Engineered biosynthesis of hybrid macrolide polyketides containing D-angolosamine and D-mycaminose moieties.
The glycosylation of natural product scaffolds with highly modified deoxysugars is often essential for their biological activity, being responsible for specific contacts to molecular targets and significantly affecting their pharmacokinetic properties. In order to provide tools for the targeted alteration of natural product glycosylation patterns, significant strides have been made to understand the biosynthesis of activated deoxysugars and their transfer. We report here efforts towards the production of plasmid-borne biosynthetic gene cassettes capable of producing TDP-activated forms of D-mycaminose, D-angolosamine and D-desosamine. We additionally describe the transfer of these deoxysugars to macrolide aglycones using the glycosyl transferases EryCIII, TylMII and AngMII, which display usefully broad substrate tolerance.
Schell
Ursula
U
Biotica Technology Ltd, Chesterford Research Park, Little Chesterford, Saffron Walden, Essex, CB10 1XL, UK.
Haydock
Stephen F
SF
Kaja
Andrew L
AL
Carletti
Isabelle
I
Lill
Rachel E
RE
Read
Eliot
E
Sheehan
Lesley S
LS
Low
Lindsey
L
Fernandez
Maria-Jose
MJ
Grolle
Friederike
F
McArthur
Hamish A I
HA
Sheridan
Rose M
RM
Leadlay
Peter F
PF
Wilkinson
Barrie
B
Gaisser
Sabine
S
D003001:Cloning, Molecular; D005818:Genetic Engineering; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D018942:Macrolides / Q000737:chemistry* / Q000378:metabolism*; D015394:Molecular Structure; D005810:Multigene Family / Q000235:genetics; D017421:Sequence Analysis; D013302:Streptomyces / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
C532512:D-angolosamine; D018942:Macrolides; C013610:mycaminose; D005944:Glucosamine