{PDOC52019}
{PS52019; PKS_MFAS_DH}
{BEGIN}
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* Polyketide and metazoan fatty acid synthase dehydratase (PKS/mFAS DH) domain profile *
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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 catalyze  formation  of  an  alpha,beta-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-beta-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 beta  sheet  in  which the beta 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 beta sheet, and a single alpha-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.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.
-Last update: March 2023 / First entry.

[ 1] Smith J.L., Sherman D.H.
     "An enzyme assembly line."
     Science 321:1304-1305(2008).
     PubMed=18772425; DOI=10.1126/science.1163785
[ 2] Akey D.L., Razelun J.R., Tehranisa J., Sherman D.H., Gerwick W.H.,
     Smith J.L.
     "Crystal structures of dehydratase domains from the curacin polyketide
      biosynthetic pathway."
     Structure 18:94-105(2010).
     PubMed=20152156; DOI=10.1016/j.str.2009.10.018
[ 3] Herbst D.A., Townsend C.A., Maier T.
     "The architectures of iterative type I PKS and FAS."
     Nat. Prod. Rep. 35:1046-1069(2018).
     PubMed=30137093; DOI=10.1039/c8np00039e
[ 4] Feng Y., Yang X., Ji H., Deng Z., Lin S., Zheng J.
     "The Streptomyces viridochromogenes product template domain represents
     an  evolutionary intermediate between dehydratase and aldol cyclase of
     type I  polyketide synthases."
     Commun. Biol. 5:508-508(2022).
     PubMed=35618872; DOI=10.1038/s42003-022-03477-8

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