04.03.2014 1 Pharmaceutical Bio-Engineering Dortmund, 04.03.2014 Laboratory of Chemical Biotechnology Natural Product Biotechnology Mattijs Julsing Laboratory of Chemical Biotechnology Construct, develop, and understand whole microbial cells as productive biocatalysts Single step/multi step biocatalaysis , pathway engineering, cellular metabolism, process setup Laboratory of Chemical Biotechnology (Prof. Andreas Schmid)
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04.03.2014
1
Pharmaceutical Bio-Engineering
Dortmund, 04.03.2014
Laboratory of Chemical Biotechnology
Natural Product Biotechnology
Mattijs Julsing
Laboratory of Chemical Biotechnology
Construct, develop, and understand whole microbial cells as productive biocatalysts
Single step/multi step biocatalaysis , pathway engineering, cellular metabolism, process setup
Laboratory of Chemical Biotechnology(Prof. Andreas Schmid)
04.03.2014
2
Outline
Introduction natural products and their relevance in pharmacy
Introduction in some basic biotechnological concepts
Natural product biotechnology
applying the concepts for terpenoid synthesis / production
examples:artemisininlimonene and perillyl alcohol
How to develop a productive process for the biotechnological production of natural products?
Natural Products
natural product:
a chemical substance produced by a living organism:
a term commonly used for small molecules
a term commonly used in reference to chemical substances found in nature that have distinctive pharmacological effects.
such a substance is considered a natural product even if it can be prepared by total synthesis. (natural product synthesis is an important field in organic chemistry)
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Nature as source for medicines
Throughout history nature has inspired humans and served as a source formedicines
In our society, the relation between medicines and natural products is oftennot visible.
The use of natural products ≠ alternative medicine or homeopathy
…. but do realize
A large fraction of the world population still depends on medicines directly derived from natural sources
In many cultures traditional health care is accepted next to modern health care
Where can we (in western health care) find natural products… even today?
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Papaver somniverum
morfineHO
HO
N
O
H H
codeineHO
N
O
H H
O
Cinchona officinalis (bark)
N
N
CH3OHO H
H
kininequinine
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Cannabis sativa
OH
O
tetrahydrocannabinol (THC)
Natural products in pharmacy
In our society, the relation between medicines and natural products isoften not visible.
Why?
Major developments in organic synthesis during 20st century:chemical industry, natural product synthesis
organic synthesis replaced isolation from natural sources: aspirin
organic synthesis was used to make new semi-synthetic compounds
screening programs to find fully synthetic lead compounds
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Salix alba (white willow) chemical synthesis
OH
O
OH
OH
O
O
O
salicylic acid acetylsalicylic acid
Chemical analogues…. semi-synthetics
Morfine heroine
Penicillin numerous antibiotics
Quinine mefloquine, chloroquine
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New drugs (1981-2006)
Newman and Cragg, J Nat Prod (2007) 70, 461-477
N: natural productND: derived from natural product (semi-synthetic)S: synthetic S*: synthetic, but natural pharmacophoreNM: natural product mimic
terpenoid bioconversion/production as a well-investigated example
• diverse class of natural products built from isoprene units
• found in (almost) all living species
• >30,000 structures known
• pharmacologically relevant as anticancer, antimalarial and antimicrobialdrugs
• ingredients of plant essential oils, flavours , odors
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Terpene biosynthesis
Ajikumar et al., 2008, Mol. Pharmaceutics
C10
C15
C20
…. + C30, C40,…
C5 + C5
Artemisinin
sesquiterpene lactone
antimalarial compound
Artemisia annua (Chinese plant: quinhao)
the content of artemisinin in the leaves is influenced by many genetic, agricultural and environmental factors (Harvesting season, drying procedures and storage conditions)
total recovery of artemisinin can vary from 0.01 to 1.4% weight% of dry leaf mass
production in S. cerevisiae/E. coli possible?
Delabays et al., 2001, Curr Med Chem Ferreira et al., 2005, Plant Gen Res