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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.

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Presentation on theme: "Bratton, Heather Bui, Steven Chan, Hiu Fai Doan, Chad Ho, Joyce Karimbabai Massihi, Anna Krasner, Danielle Loi, William Malette, Jacqueline Nguyen, Trang."— Presentation transcript:

1 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

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 sugarspolysaccharides amino acidsproteins fatsphospholipid 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 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 - 1 st drug used as muscle relaxant in surgery Rotenone - Natural fish + insect poison

6 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)

7 Natural Products 2: Medicines Salicin COCH 3 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 - 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

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 - 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

11 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

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 Morphine Enkephalin * * * * Similar spatial relationships of ( * )-marked atoms responsible for similar pharmacological effects

14 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 acid Tetrahydrocannabinol Lysergic acid Diethylamine (LSD, synthetic)

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 -2 o 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 - C 3 chain) (2) Amino acids Alkaloids, Penicillins (N-containing) (3) Mevalonate Terpenes, Steroids (4) Acetate Polyketides (aromatics, macrocycles)

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

19 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

20 Shikimate biosynthesis Chorismate Shikimate + PEP Prephenate + NH 3 Tyrosine, Phenylalanine - NH 3 Cinnamic acid Other shikimate metabolites: ring-C 3...ring-C 2...ring-C 1

21 Biosynthesis of phenyl compounds vanillinvanillic acidsalicin 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-C 1 type

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

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

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

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

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

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 sugar - sugar - phospholipid L -ala — D -glu — L -lys — D -ala — D -ala (glycine) 5 (1) cleave here (transpeptidase) (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  -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


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