{PDOC00529}
{PS00606; KS3_1}
{PS52004; KS3_2}
{BEGIN}
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* Ketosynthase family 3 (KS3) active signature and domain profile *
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In all  organisms  studied to date, fatty acid synthases (FASs) and polyketide
synthases (PKSs)  are  closely related and have a common evolutionary history.
FASs and  PKSs  share  a  similar  enzymatic  domain  structure  in which acyl
transferase (AT), ketosynthase (KS) and an acyl carrier protein (ACP) form the
core structure for condensation of acyl units, and are essential for both PKSs
and FASs.  The  other  domains,  ketoreductases (KR), enoyl reductase (ER) and
dehydratase (DH)  modify the acyl units after condensation, which is essential
for FASs, but selectively present/absent in PKS [1].

Ketoacyl synthases  (KSs)  (more officially 3-oxoacyl synthases and also known
as beta-ketoacyl  synthases)  are  the  condensing  enzymes  that catalyze the
reaction of acyl-coenzyme A (acyl-CoA) or acyl-acyl carrier protein (acyl-ACP)
with malonyl-CoA, malonyl-ACP, or occasionally other substrates. KSs fall into
five families  separated  by  their  characteristic  primary  structures, each
having members  with  the  same  catalytic  residues, mechanisms, and tertiary
structures. KS3,  a very large family, is composed of bacterial and eukaryotic
3-ketoacyl-ACP synthases  I  and II, often found in multidomain fatty acid and
polyketide synthases [2].

The KS3  domain  possesses a thiolase fold, comprised of alternating layers of
alpha-helices and    beta-sheets    with   alpha/beta/alpha/beta/alpha-layered
architecture (see  <PDB:2ALM>).  The KS3 domain has a catalytic triad Cys-His-
His, in  which  the  cysteine  is  the  nucleophile  involved  in  the  trans-
thioesterification reactions.  The  two  histidine  residues  located  in  the
vicinity of  the cysteine contribute to the formation of an oxyanion hole that
stabilizes the    terahedron   intermediate   and   presumably   promote   the
decarboxylation of  the  extender  unit. The catalytic triad is located within
a deep pocket that must be accessed by the phospho-pantetheine arm attached to
the acyl carrier protein [3,4].

The sequence around the active site cysteine is well conserved and can be used
as a  signature pattern. We also developed a profile that covers the entire KS
family 3 domain.

-Consensus pattern: G-{A}-{KGR}-x(2)-[LIVMFTAP]-{R}-x-[AGC]-C-[STA](2)-[STAG]-
                    x(2)-{LI}-[LIVMF]
                    [C is the active site residue]
-Sequences known to belong to this class detected by the pattern: ALL,  except
 for bacterial and plant beta-ketoacyl synthase III (KAS III).
-Other sequence(s) detected in Swiss-Prot: 15.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Last update: March 2023 / Profile revised.

[ 1] Kohli G.S., John U., Van Dolah F.M., Murray S.A.
     "Evolutionary distinctiveness of fatty acid and polyketide synthesis
     in eukaryotes."
     ISME. J. 10:1877-1890(2016).
     PubMed=26784357; DOI=10.1038/ismej.2015.263
[ 2] Chen Y., Kelly E.E., Masluk R.P., Nelson C.L., Cantu D.C.,
     Reilly P.J.
     "Structural classification and properties of ketoacyl synthases."
     Protein. Sci. 20:1659-1667(2011).
     PubMed=21830247; DOI=10.1002/pro.712
[ 3] Xu W., Qiao K., Tang Y.
     "Structural analysis of protein-protein interactions in type I
     polyketide synthases."
     Crit. Rev. Biochem. Mol. Biol. 48:98-122(2013).
     PubMed=23249187; DOI=10.3109/10409238.2012.745476
[ 4] Abdel-Hameed M.E., Bertrand R.L., Donald L.J., Sorensen J.L.
     "Lichen ketosynthase domains are not responsible for inoperative
     polyketide synthases in Ascomycota hosts."
     Biochem. Biophys. Res. Commun. 503:1228-1234(2018).
     PubMed=30007436; DOI=10.1016/j.bbrc.2018.07.029

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