1. Biol 444 Chem 444 Bratton, Heather Bui, Steven Chan, Hiu Fai
Doan, Chad
Ho, Joyce
Karimbabai Massihi, Anna
Krasner, Danielle
Loi, William
Malette, Jacqueline
Nguyen, Trang
Robles, Marisa
Tallorin, Lorillee
Truong, Daniel C
Udeh, Francis
Villalvazo, Adrianne
Yeh, Enrenn
Bautista, Candie
Chen, John
Chida, Odette
Cueva, Carla
Golanbar, Gelareh
Kashiwabara, Claudine
Kopilec, Jaimisyn
Lau, Jensen
Le, Giang-Tuong
Lee, Margaret
Mata, Francisca
Nguyen, Thuy Nhi
Phillips, Irving
Romero, Marcelo
Wang, Tony
Wittig, Michelle
Chem 444
Biol 444

2. Primary (1°) Metabolism
- Construct common biological macromolecules from simple
building blocks found within every cell
- Typically a process of polymerization, stringing monomers
together into a macromolecule that performs a cellular function
sugars polysaccharides
amino acids proteins
fats phospholipid bilayers
- Block production: cell dies (primary metabolites are essential)

3. Secondary (2°) Metabolism
- Synthesize compounds that are unique to a particular species
or genus (unlike common proteins, lipids, etc.)
- Molecules may have extremely complex structures
- These molecules typically have no effect on the producing
organism, but are often highly biologically active against
other organisms (competitors, pathogens, predators)
- Often present at extraordinary concentrations, >10%
of the dry weight of the organism
inference is, they must do something

4. Natural Products: Folk to Modern Medicines
- Humans have long used chemicals in plant and animal extracts
for many purposes: medicines, poisons, recreational stimulants
- Since the 1800’s, chemists have characterized and synthesized
such natural products, uncovering the basis for folk remedies
Identifying the mechanism of action of natural products was
the genesis of modern drug discovery -
- The active ingredients in many ancient curatives are still used
medicinally today

5. Natural Products 1: Toxins
Rotenone
- Natural fish + insect poison
Curare (Tubocurarine chloride)
- Derived from 2 South American plant genera
- Used as arrow-tip poison by native peoples
- Blocks transmission of acetylcholine signal to muscles, causing
instant paralysis
- 1st drug used as muscle relaxant in surgery

6. Natural Products 1: Toxins
Hyoscine (= scopolamine)
- Derived from plants: deadly nightshade (belladonna), mandrake
- In ancient Greece, mandrake was used as an anaesthetic
(or poison, in higher doses)
- “Witches” smeared extracts on their armpits: avoided toxic oral route,
got maximum hallucinogenic effect = felt like they were flying
- Blocks certain acetylcholine receptors
- Modern use: prevention of motion sickness (patches behind the ear)

7. Natural Products 2: Medicines
COCH3
Salicin
Acetyl-salicilic acid: aspirin
- From Willow tree bark, which was used in folk remedies
for treating fevers
- Led to synthetic analogue, modern aspirin

8. Natural Products 2: Medicines
Ventolin
Ephedrine
- From Ephedra plants, basis of ancient Chinese herbal remedy
“Ma Huang” (100 AD) for treating respiratory illness
- Used clinically since 1926 as bronchodilator to treat asthma
- Similar to adrenaline, but also stimulates heart (not good in a drug)
- Stimulated research resulting in the non-stimulant drug Ventolin

9. Natural Products 2: Medicines
Quinine
- Found exclusively in the bark of the Chinona tree
- Used as a malaria treatment since 1600’s
- Now synthetic derivatives used, due to widespread resistance

10. Natural Products 3: Stimulants
Nicotine
Caffeine
Caffeine-containing plant leaves + seeds have long been brewed to
produce stimulant drinks
- Such stimulants naturally act as feeding deterrents to repel insect
herbivores that consume plants leaves
- Tobacco plant can up its production of nicotine 4-fold when under
attack by insects; nicotine by-products are used as insecticides

11. Natural Products 3: Stimulants
Cocaine
Coca leaves have been used as a source of cocaine for > 2,000 yrs
- Used by Incas in religious ceremonies
- Introduced to Europe by conquistadores
- Leaves chewed daily by >8 million native peoples in the Andes,
to alleviate feelings of hunger and fatigue
- Inhibits re-uptake of excitatory neurotransmitter dopamine

12. Natural Products 4: Halucinogens
Morphine (= opium)
Heroin (synthetic derivative)
- Found in only 2 species of poppy flower (Papaver)
- Milky exudate of seed capsules is 25% opiate
- Used as a baby calming treatment in ancient Egypt
- Binds to brain receptors for short peptides called enkephalins,
derived from endorphins

13. Natural Products 4: Halucinogens
Similar spatial relationships of
(*)-marked atoms responsible for
similar pharmacological effects
Enkephalin
Morphine * * * *

14. Natural Products 4: Halucinogens
Tetrahydrocannabinol
Lysergic acid
Lysergic acid
Diethylamine
(LSD, synthetic)
- Lysergic acid is the parent compound from
which ergot alkaloids are derived, such as LSD
- Produced by fungus; often affected stored grain in Middle Ages
- Such compounds found in Aztec “magical” preparation ololuiqui
- Structural mimics of human neurotransmitter 5-hydroxytryptamine

15. Secondary Metabolites
- Produced from a small number of key intermediates, often
generated as by-products of primary metabolism
acetate (in the form of acetyl coA)
mevalonate
4-carbon sugars
- Perhaps arose as a means of dealing with excess metabolic
intermediary compounds
-2o metabolites then took on ecological roles as toxins, etc.

