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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 444Chem 444
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)
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
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
Natural Products 1: Toxins
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
Rotenone
- Natural fish + insect poison
Natural Products 1: Toxins
- 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)
Hyoscine (= scopolamine)
Natural Products 2: Medicines
Salicin
COCH3
Acetyl-salicilic acid: aspirin
- From Willow tree bark, which was used in folk remedies for treating fevers
- Led to synthetic analogue, modern aspirin
Natural Products 2: Medicines
- 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
Ephedrine
Ventolin
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
Natural Products 3: Stimulants
- 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
Caffeine Nicotine
Natural Products 3: Stimulants
- 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
Cocaine
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
Natural Products 4: Halucinogens
MorphineEnkephalin
*
**
*
Similar spatial relationships of
(*)-marked atoms responsible for
similar pharmacological effects
Natural Products 4: Halucinogens
- 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
Lysergic acidTetrahydrocannabinol
Lysergic acid Diethylamine(LSD, synthetic)
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)mevalonate4-carbon sugars
- Perhaps arose as a means of dealing with excess metabolic intermediary compounds
-2o metabolites then took on ecological roles as toxins, etc.
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
-
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)
PolysaccharidesGlycosidesNucleic Acids
Shikimate pathwayAromatic CompoundsLignans
aromatic amino acidsaliphatic amino acids
CH3COSCoA
CH3COSCoA
(photosynthesis)
phosphoenol pyruvate
pyruvate
acetylCoA CH3COSCoA
-O2CCH2COSCoA
CH3COSCoA
Polyketides, Fatty Acids Prostaglandins, Macrocyclic Antibiotics
Shikimate
CH3COCH2COSCoA
mevalonate
Isoprenoids (terpenes, steroids, carotenoids)
AlkaloidsPeptidesPenicillinsCyclic Peptides
CITRICACIDCYCLE
(1)
(2)
(3) (4)
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
Podophyllotoxin
(1) Shikimate pathway
Shikimate
Shikimate biosynthesisChorismateShikimate + PEP
Prephenate
+ NH3
Tyrosine,Phenylalanine
- NH3Cinnamic
acid
Other shikimatemetabolites:
ring-C3
...ring-C2
...ring-C1
Biosynthesis of phenyl compounds
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
ring-C1 type
Lignans & Lignins
Podophyllotoxin
Polymerization:complex lignins
Cinnamyl alcohol
Large % ofwoody plant biomass
Enzymatic coupling:dimeric lignans
phenylalanine
Cinnamic acid
Podophyllotoxin
- An important shikimate compound
- Used by native Americans to cure warts
- Powerful inhibitor of mitosis; found to block enzyme tubulin polymerase
-
-
-
Flavanoid BiosynthesisShikimate + 3 acetates = flavanones
Cause bitter tastes in plants,especially polymerized tannins; deter feeding by herbivores
Derived compounds are responsible for much of plantcolor
(2) Amino acids Alkaloids, Peptides, Penicillins
Penicillin
Cyclosporin A(cyclic peptide)
Strychnine(alkaloid)
(2) Alkaloids
Alkaloid characteristics
- Non-(normal)-peptide, non-nucleic acid compounds that contain nitrogen - Common in fungi, plants, insects + amphibians
- Derived from amino acid precursors
Tyrosine
Tyramine
Dopamine
Mescaline
- potent hallucinogen from the peyote cactus
- competitively binds to dopamine receptors
-adipate
+
cysteine
+
valine
Penicillin Biosynthesis
- start with peptide made of 3 amino acids (including a non-standard a.a., -adipate)
-adipate +cysteine +valine
isopenicillin synthase
epimerasepenicillin Nisopenicillin N
penicillinscephalosporins
Penicillins: Mechanism of ActionThis 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
sugar - sugar - phospholipid
L-ala — D-glu — L-lys — D-ala — D-ala
(glycine)5
(1) cleave here (transpeptidase)
(2) cross-link here
Penicillins: Mechanism of ActionPenicillins inhibit the bacterial transpeptidase enzyme by mimicking its natural substrate, the terminal D-ala—D-ala
Transpeptidase attacks the -lactam ring of penicillin, forms a covalent bond; enzyme is now out of business
(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