This entry represents the dehydratase domain (DH) found in polyketide synthases, fatty acid synthase and some nodulation proteins.

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 … expand

This entry represents the dehydratase domain (DH) found in polyketide synthases, fatty acid synthase and some nodulation proteins.

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 beta-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 catalyse 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) [ PUBMED:18772425 PUBMED:20152156 PUBMED:30137093 ]. The product template (PT) domains are PKS/mFAS DH domains that act as an aldol cyclase to control theregiospecific aldol cyclisation of the extremely reactive poly-beta-ketone intermediate assembled by an iterative type I polyketide synthases (PKSs) [ PUBMED:35618872 ].

The PKS/mFAS DH domain comprises two repeats of the hotdog fold. 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 (alphaHD1 from the N-terminal and alphaHD2 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 DHactive site is a His-Asp "catalytic dyad" with the histidine from the N-terminal hotdog and the aspartate from the C-terminal hotdog [ PUBMED:20152156 PUBMED:35618872 ].