16. Secondary Metabolites
- Typically play ecological roles in nature, deterring would-be
pests, predators or pathogens
- Affect humans due to structural resemblance to innate
neurotransmitters, or by binding to proteins in a way that
disrupts normal cellular function
- Natural products are the basis for a big % of pharmaceutical
drugs currently on the market -

17. Simple building blocks serve as the basis for each major
pathway of secondary metabolism:
(1) Shikimate Aromatics (ring - C3 chain)
(2) Amino acids Alkaloids, Penicillins
(N-containing)
(3) Mevalonate Terpenes, Steroids
(4) Acetate Polyketides
(aromatics, macrocycles)

18. (1) (2) (3) (4) Shikimate pathway Alkaloids
(photosynthesis)
Polysaccharides
Glycosides
Nucleic Acids
phosphoenol
pyruvate
(1)
Shikimate pathway
Aromatic Compounds
Lignans
Shikimate
(2)
aromatic amino acids
aliphatic amino acids
Alkaloids
Peptides
Penicillins
Cyclic Peptides
pyruvate
CITRIC ACID
CYCLE
acetyl
CoA
CH3COSCoA
CH3COSCoA
-O2CCH2COSCoA
CH3COCH2COSCoA
CH3COSCoA
Isoprenoids (terpenes, steroids,
carotenoids)
CH3COSCoA
(3)
(4)
mevalonate
Polyketides, Fatty Acids Prostaglandins, Macrocyclic Antibiotics

19. (1) Shikimate pathway
from the Japanese flower shikimi (シキミ, Illicium anisatum)
(A) Biosynthesis of aromatic amino acids (tyrosine,
phenylalanine, and tryptophan) lead to alkaloids
(B) Build aromatic secondary metabolites
Shikimate
Podophyllotoxin

20. Shikimate biosynthesis
Chorismate
Shikimate PEP
Prephenate
Other
shikimate
metabolites:
ring-C3
...ring-C2
...ring-C1
+ NH3
- NH3
Cinnamic
acid
Tyrosine,
Phenylalanine

21. Biosynthesis of phenyl compounds
ring-C1 type
vanillin vanillic acid
salicin salicylic acid
- In plants, many shikimate metabolites are allelopathic:
they inhibit growth of competitors
- Insoluble forms often linked to sugars in plant tissue
- Soluble acidic forms leach out into surrounding soil in rain

22. Lignans & Lignins Polymerization: complex lignins Enzymatic coupling:
phenylalanine
Cinnamic
acid
Polymerization:
complex lignins
Enzymatic coupling:
dimeric lignans
Cinnamyl
alcohol
Large % of
woody plant
biomass
Podophyllotoxin

23. Podophyllotoxin - An important shikimate compound
- Used by native Americans to cure warts
- Powerful inhibitor of mitosis; found to
block enzyme tubulin polymerase -

24. Flavanoid Biosynthesis
Shikimate + 3 acetates = flavanones
Cause bitter tastes in plants,
especially polymerized tannins;
deter feeding by herbivores
Derived compounds are
responsible for much of plant
color

25. (2) Alkaloids (2) Amino acids Alkaloids, Peptides, Penicillins
Strychnine
(alkaloid)
Cyclosporin A
(cyclic peptide)

26. Alkaloid characteristics
- Non-(normal)-peptide, non-nucleic acid compounds that
contain nitrogen
- Common in fungi, plants, insects + amphibians
- Derived from amino acid precursors

27. Tyramine
Tyrosine
Dopamine
Mescaline
- potent hallucinogen from the peyote cactus
- competitively binds to dopamine receptors

28. Penicillin Biosynthesis
a-adipate +
cysteine
valine
- start with peptide made of 3 amino acids
(including a non-standard a.a., a-adipate)

29. isopenicillin synthase
a-adipate +
cysteine
valine
isopenicillin synthase
epimerase
penicillin N
isopenicillin N
cephalosporins
penicillins

30. Penicillins: Mechanism of Action
This class of antibiotics interferes with synthesis of the cell wall
of Gram-positive bacteria (Staphylococci, Streptococci)
Cell wall is a repeating polymer of disaccharide, tetrapeptide
repeats cross-linked into a 3D matrix
(1) cleave here
(transpeptidase)
sugar - sugar - phospholipid
L-ala — D-glu — L-lys — D-ala — D-ala
(glycine)5
(2) cross-link here

31. Penicillins: Mechanism of Action
Penicillins inhibit the bacterial transpeptidase enzyme by
mimicking its natural substrate, the terminal D-ala—D-ala
Transpeptidase attacks the b-lactam ring of penicillin, forms a
covalent bond; enzyme is now out of business

32. (1) NO CLASS next Monday
(2) For NEXT WEDNESDAY –
- bring to class a small amount of some spice, seeds, leaves,
fruit, or medicinal herb
- pick something with a strong taste/smell, or that you
know is used in a folk remedy
- at Wednesday’s lecture, you will put your material in a tube
and label it; I will then add solvent and extract the natural
products from it over the weekend
- in the next lab, you will bioassay the extracts of your material
for antibiotic activity and cytotoxicity