Fundamentals of Chemical Biology

1
Fundamentals of Chemical Biology
Biosynthesis and Biomediatiors
Brian O. Bachmann Larry Marnett
CPBP320A
2
Fundamentals in Chemical Biology
Introduction and Overview
What is Chemical Biology? Why Study Chemical
Biology?
3
Fundamentals in Chemical Biology
Introduction and Overview
Chemical Biology
Term originates ca. 1945 (Linus Pauling)
Research at the interface of chemistry and
biology
Application of chemical tools and ideas to
biology
Wikipedia(2005) Chemical biology is a
scientific discipline spanning chemistry and
biology that employs synthetic chemistry to study
and manipulate biological systems.
Schreiber Chemical biologists make both small
and large 'small molecules'. They make them in
tubes and cells, on the surfaces of glass, in
monolayers and even on phage viruses, and they
use them to illuminate the principles that
underlie life.
4
Fundamentals in Chemical Biology
Competing paradigms
Reductionism 1 explanation of complex
life-science processes and phenomena in terms of
the laws of physics and chemistry also a
theory or doctrine that complete reductionism is
possible 2 a procedure or theory that reduces
complex data and phenomena to simple terms.

• (bio)chemical reductionism

• genetic reductionism

Chemical Biology
Chemical Biology
Holism (from holos, a Greek word meaning whole)
a theory that the universe and especially living
nature is correctly seen in terms of interacting
wholes (as of living organisms) that are more
than the mere sum of elementary particles.

• emergent systems

• signaling pathways and networks

5
Fundamentals in Chemical Biology
Course Philosophy
Theme 1biosynthesis
Biosynthetic Pathways
Genes
Proteins
Molecules
RNA
DNA target
Theme 2 biomediation
Protein targets
Cellular pathways
6
Natural Product Biosynthesis
Introduction and Overview
Natural products biosynthesis a case study
demonstrating the power of basic chemistry in
reductionist analysis of biological systems.
What are natural products? Why do they
exist? Why are they important? Why study
biosynthesis?
7
Natural Product Biosynthesis
Origin are in primary metabolism
Primary Metabolism
Secondary Metabolism
Polyketides
Nucleotides
Sugars
Polypeptides
Terpenoids
Amino acids
Alkaloids
Fatty Acids
Polysaccharides
DOS
Applications
8
Natural Product Biosynthesis
Introduction and Overview
Polyketides
Polypeptides
Terpenoids
Alkaloids
Polysaccharides
9
Natural Product Biosynthesis
Polyketides
Type I
Type II
Type III
10
Natural Product Biosynthesis
Terpenoids
11
Natural Product Biosynthesis
Shikimate derived products
mitomycin
Rifamycin
shikimic acid
12
Natural Product Biosynthesis
Alkaloids
morphine
cocaine
ergotamine
caffeine
strychnine
13
Natural Product Biosynthesis
Polypeptides (nonribosomally encoded and modifed)
Vancomycin
14
Natural Product Biosynthesis
Why do natural products exist?
Case Study Rhizoxin
rhizoxin is potent antimitotic polyketide
predicted to be synthesized by a polyketide
synthase
Rhizopus microsporus scan for polyketide synthase
genes reveal a bacterial symbiont
A bacterial endosymbiont (Burkholderia ) lives in
the rice fungus and synthesizes a compound that
makes it the fungus pathogenic to rice!
Nature 437, 884-888 (6 October 2005)
15
Natural Product Biosynthesis
Why do natural products exist?
Case Study Patellamides
Lissoclinum patella
Prochloron didemni
ribosomal biosynthesis
extensive post-translational modification
Proc Natl Acad Sci U S A. 2005 May
17102(20)7315-20.
16
Natural Product Biosynthesis
Why do natural products exist?
Case Study Pederin

• Isolated from beetle in 1953
• Protects beetles eggs from preditors
• Causes servere rashes in humans Night burn
  Nairobi Eye Dracula
• Actually from an endosymbiont pseudomonas
  bacterium!
• Related compounds (theoperedins) are promising
  anticancer leads

17
Natural Product Biosynthesis
Why do natural products exist?
Case Study Pederin
18
Natural Product Biosynthesis
Why do natural products exist?
Case Study Beewolfs and Leafcutters
Female European beewolf (Philanthus triangulum)
catches a bee, she stings it into immobility and
then lugs it back to a burrow she has dug in
sandy ground. She tucks one to five honeybees
into each of the chambers, where she later lays
an egg. The bees, which remain alive, although
paralyzed, for the first few days after a sting,
serve as baby food. Researchers have long known
that female beewolf wasps secrete goo from their
antennal glands. A decade ago, Erhard Strohm, one
of the coauthors of the new paper, showed that
the white spot orients young wasps in their
chambers.
19
Natural Product Biosynthesis
Why Study Natural Product Biosynthesis?
tools of drug discovery and natural product
biosynthesis studies are same
genomics chemical synthesis enzymology structural
biology systems biology
20
Natural Product Biosynthesis
Introduction and Overview