12 shikimate - MIT OpenCourseWare
Transcript of 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
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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
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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
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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.
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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.
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5.451 F2005 Shikimate Pathway
Angew Chem Intl Ed 42 (2003): 730-765.
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5.451 F2005 Shikimate Pathway
Angew Chem Intl Ed 42 (2003): 730-765.
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5.451 F2005 Shikimate Pathway
Angew Chem Intl Ed 42 (2003): 730-765.
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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
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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
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5.451 F2005 Shikimate Pathway Amino Derivatives
Copyright 2003 National Academy of Sciences, U.S.A.
from PNAS(2003) 100, 9774-9778
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5.451 F2005 Shikimate Pathway Amino Derivatives
Copyright 2003 National Academy of Sciences, U.S.A.
from PNAS(2003) 100, 9774-9778
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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
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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.
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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
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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.
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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.
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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