PROSITE documentation PDOC52019
Polyketide and metazoan fatty acid synthase dehydratase (PKS/mFAS DH) domain profile


The fundamental polymers of biology—proteins, DNA, and RNA—are products of repetitive condensation of simple amino acid or nucleotide building blocks and are comparatively easy to assemble. However, other biomolecules require additional reactions beyond condensation of building blocks. Examples are the fatty acids and the polyketide and nonribosomal peptide secondary metabolites. These molecules are produced by complex enzyme assembly lines that include multiple catalytic domains. Modular polyketide synthases (PKSs) systems are thought to share a common ancestor with metazoan fatty acid synthases (mFAS). Both have multifunctional polypeptide chains with catalytic domains for elongation and modification of intermediate products, which are covalently attached to an acyl carrier protein (ACP) domain via a thioester linkage. In the mFAS and modular PKS pathways, intermediate compounds are extended by the action of two elongation domains: the acyltransferase (AT) and ketosynthase (KS). The β-keto product of the elongation reactions may be altered by the sequential actions of ketoreductase (KR), dehydratase (DH), and enoylreductase (ER) modifying domains, which form a hydroxyl group, double bond and single bond, respectively. Although fatty acids are synthesized in an iterative fashion, with the intermediate chain extended and modified within the same polypeptide, modular PKS systems operate in an assembly-line fashion, in which intermediates are passed to successive modules in a megacomplex. Dehydratase domains catalyze formation of an α,β-double bond in the nascent polyketide intermediate. The mFAS and PKS dehydratase domains are evident products of gene duplication and fusion, and share a common ancestor with the bacterial FAS DH enzymes (FabA and FabZ) [1,2,3]. The product template (PT) domains are PKS/mFAS DH domains that act as an aldol cyclase to control the regiospecific aldol cyclization of the extremely reactive poly-β-ketone intermediate assembled by an iterative type I polyketide synthases (PKSs) [4].

The PKS/mFAS DH domain comprises two repeats of the hotdog fold (see <PDB:3KG6>). The ~125-residue N-terminal hotdog is slightly shorter than the ~140-residue C-terminal hotdog. The double-hotdog fold forms a continuous antiparallel β sheet in which the β strands curve around the ‘‘hotdog’’ helices (αHD1 from the N-terminal and αHD2 from the C-terminal hotdog folds). The double-hotdog core is topped by a cap motif comprising a 3(10) helix, a four-stranded β sheet, and a single α-helix, and additionally, a short C-terminal 3(10) helix can be considered part of the cap. The DH active site is a His-Asp ‘‘catalytic dyad,’’ with the histidine from the N-terminal hotdog and the aspartate from the C-terminal hotdog [2,4].

The profile we developed covers the entire PKS/mFAS DH domain.

Last update:

March 2023 / First entry.


Technical section

PROSITE method (with tools and information) covered by this documentation:

PKS_MFAS_DH, PS52019; Polyketide and metazoan fatty acid synthase dehydratase (PKS/mFAS DH) domain profile  (MATRIX)


1AuthorsSmith J.L. Sherman D.H.
TitleAn enzyme assembly line.
SourceScience 321:1304-1305(2008).
PubMed ID18772425

2AuthorsAkey D.L. Razelun J.R. Tehranisa J. Sherman D.H. Gerwick W.H. Smith J.L.
TitleCrystal structures of dehydratase domains from the curacin polyketide biosynthetic pathway.
SourceStructure 18:94-105(2010).
PubMed ID20152156

3AuthorsHerbst D.A. Townsend C.A. Maier T.
TitleThe architectures of iterative type I PKS and FAS.
SourceNat. Prod. Rep. 35:1046-1069(2018).
PubMed ID30137093

4AuthorsFeng Y. Yang X. Ji H. Deng Z. Lin S. Zheng J.
TitleThe Streptomyces viridochromogenes product template domain represents an evolutionary intermediate between dehydratase and aldol cyclase of type I polyketide synthases.
SourceCommun. Biol. 5:508-508(2022).
PubMed ID35618872

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