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5.451 F2005
Saccharide Biosynthesis
Deoxy sugar biosynthesis review
Amination requires the presence of a keto group; otherwise timing not specified
Me
O
O
Me
O
Me
PMP
HO
ONDP
H2N
tautomerization
O
O
4,6 dideoxy
HO
ONDP
Me
HO
O
PMP
HO
ONDP
O
ONDP
Me
HO
H2N
O
�
Desosimine --> erythromycin
ONDP
5.451 F2005
Shikimate Pathway
Normally usd in synthesis of aromatic amino acid
Branch points from a primary metabolic pathway to make a variety of natural products
1.
phenyl-glycine amino acids --> vancomycin --> comparison (incorporated peptide products)
PKS
2.
amino shikimate --> rifamycin --> PK product
3.
cyclohexyl CoA --> avermectins --> incorporated into a PK product
4.
coumaryl CoA derivatives for flavonoid biosynthesis
starting materials
5.451 F2005
Shikimate Pathway
transfer plant genes to e. coli
+ express S.A. in e.coli
another technique
28g/L
culture presence of a solid
ion exchange resin
14% yield based glucose
starting material
Figure removed due to copyright reasons. Please see Scheme 1a in JACS 123 (2001): 10173-10172.
based coumpounds accumulate
Knock out transporter = leave shik. acid
in media outside cell --> 52g/L 18% yield
J
5.451 F2005
Shikimate Pathway
Figure removed due to copyright reasons.
Please see: Hubbard, Brian K., and Christopher T. Walsh.
Scheme 2 in “Vancomycin Assembly: Nature's Way.” Angew Chem Intl Ed 42 (2004): 730-765.
5.451 F2005
Shikimate Pathway
Figure removed due to copyright reasons.
Please see: Hubbard, Brian K., and Christopher T. Walsh.
Figure 6 in “Vancomycin Assembly: Nature's Way.” Angew Chem Intl Ed 42 (2004): 730-765.
5.451 F2005
Shikimate Pathway
Angew Chem Intl Ed 42 (2003): 730-765.
5.451 F2005
Shikimate Pathway
Angew Chem Intl Ed 42 (2003): 730-765.
5.451 F2005
Shikimate Pathway
Angew Chem Intl Ed 42 (2003): 730-765.
5.451 F2005
Shikimate Pathway
Ansa macrolides: incorporation of amino shikimate
OH O
H
N
O
O
O
O O
OH OH
O
H
N
OH
O
MeO
N
O
O
Rifamycin W
OH
MeO
NH
O
OH
HO
Mitomycin
O
O
Napthomycin
MeO
O
NH2
MeO
OH
HO
O
O
O
O
O
O
OH
N
H
OMe
O
Geldanamycin
NH
OH O
O
H
N
S-CoA
NH2
O
O
HO
O
O OH
OH OH
OH
NH
OH
OH
O
OH
HO
Rifamycin W
OMe
O
O
O
O O
OH OH
O
Proansamycin X
Ansatrienin A
5.451 F2005
Shikimate Pathway
Amino Derivatives
HO2C
O3P O
O3PO
H
HO
O
OH
DAHP
synthase
CO2
HO
CO2H
CO2H
CO2H
CO2H
O3PO O
HO
OH
O
OH
O
OH
OH
OH
dehydroquinate
synthase
CO2
OH
CO2H
CO2H
O3PO
OH
OH
shikimate
kinase
shikimate
dehydrogenase
dehydroquinate
dehydratase
HO
OH
HO
OH
CO2H
CO2H
O3PO O
NH2
HO
OH
O
NH2
OH
O
NH2
OH
enzymes of amino shik. require amine moiety for recognition
HO
NH2
OH
HO
NH2
amino shik.
5.451 F2005
Shikimate Pathway
Amino Derivatives
Copyright 2003 National Academy of Sciences, U.S.A.
from PNAS(2003) 100, 9774-9778
5.451 F2005
Shikimate Pathway
Amino Derivatives
Copyright 2003 National Academy of Sciences, U.S.A.
from PNAS(2003) 100, 9774-9778
5.451 F2005
Shikimate Pathway
Cyclohexyl-CoA
OMe
HO
O
O
OH O
MeO
O
O
NH
O
HO
N
O
O MeO
OH H
O
OMe
O
O
NH
Rapamycin
(Ascomycin, FK506)
O
O
Ansatrienin A
5.451 F2005
Shikimate Pathway
Cyclohexyl-CoA
Figure removed due to copyright reasons.
Please see Figure 2 in J Indus Microbiol Biotech 20 (1998): 299-303.
5.451 F2005
Shikimate Pathway
Adding on a cyclohexyl starter unit
antiparasitic agents
O
H
O
O
OH
Avermectin
S avermitilis
O
H
OH
O
H
O
O
O
OH
CoA-S
O
2-methyl-butyryl CoA
Doramectin
S. collinus
O
O
H
OH
CoA-S
O
2-cyclohexyl CoA
Figures removed due to copyright reasons.
Please see Figure 3 in Nature Biotech 18 (2000): 980-983.
f
vector or a plasmid containg all cyclo hexyl biosyn genes
5.451 F2005
Shikimate Pathway
Coumarin
Figure removed due to copyright reasons.
Please see Figure 1 in J Indus Microbiol Biotech 30 (2003): 456-461.
5.451 F2005
Shikimate Pathway
Coumarin
O
O
OH
O
S
OH
O
S
NH2
HO
O
S
NH2
HO
NH2
HO
NH2
HO
L-Tyrosine
NovI
A PCP
NovH
NovJ/K
A PCP
A PCP
NovO
OH
H2N
O
O
O
OH
OH
O
O
OH
OH
O
O
Novobiocin
HO
O
OH
HO
NH2
OH
S
HO
NH2
NovC ?
O
4-hydroxy-3-amino
coumarin
A PCP
amino coumarin
coumarin --> PKS | shik.
O
S
NH2
H
N
O
O
A PCP
5.451 F2005 HO2C
Shikimate Pathway
O3biosynthesis
P O
Deoxy sugar
O3PO
HO
CO2H
CO2H
CO2H
CO2H
O3PO O
H
HO
CO2
OH
HO
O
OH
OH
O
OH
O
OH
OH
HO
OH
OH
O3PO
OH
OH
OH
CO2H
CO2
CoA-S
O3PO O
HO
NH2
O
O3PO
O
CO2
OH
polyketide starter units
OH
CO2H
O
CO2H
HO
NH2
OH
OH
non-ribosomal peptide biosynthesis
CO2
O2C
H2N
polyketide starter units
O
COOH
OH
flavonoids
CO2
HO
CO2H
Tyr, Phe