-branch.
  

Class: Iterative cis-AT (iPKS)
Cis-AT type I PKSs that function iteratively, observed in bacteria and fungi.

• Subclass: Polyunsaturated fatty acid (iPKSPUFA)
  Produce long chain fatty acids that contain multiple cis double bonds.
  
  
• Subclass: Enediyne (iPKSenediyne)
  Produce nine- or ten-membered rings that contain a conjugated alkyne-alkene-alkyne moiety.
  
  
• Subclass: Aromatic (iPKSaromatic)
  Produce simple aromatic compounds that usually consist of mono- or bicyclic rings.
  
  
• Subclass: Polycyclic tetramate macrolactam-like (iPKSPTM)
  Produce compounds usually consisting of a tetramic acid moiety and 2-3 rings fused to a macrolactam.
  
  
• Subclass: Non-reducing (iPKSNR)
  Associated with PKSs that lack all KR, DH, and ER domains. Produce mono- or polycyclic aromatic polyketides from poly-beta-keto chains. Observed in fungi.
  
  
• Subclass: Partially reducing (iPKSPR)
  Associated with PKSs that lack some KR, DH, and ER domains. Produce simple mono- or bicyclic aromatic compounds similar to the products of bacterial aromatic iPKSs. Observed in fungi.
  
  
• Subclass: Highly reducing (iPKSHR)
  Associated with PKSs that possess all KR, DH, and ER domains. Produce linear and cyclic non-aromatic compounds. Observed in fungi.
  

Class: trans-AT (transAT)
Modular, assembly line PKS in which the AT domain(s) are freestanding as opposed to occuring in the module.

• Subclass: B domain (transBdomain)
  KS domains that occur together with a branching (B) domain and facilitate the formation of a beta branch.
  
  
• Subclass: Hybrid (transHybridKS)
  Similar to cisHybridKSs (see above) except the AT domain occurs in trans.
  
  
• Subclass: Hybrid non-elongating KS (transHybridKS0)
  Non-elongating KS domains (KS0) in trans-AT modules that follow an NRPS module.
  

Class: Metazoa (MetazoaPKS)
Type I KS domains detected in metazoa.

Class: Protist (ProtistPKS)
Type I KS domains detected in protists.

3. Type II

Discrete, monofunctional proteins.

Class: Aromatic (aromaticKSa or aromaticKSb)
Heterodimers that consist of alpha and beta subunits and produce polycyclic aromatic compounds through the iterative decarboxylative condensation of malonyl-CoA extender units onto an acyl starting unit.

• Subclass: angucycline-derived I (angucyclineIKSa or angucyclineIKSb)
  Compounds contain or were derived from an angular tetracyclic structure comprising a benzanthracene moiety. Most frequently initiated with acetyl-CoA starting unit.
  
  
• Subclass: angucycline-derived II (angucyclineIIKSa or angucyclineIIKSb)
  Distinguished from angucycline-derived I by initiation with a methylmalonyl-CoA starting unit.
  
  
• Subclass: anthracycline-derived I (anthracyclineIKSa or anthracyclineIKSb)
  Compounds possess a linear tetracyclic core derived from 7,8,9,10-tetrahydro-5,12-naphtacenoquinones. Initiated with acetyl-CoA starting unit.
  
  
• Subclass: anthracycline-derived II (anthracyclineIIKSa or anthracyclineIIKSb)
  Distinguished from anthracycline-derived I by initiation with methylmalonyl-CoA starting unit.
  
  
• Subclass: isochromanequinone-derived (isochromanequinoneKSa or isochromanequinoneKSb).
  Compounds with a linear tricyclic core structure containing isochromane and quinone moieties often forming dimers.
  
  
• Subclass: pentangular polyphenol-derived (pentangularpolyphenolKSa or pentangularpolyphenolKSb)
  Produce long-chain polyphenols that form angular polycyclic core structures.
  
  
• Subclass: tetracenomycin-derived (tetracenomycinKSa or tetracenomycinKSb)
  Produce linear tetracyclic decaketide core structures resulting from nine elongations of an acetyl-CoA starting unit.
  
  
• Subclass: tetracycline-derived (tetracyclineKSa) or (tetracyclineKSb)
  Produce compounds with a tetracyclic ring structure characterized by a carboxamido moiety resulting from a malonamyl-CoA starting unit.
  
  
• Subclass: spore pigment (sporepigmentKSa or sporepigmentKSb)
  Associated with the biosynthesis of streptomycete spore pigments (e.g. whiE in S. coelicolor) although compounds are not well characterized.
  

Class: Beta-branching cassettes (betabranch)
KS domains associated with HMGS cassettes that introduce a beta-branch to a beta-keto group. These stand alone KSs lack the active site cysteine required for condensation and function to decarboxylate ACP-bound malonyl as an early step in beta branch formation

Class: Polyenes (polyeneKSa or polyeneKSb)
Iteratively acting KSs that produce reduced, linear polyenes rather than polycyclic aromatic compounds.

Class: Aryl polyenes (arylpolyeneKSa or arylpolyeneKSb)
Iteratively acting PKSs that produce polyene chains with an aryl moiety that is often substituted.

Class: Non-iterative (noniterative)
Discrete monofunctional proteins that function as an assembly line to produce compounds such as pamamycin and nonactin.

C Domains

Class: Starter (starter)
Typically, the first module of a NRPS usually does not contain a C domain. But, when present, these starter C domains acylate the first amino acid with a fatty acid, polyketide, or other molecule.

Class: LCL (LCL)
Catalyzes the formation of a peptide bond between two L-amino acids.

Class: DCL (DCL)
Catalyzes the formation of a peptide bond between an L-amino acid and a growing peptide ending with a D-amino acid.

Class: Cyclization (cyclization)
Catalyzes both peptide bond formation and the subsequent cyclization of cysteine, serine or threonine residues.

Class: Epimerization (epimerization)
Changes the chirality of the last amino acid in the chain from L to D.

Class: Dual (dual)
Catalyzes both condensation and epimerization reactions.

Class: Modified amino acid (modifiedAA)
Modifies the incorporated amino acid: for example the dehydration of serine to dehydroalanine.

Class: Hybrid (hybridC)
Occur in PKS-NRPS BGCs. The condensation domain that occurs immediately downstream of a PKS module; condenses an amino acid to a growing polyketide.

Class: Condensation (condensation)
Condensation domains with no known specialized functionality.