12 shikimate - mit opencourseware
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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 PMP Me O
H2N 4,6 dideoxyHO HO
O ONDP ONDP
Me tautomerization Me O PMP
Me O �O
O HO HO Desosimine --> erythromycinH2NHO
O ONDP ONDPONDP
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
J
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
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 HN
O O H O
O O N O O NH2O O
MeO OOH OH OH MeO
N NHOH O O
OH OHO Rifamycin W OH Mitomycin
HO O
MeO O MeO Napthomycin
OO OHO O N OMe H O
Geldanamycin
NH
O OOH O
H O S-CoA HO N NH2 OMe O O
O O O
O O NH Ansatrienin A O OH
OH OH OH OH OH OH O
OH OH
HO Rifamycin W Proansamycin X
5.451 F2005 Shikimate Pathway Amino Derivatives
HO2C
O3P O
O3PO
HO
OH
O
H
DAHP synthase
CO2 HO CO2H CO2H CO2H CO2H
O3PO O
OH OHO OH O OH HO OH O3PO OH OH OH OH OH OHshikimate
shikimatedehydroquinate dehydroquinate kinase synthase dehydratase
dehydrogenase
CO2 CO2H CO2HHO CO2H CO2H O3PO O
HO NH2 ONH2 O NH2 HO NH2 OH OH OH OH
HO NH2
amino shik.
enzymes of amino shik. require amine moiety for recognition
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
HO O
MeO
OMe
O
O
O
OH O
MeOO
O
N
O O
OH H
OMe
Rapamycin (Ascomycin, FK506)
O
NH
O
O
NH
O HO
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.
f
5.451 F2005 Shikimate Pathway Adding on a cyclohexyl starter unit
antiparasitic agents
O
O
OH
O
O
O
CoA-S
Figures removed due to copyright reasons. Please see Figure 3 in Nature Biotech 18 (2000): 980-983.
O
O O
O
O H
H
OH
OH
H
H OH
O 2-methyl-butyryl CoA
CoA-S
O 2-cyclohexyl CoA
Avermectin Doramectin
S avermitilis S. collinus
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 OH O O O
O S S S
NH2 NH2 NH2OH HO HO HO NH2HO
NovI NovJ/K L-Tyrosine A PCP A PCP A PCP NovH
NovO
OH O OH O
O OH OHH2N S S OH OH
H NH2 NH2 NH2O HO OH HONO NovC ? O OHO OO
O O O A PCP A PCP
4-hydroxy-3-aminoNovobiocin coumarin
amino coumarin
coumarin --> PKS | shik.
5.451 F2005 HO2C Shikimate Pathway Deoxy sugar biosynthesis CO2O3P O HO CO2H CO2H CO2H CO2H
O3PO H O3PO O
O OH O OH HO OH O3PO OHO HO OH
OH OH OH OH OH OH
HO
CO2H
CO2
CoA-S O O3PO O CO2O3PO O
OH NH2
polyketide starter units HO
OH
CO2H
O CO2 CO2H OH
OH
HO CO2NH2 non-ribosomal peptide biosynthesis O2C
O polyketide starter units H2N COOH
OH
flavonoids HO CO2H Tyr, Phe
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