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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 amino acids fats polysaccharides proteins 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

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

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

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

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

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

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

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

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

Natural Products 4: Halucinogens Morphine (= opium) Heroin (synthetic derivative) . derived from endorphins .Binds to brain receptors for short peptides called enkephalins.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 .

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

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

Produced from a small number of key intermediates. etc.Secondary Metabolites . 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.

deterring would-be pests. predators or pathogens .Secondary Metabolites . 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 - .Affect humans due to structural resemblance to innate neurotransmitters.Typically play ecological roles in nature.

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

mevalonate (3) carotenoids) (4) Polyketides. Fatty Acids Prostaglandins. steroids. Macrocyclic Antibiotics .(photosynthesis) Polysaccharides Glycosides Nucleic Acids phosphoenol pyruvate Shikimate pathway Shikimate Aromatic Compounds Lignans (1) pyruvate aromatic amino acids aliphatic amino acids CITRIC ACID CYCLE CH3COSCoA Alkaloids (2) Peptides Penicillins Cyclic Peptides acetyl CoA CH3COSCoA -O 2CCH2COSCoA CH3COCH2COSCoA CH3COSCoA CH3COSCoA Isoprenoids (terpenes.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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