Bratton, Heather

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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
Biol 444
Chem 444
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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)
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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
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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 1800s, 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

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

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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

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




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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
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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.
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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 -
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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)
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(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
CITRICACID CYCLE
acetyl CoA
CH3COSCoA
CH3COSCoA
-O2CCH2COSCoA
CH3COCH2COSCoA
Isoprenoids (terpenes, steroids,
carotenoids)
CH3COSCoA
CH3COSCoA
(3)
(4)
mevalonate
Polyketides, Fatty Acids Prostaglandins,
Macrocyclic Antibiotics
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(1) Shikimate pathway
from the Japanese flower shikimi (???, Illicium
anisatum) (A) Biosynthesis of aromatic amino
acids (tyrosine, phenylalanine, and
tryptophan) lead to alkaloids (B) Build
aromatic secondary metabolites
Shikimate
Podophyllotoxin
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Shikimate biosynthesis
Chorismate
Shikimate PEP
Prephenate
Other shikimate metabolites ring-C3
...ring-C2 ...ring-C1
NH3
- NH3
Cinnamic acid
Tyrosine, Phenylalanine
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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
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Lignans Lignins
phenylalanine
Cinnamic acid
Polymerization complex lignins
Enzymatic coupling dimeric lignans
Cinnamyl alcohol
Large of woody plant biomass
Podophyllotoxin
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Podophyllotoxin
- An important shikimate compound - Used by
native Americans to cure warts - Powerful
inhibitor of mitosis found to block enzyme
tubulin polymerase
- - -
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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
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(2) Alkaloids
(2) Amino acids Alkaloids, Peptides,
Penicillins
Penicillin
Strychnine (alkaloid)
Cyclosporin A (cyclic peptide)
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Alkaloid characteristics
- Non-(normal)-peptide, non-nucleic acid
compounds that contain nitrogen - Common in
fungi, plants, insects amphibians - Derived
from amino acid precursors
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Tyramine
Tyrosine
Dopamine
Mescaline
- potent hallucinogen from the peyote cactus -
competitively binds to dopamine receptors
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Penicillin Biosynthesis
a-adipate cysteine valine
- start with peptide made of 3 amino acids
(including a non-standard a.a., a-adipate)
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a-adipate cysteine valine
isopenicillin synthase
epimerase
penicillin N
isopenicillin N
cephalosporins
penicillins
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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
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Penicillins Mechanism of Action
Penicillins inhibit the bacterial transpeptidase
enzyme by mimicking its natural substrate, the
terminal D-alaD-ala Transpeptidase attacks the
b-lactam ring of penicillin, forms a covalent
bond enzyme is now out of business
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(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 Wednesdays 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