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J Biol Chem, Vol. 273, Issue 5, 2669-2675, January 30, 1998
The Biosynthesis of Differentiation-Inducing Factor, a
Chlorinated Signal Molecule Regulating Dictyostelium
Development
Robert R.
Kay
From the Medical Research Council Laboratory of Molecular Biology,
Hills Road, Cambridge, CB2 2QH, United Kingdom
Differentiation-inducing factor (DIF)-1 is a
chlorinated alkyl phenone released by developing
Dictyostelium amoebae, which induces them to differentiate
into stalk cells. A biosynthetic pathway for DIF-1 is proposed from
labeling, inhibitor, and enzymological experiments. Cells incorporate
36Cl into DIF-1 during development, showing
that the chlorine atoms originate from chloride ions; peak
incorporation is at the first finger stage. DIF-1 synthesis can be
blocked by cerulenin, a polyketide synthase inhibitor, suggesting that
it is made from a polyketide. This is most likely the C12
polyketide (2,4,6-trihydroxyphenyl)-1-hexan-1-one (THPH). Feeding
experiments confirm that living cells can convert THPH to DIF-1.
Conversion requires both chlorination and methylation of THPH, and
enzymatic activities able to do this exist in cell lysates. The
chlorinating activity, assayed using 36Cl , is
stimulated by H2O2 and requires both soluble
and particulate components. It is specific for THPH and does not use
this compound after O-methylation. The
methyltransferase is soluble, uses
S-adenosyl-L-methionine as a co-substrate, has
a Km for dichloro-THPH of about 1.1 µM, and strongly prefers this substrate to close
analogues. Both chlorinating and methyltransferase activities
increase in development in parallel with DIF-1 production, and both are
greatly reduced in a mutant strain that makes little DIF-1. It is
proposed that DIF-1 is made by the initial assembly of a
C12 polyketide skeleton, which is then chlorinated and
methylated.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 1998 by the American Society for Biochemistry and Molecular Biology.
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