Modulation of Polyketide Synthase Activity by Accessory Proteins During Lovastatin Biosynthesis
Jonathan Kennedy,
1
Karine Auclair,
3
Steven G. Kendrew,
1*
Cheonseok Park,
1
John C. Vederas,
3
C. Richard
Hutchinson
12
Polyketides, the ubiquitous products of secondary metabolism in
microorganisms, are made by a process resembling fatty acid biosynthesis that allows the suppression of reduction or dehydration reactions at specific biosynthetic steps, giving rise to a wide range
of often medically useful products. The lovastatin biosynthesis cluster
contains two type I polyketide synthase genes. Synthesis of the main
nonaketide-derived skeleton was found to require the previously known
iterative lovastatin nonaketide synthase (LNKS), plus at least one
additional protein (LovC) that interacts with LNKS and is necessary for
the correct processing of the growing polyketide chain and production
of dihydromonacolin L. The noniterative lovastatin diketide synthase
(LDKS) enzyme specifies formation of 2-methylbutyrate and interacts
closely with an additional transesterase (LovD) responsible for
assembling lovastatin from this polyketide and monacolin J.
1 School of Pharmacy,
2 Bacteriology Department, University of Wisconsin,
Madison, WI 53706, USA.
3 Department of Chemistry,
University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
*
Present address: Dipartimento di Scienze Biochimiche, University
"La Sapienza," Rome, Italy.
To whom correspondence should be addressed.
E-mail: crhutchi{at}facstaff.wisc.edu (C.R.H.);
john.vederas{at}ualberta.ca (J.C.V.)
